The tumor cell death mechanisms of HAMLET and HAMLET-like complexes.
\r\n\tThe protection of biodiversity is a major target of the European Union Marine Strategy Framework Directive, requiring an assessment of the status of biodiversity on the level of species, habitats, and ecosystems including genetic diversity and the role of biodiversity in food web structure and functioning. The restoration of marine ecosystems can support the productivity and reliability of goods and services that the ocean provides to humankind, to maintain ecosystem integrity and stability. Some of the goods produced by the marine ecosystem services are fish harvests, wild plant and animal resources, water, some of the services provided recreation, tourism, breeding and nursery habitats, water transport, carbon sequestration, erosion control, and habitat provision.
",isbn:"978-1-83968-460-9",printIsbn:"978-1-83968-459-3",pdfIsbn:"978-1-83968-544-6",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"727e7eb3d4ba529ec5eb4f150e078523",bookSignature:"Dr. Ana M.M. Marta Gonçalves",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10845.jpg",keywords:"Non-indigenous Species, Dynamics, Ecosystem Maturation, Ecological Succession, Water Quality, Recovery, Biodiversity, Environmental Status, Ecosystem Services, Goods Production, Carbohydrates, Carrageenan",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 14th 2022",dateEndSecondStepPublish:"June 22nd 2022",dateEndThirdStepPublish:"August 21st 2022",dateEndFourthStepPublish:"November 9th 2022",dateEndFifthStepPublish:"January 8th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"12 days",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Ana Marta Gonçalves (h-index 19) holds a Ph.D. in Biology, from the University of Coimbra, Portugal, in collaboration with Ghent University, in 2011. During her research career obtained several grants is highly international competitive calls, including the MARS award for young scientists funded by The Royal Netherlands Institute for Sea Research (NIOZ) and the Foundation for Science and Technology (FCT, Portugal) grants.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"320124",title:"Dr.",name:"Ana M.M.",middleName:"Marta",surname:"Gonçalves",slug:"ana-m.m.-goncalves",fullName:"Ana M.M. Gonçalves",profilePictureURL:"https://mts.intechopen.com/storage/users/320124/images/system/320124.jpg",biography:"Ana Marta Gonçalves obtained a Ph.D. in Biology with a specialization in Ecology from the University of Coimbra, Portugal, in collaboration with Ghent University, Belgium, in 2011. Currently, she is an auxiliary researcher at the Marine and Environmental Sciences Center (MARE), Portugal, where she is also a member of the Directive Board. Since 2016, she has been a member of the Scientific Council of the Institute for Interdisciplinary Research, University of Coimbra (IIIUC). Dr. Gonçalves holds various administrative and management positions in international networks, societies (e.g., Society of Environmental Toxicology and Chemistry, AIL), and associations (e.g., PROAQUA). She is an editorial board member and reviewer for several indexed journals. She has published more than 70 journal articles, 50 book chapters, and 165 communications in international scientific events. She participated as a member and/or coordinator in more than twenty-five national and international projects and is currently the coordinator of four research projects. She has supervised more than ninety-five national and international undergraduate and graduate students. She has experience as a teacher of university courses and in accredited training sessions for teachers. Additionally, she has coordinated several ocean literacy and environmental education activities for kindergarten and school students. During her research career, Dr. Gonçalves obtained several grants and a MARS award for young scientists funded by The Royal Netherlands Institute for Sea Research (NIOZ).\n\nShe has expertise in biosafety, biochemical pathways, and impacts of stressors in aquatic species. Her research focus is on the valorization of marine resources and their applications in the industrial sector, such as the food and pharmaceutical industries. Her studies also highlight the application of biomarker tools for monitoring and managing aquatic systems",institutionString:"University of Coimbra",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Coimbra",institutionURL:null,country:{name:"Portugal"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"12",title:"Environmental Sciences",slug:"environmental-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"278926",firstName:"Ivana",lastName:"Barac",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/278926/images/8058_n.jpg",email:"ivana.b@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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Here it has a well-described function of controlling the specificity of a galatosyltransferase towards the formation of lactose, the common sugar present in milk. In recent years an entirely different activity has been associated with the protein. By forming a complex with oleic acid (OA) it shows cytotoxic activity against cells with an apparent selectivity for cancer cells. The complex is called HAMLET (Human α-lactalbumin Made LEthal to Tumor cells) and was originally discovered by serendipity. The complex was revealed during studies of the effect of anti-adhesive molecules from human milk on bacterial attachment to alveolar lung carcinoma cells [1]. A casein fraction, obtained after low pH precipitation of human milk at pH 4.3, was shown to exhibite cytotoxic activity. The dying cells displayed changes in morphology, cytoplasmic blebbing, nuclear condensation, and formed apoptotic bodies, comparable to cells that undergo classical apoptosis [2]. The tumoricidal component of the casein was retained in a DEAE-Trisacryl M column upon ion exchange chromatography, but eluted at high salt concentration (1M).
The active component was identified as multimeric α-LA (MAL) by its oligomeric appearance in SDS-PAGE analysis with bands at 14, 28, and 100 kDa and was subsequently confirmed by Edman degradation and mass spectrometry [1,3]. The MAL was shown to contain a molten globule-like structure and cause apoptosis-induction in a variety of transformed and immature cells, but not in healthy differentiated cells [1,2,4]. The affected cells were carcinomas of lung, kidney, throat, bladder, colon, ovaries and the prostate, glioblastomas in the brain, melanomas, and leukemias. In contrast, native monomeric α-LA isolated from human whey showed no apoptosis-inducing activity.
The difference in cytotoxic activity between the native-state α-LA and α-LA in MAL was not a consequence of post-translational modifications, but rather a conformational change altering the tertiary structure while leaving the secondary structure intact, resulting in the partial unfolding and molten globule-like conformation of the protein in MAL [3].
The link between the altered folding of α-LA and apoptosis induction was subsequently identified by deliberate
Human α-LA is an acidic globular protein composed of 123 amino acids with a molecular mass of 14.2 kDa and homologous with the lysozyme protein family. It is secreted by the epithelia cells of the mammary gland during lactation, and this is the only tissue which expresses the protein [7-9]. The crystal structure of human and bovine α-LA has been resolved by X-ray crystallography [10,11]. The protein consists of two domains, a large one composed mainly of α-helical structures and a smaller β-sheet domain. The overall three dimensional structure is stabilized by a Ca2+ binding loop [12,13] (Figure 1).
The large domain contains four α-helixes corresponding to amino acids 5-11 (A, dark blue), 23-34 (B, light blue), 86-98 (C, yellow) and 105-109 (D, orange) and three short 310-helical domains corresponding to amino acids 12-16, 101-104 and 115-119. The smaller β-sheet domain contains a triple-stranded antiparallel β-sheet (amino acids 40-50, green) and a short 310-helical domain (amino acids 76-82) [14]. The two domains are connected through a cysteine bridge (amino acids 73,91) creating the Ca2+ binding loop region. Additionally, two cysteine bridges are located in the α-helical structures (amino acids 6,120 and 28,111) and finally one bridge in the β-sheet domain (amino acids 61,77), aiding in the stabilization of the native conformation of α-LA [10,12]. The binding of Ca2+ to α-LA is required for correct formation of the disulfide bonds during protein folding [15].
The native human α-LA is a metalloprotein containing a high-affinity primary Ca2+ binding site and Ca2+-binding is required for the stabilization and structural integrity of the native fold [13,16-19]. The strong Ca2+ binding site, with an apparent association constant of 3 × 108 M-1 at 20°C, is located in a loop between the two domains, and is coordinated by the side chain carboxylates of Asp82, Asp87, Asp88 and carbonyl oxygens of Lys79 and Asp84 [10,20,21]. In Figure 1 only the side chains Asp82, Asp87 and Asp88 are shown. Furthermore, two water molecules also participate in the coordination of Ca2+ at the site, creating a distorted pentagonal bipyramidal structure [10-13]. A secondary surface-located and low-affinity Ca2+ binding site was discovered by X-ray crystallography, which only binds Ca2+ at high concentrations. However, this binding site is believed to play no structural role in human α-LA [22].
Model of human α-lactalbumin drawn by PyMOL Molecular Graphics System, Version 1.5.0.1 Schrödinger, LLC using the coordinates from [
Other divalent cations, such as Mn2+, Mg2+, Na+ and K+ can also bind α-LA, competing with Ca2+ for the same binding site [13,23,24]. A distinct zinc binding site different from the calcium binding site has also been localized [25]. However, binding of these cations causes only minor structural changes and does not play a major structural role in α-LA, compared to the binding of Ca2+ [13].
The binding of Ca2+ to α-LA through re-normalization of the solvent Ca2+, temperature or pH conditions, and the release of Ca2+ through low pH, EDTA or heat treatment, have been shown in both circular dichroism spectroscopy and fluorescence spectroscopy data analysis, to cause structural and functional changes mainly in the tertiary structure, while leaving a native-like secondary structure [13,18,20,24,26]. The native folded Ca2+-bound α-LA has higher structural stability against increased temperatures, pressures or denaturant concentrations [13,24,27-30].
Alpha-lactalbumin folding occurs in the lumen of the endoplasmatic reticulum and the protein is subsequently transported to the membrane surface of the Golgi apparatus, where it interacts with galactosyltransferase creating the lactose synthase complex [13,31]. In the absence of α-lactalbumin, the enzyme is a non-specific galactosyltransferase involved in transferring galactosyl groups from UDP-galactose to a range of different substrates [13,31]. Alpha-lactalbumin functions as a substrate modifier, increasing specificity and affinity of the galactosyltransferase for glucose, when catalyzing the final step of lactose production in a lactating mammary gland [7,32].
A noteworthy property of α-LA is the ability of the protein to adopt relatively stable partially unfolded intermediates under various conditions. Accordingly, it has been intensely used as a protein folding model in many studies. The classical molten globule of α-LA was defined as the acid denatured compact state of α-LA at pH 2.0 with fluctuating tertiary structure [13,33,34]. However, α-LA can adopt molten globule-like states during Ca2+-free (apo-state) conditions, during high temperatures at 90°C and in the presence of denaturants [14,17,35,36]. Similar conformational states can also be formed by reduction of the disulfide bonds in α-LA [37,38].
The molten globule-like conformational states of α-LA are not significantly populated at physiological conditions [26]. In addition, stable unfolded states of α-LA only persist at low pH or in the absence of metal ions, since the protein instantly returns to the native conformation, if solution conditions are re-normalized [19]. In the molten globule conformation, α-LA has a native-like secondary structure, a less well-defined tertiary structure and a larger stokes radius compared to the native protein [14,34,39].
The apo-state of α-LA, a molten globular-like conformation, is required for the formation of HAMLET. This conformation has high instability and sensitivity towards the ionic strength of the solution, compared to the native state of the protein [19]. However, the apo-state α-LA is more hydrophobic than the native state of the protein, rendering it prone to fatty acid binding [2]. The apo-state of α-LA is thus stabilized by binding to specific fatty acids in the HAMLET complex [6]. The proposed requirement of a special molten globular-like conformation of the proteinaceous component in HAMLET-like complexes has been challenged, as bovine β-lactoglobulin in complex with OA had cytotoxic activity exceeding that of HAMLET without retaining such a structure [40].
Alpha-lactalbumin possesses several fatty acid binding sites, and has been shown to bind stearic acid, palmitic acid and oleic acid spin-labelled fatty acid analogs [6,41]. The release of the Ca2+ ion and subsequent unfolding of the protein triggers α-LA to achieve a new fatty acid binding profile, with a higher affinity for cis-unsaturated fatty acids than for the corresponding trans conformations.
The interaction between apo-state α-LA and distinctive fatty acids has been studied, with the observation that certain fatty acids interact with apo-state α-LA in a stereo-specific manner [6]. Is has been found, that saturated C18 fatty acids, unsaturated C18:1
Based on the three-dimensional structures of native and apo-state α-LA, two tentative hydrophobic regions and possible fatty acid binding sites within α-LA have been proposed. One is suggested in the interface between the two sub-domains including the C- and D-helix and the β-sheet domain [6,43,44]. The other is anticipated to be formed by residues within the A, B and 310-helices.
The binding of oleic acid to bovine apo-state α-LA has previously been shown to induce changes in the secondary structure of the protein, resulting in a typical molten globule state of the protein [45]. Far-UV CD of oleic acid binding to human apo-state α-LA showed similar results, with an increase in α-helical structure, largely independent of the temperature conditions [30].
Upon Ca2+ release structural changes in α-LA also occur in the cleft between the two domains, with the slight expansion of the Ca2+-binding loop tilting the 310 helix toward the C helix, causing disruption of the aromatic cluster composed of Trp60, Trp104, Phe53 and Tyr103 in the interface between the two domains [11]. X-ray crystallography and NMR spectroscopy studies have revealed that apo-state bovine α-LA contains a largely intact α-helical domain with native side chain packing and an unstructured β-sheet domain [11,46]. Similar findings have been made for the molten globule-like conformation of human apo-state α-LA [47]. Therefore, it has been proposed that oleic acid binds in the area between the two domains, thus stabilizing the molten globule-like state of HAMLET and allowing Ca2+ binding without any effect on the tumoricidal activity [2,6]. Nevertheless, it is still unclear exactly how oleic acid binds to apo-state α-LA. Although the apo-state of α-LA is negatively charged, it may be hydrophobic interactions mediating the binding of the oleic acid, considering the increased hydrophobicity of apo-state α-LA compared to native α-LA [11,46,48,49]. Furthermore, even though the apo-state is negatively charged, it may also possess positively charged residues that are able to bind to the negatively charged polar head-groups of the oleic acids through electrostatic interactions [48,49]. Accordingly, it has been suggested that hydrophobic amino acids in the interface between the two domains may bind the fatty acid tail, while positively charged amino acids such as Arg70, Lys94 and Lys99 are plausible coordination residues for the fatty acid head group [2].
In contrast to these above-mentioned suggestions, one of the same studies showed that several proteolytically generated fragments of α-LA were able to incorporate oleic acid, implying that there is not only one single fatty acid binding site in HAMLET [48]. The exact mechanism of fatty acid binding to α-LA remains uncertain.
HAMLET is defined as a conversion complex between apo-state α-LA and a C18:1
Studies of the HAMLET structure by tryptophan fluorescence spectroscopy, near-UV CD spectroscopy and far-UV CD spectroscopy have revealed that the complex retains a stable, partially unfolded, molten globule-like conformation even at physiological conditions, in contrast to partially unfolded α-LA, which reverts to the native conformation, if solution conditions are re-normalized [3,5,14,19,29,45]. In this molten globule-like conformation, α-LA in the HAMLET complex showed retention of the secondary structure, near-complete loss of the tertiary structure, a larger stokes radius, and increased exposure of hydrophobic surfaces, compared to native α-LA [3,5,14,34,39,50].
The formation, stabilization and cytotoxic activity of the HAMLET complex have been shown to require both partial unfolding of α-LA and the binding of a fatty acid co-factor [5,6,19,51]. The partial unfolding of α-LA, e.g. through metal ion depletion, results in destabilization of the β-sheet domain, while leaving the α-helix domain largely unchanged, paving the way for fatty acid binding and subsequent HAMLET formation [19,50]. In accordance with this, it has been shown that the tumoricidal activity of HAMLET is largely independent of the β-sheet domain and C-terminal portion of human α-LA, since the isolated α-helix domain of α-LA was able to form a cytotoxic complex with OA [52].
Additional changes in the α-LA structure can induce the formation of HAMLET or HAMLET analogs. It has been proposed that the entire 123-residue sequence of α-LA is not required for cytotoxic activity, as fragments of α-LA in a complex with OA were able to induce apoptosis in Jurkat tumor cells [48]. Furthermore, it has been shown that a recombinant variant of human α-LA, where all cysteine residues were substituted with alanine residues, had the ability to form cytotoxic HAMLET complex analogs [38]. In addition, an α-LA mutant where Asp87 was shifted to an alanine with no Ca2+ binding activity was also able to form cytotoxic complexes with oleic acids, implying that a functional Ca2+ site is not required for the conversion of α-LA to the active complex or to cause cell death [19]. This being the case despite the fact that HAMLET has a high Ca2+-affinity, with a Ca2+ association constant of 5.3×106 M-1 at physiological salt conditions [19]. However, the structural changes induced upon Ca2+ binding have no effect on the cytotoxic activity of the complex [19,30].
Interestingly, human α-LA is not the only variant of the protein able to form cytotoxic complexes with OA. Alpha-lactalbumin of bovine, equine, caprine, and porcine origin also have the ability to form complexes with OA, showing HAMLET-like cytotoxicity, while natural HAMLET formation in acid precipitates of casein was unique to human milk [9]. Comparison of highly purified human and bovine α-LA´s ability to form complexes with OA showed that the two proteins behaved very similarly and that the cytotoxic activity was comparable [53].
The revelations that neither native-state, apo-state nor otherwise partially unfolded α-LA alone shows significant cytotoxic activity, in addition to the above-mentioned findings, have caused researchers to focus on the possibility that the cytotoxic component of HAMLET may be the fatty acid and not the α-LA protein [3,5,19,50]. As a consequence, it has been suggested that α-LA is merely a carrier or synergist of the tumor-killing activity of the associated oleic acid [48,49]. In agreement with this, studies have found that the cytotoxicity of OA alone is very similar to that of BAMLET, the bovine ortholog of HAMLET, and that of HAMLET-like complexes composed of bovine β-lactoglobulin and pike parvalbumin in complex with OA [40,54]. The cytotoxic activity of the β-lactoglobulin and paralbumin complexes even exceeded that of HAMLET, indicating that the proteinaceous component of the complexes is of less importance than the OA component in relation to the cytotoxic activity [40]. The potent toxicity of free oleic acid against Jurkat and HL-60 tumor cells has been shown, supporting the proposal that the fatty acid could be the cytotoxic component of the HAMLET complex [54,55]. However, in contrast with this proposal, α-LA has previously been found to be cytotoxic in the absence of oleic acid [56-60].
The stoichiometry of protein and fatty acid in HAMLET or HAMLET-like complexes remains a topic of debate. Initial gas chromatography and mass spectrometry data suggested that the average number of oleic acid molecules bound in the HAMLET complex was 0.9, with some batch variation [6]. The assumption of a 1:1 protein/fatty acid ratio was also reported in the preparation of BAMLET by chromatography [61]. By gas chromatography and mass spectrometry a later study estimated an α-LA to OA ratio of 1:5.4 in a HAMLET complex prepared by the OA-preconditioned anion exchange chromatography method [38]. An α-LA to OA ratio of 1:8.2 in HAMLET determined by LC-MS has also been reported [52]. A ratio of 1:10-1:13 was found for BAMLET and HAMLET complexes formed by a new alternative preparation method, using two consecutive DEAE-Sepharose ion exchange columns for the purification of α-LA and subsequent complex formation, but high variation in stoichiometry was common within different batches [53].
The average number of oleic acid molecules bound per α-LA in LA/OA complexes has been spectrofluorimetrically estimated to be 2.9 for LA/OA formed at 17°C and 9 for LA/OA formed at 45°C [30]. Another study has reported that the bovine LA/OA complex, prepared by direct mixing of the constituents, consists of 4-5 protein molecules with 68-85 bound molecules of OA, thus indicating that every α-LA binds on average 17 OA molecules [49].
A possible explanation for the variation in the observed α-LA to OA ratios might be that the different preparation techniques and experimental conditions (e.g. changes in temperature or altered α-LA to OA ratios) could have a major impact on the observed stoichiometry. In addition, it has been proposed that some of the OA might be present in an unbound form resulting in a higher OA to α-LA ratio [30].
Several different methods have been utilized for the
The conventional method of HAMLET preparation is OA-preconditioned anion exchange chromatography [5]. This method is initiated with the purification of native-state α-LA by hydrophobic interaction chromatography and subsequent EDTA-treatment, resulting in the loss of Ca2+ and partial unfolding of the protein. The apo-state α-LA is subjected to a DEAE- Trisacryl M ion exchange chromatographic column previously exposed to human milk or pre-loaded with fatty acids. The apo-state α-LA interacts with the OA pre-loaded column, forming the HAMLET complex, which elutes at a salt concentration of 1M. The eluted complex is desalted by dialysis and lyophilized to obtain HAMLET dry powder.
Regardless of the preparation method used in the different experiments, it has been shown that the cytotoxicity of the resulting complexes was similar to that of conventionally prepared HAMLET or BAMLET [30,36,48,49,54,61-65].
In order to clarify the subcellular localization of HAMLET and the interactions of the complex with different tumor cell compartments, researchers have used biotinylated [5,66], I125 radioactive labeled [66,67] and Alexa Fluor 568-labeled HAMLET complexes in confocal microscopy and subcellular fractionation experiments [67-69]. Site-specific labeling of HAMLET and HAMLET-like complexes with aminooxy-Alexa Fluor 488 or biotin molecules has also been used [52].
It has previously been described that α-LA interacts with cell membranes and lipid bilayers, as well as fatty acids [41,70-74]. In addition, it has been observed that α-LA is able to rapidly insert itself into the lipid bilayer at pH 2 [75]. However, native human α-LA is only inefficiently bound to and internalized by tumor cells, and does not translocate to the nucleus, nor influence tumor cell viability [3,5,68,69,76]. Even partial unfolding of human α-LA has been shown to be insufficient for increased protein internalization into tumor cells [38]. In addition, human α-LA and oleic acid alone were unable to alter membrane structures, further indicating the necessity of interaction between unfolded α-LA and an associated fatty acid for efficient internalization of the HAMLET complex in tumor cells [76].
Even though a number of studies have focused on investigating the mechanism of HAMLET uptake by tumor cells, it still remains unclear. HAMLET has been shown to interact with the cell surface of tumor cells, be internalized and subsequently accumulate in the nucleus [3,5,67,68]. In the case of healthy cells, HAMLET interacted with the cell membrane and was internalized, but did not accumulate in the nuclei of the cells [4,67].
A study of the interaction between HAMLET and natural or artificially generated, negatively charged, model lipid membranes has revealed that the interaction results in loss of cell membrane integrity, leakage of vesicular contents and morphological changes of the membranes [76]. Interestingly, HAMLET disturbs the integrity of the tested membranes, even under physiological conditions, as opposed to native-state α-LA that only disrupts liposomes at acidic pH [77]. Similarly, at physiological conditions HAMLET readily distorts lipid monolayers at low concentrations, while forming pore-like oligomeric structures resembling annular oligomers at higher concentrations [78]. The ability to form oligomers is suggested to be a property of the α-LA polypeptide chain, enhanced by the fatty acid component, which might be important for the cytotoxic activity of HAMLET [78]. It has been suggested that the degree to which HAMLET and other LA-OA-complexes are able to disturb the membrane integrity, depends on the lipid composition and physical characteristics of the membrane [74,76].
HAMLET binds to the cell surface of intact tumor cells in a patchy distribution, indicating the possible targeting (e.g. receptor-binding) of the complex to specific membrane regions [76]. Another study found that HAMLET and an α-LA/OA complex formed at 17°C, interacts with and alters trans-membrane integral currents of artificial vesicles and natural plasma membranes of the green alga
Translocation of HAMLET from the membrane to the cytoplasm has been followed by confocal microscopy, showing the formation of intracellular aggregates in both normal cells and in tumor cells, although accumulation of HAMLET was higher in tumor cells [4]. The mechanism of HAMLET redistribution from the cytoplasm to different organelles of the cell, especially the nucleus, remains to be clarified. Initial studies found that the nuclear uptake of α-LA/OA occurred through the nuclear pore complex in a Ca2+-independent manner, and that the accumulation of α-LA in the nucleus resulted in Ca2+-dependent DNA fragmentation in the tumor cells [66]. Later, it was suggested that the interaction between HAMLET and ribosomal proteins could initiate nuclear translocation and targeting of the complex [2].
A key unresolved issue regarding HAMLET is by what biological mechanisms the complex induces tumor cell death. A broad variety of transformed and immature tumor cells, but not healthy differentiated cells, have been found to be affected by the complex and even antibiotic-resistant strains of
Besides the three major responses, it has been shown that BAMLET activates a caspase-independent lysosomal cell death pathway mainly in tumor cells, causing lysosomal membrane permeabilization possibly contributing to BAMLET-induced cell death [61]. In a study of HAMLET binding to α-actinin, it has been indicated that the apoptosis-promoting p38 pathway is the top-scoring pathway in HAMLET-induced cell death, with p38 inhibition delaying death of HAMLET-treated tumor cells [82].
An elevated expression level of c-Myc, an oncogene that has the ability to bind a significant fraction of all known gene promoters, has been shown to increase HAMLET-sensitivity of various tumor cells, suggesting that the level of c-Myc expression could be a direct determinant of HAMLET susceptibility [83]. Furthermore, a reduction in the extracellular glucose levels or degree of glycolysis, predominantly the aerobic glycolysis of tumor cells known as the Warburg Effect, of A549 lung carcinoma cells resulted in an enhanced HAMLET-sensitivity [83]. HAMLET was shown to bind and reduce the activity of the glycolytic enzyme hexokinase 1 in the A549 carcinoma cells, which could partly explain the inhibitory effect of HAMLET on glycolysis [83].
HAMLET has been shown to interact directly with 20S proteasome subunits
Major responses: Apoptotic pathway [2,54,84,87,90,91] Autophagic pathway [81,91] Chomatin structure disorder [67,90,100] Other responses: Anti-adhesion [1,82,102] c-Myc oncogene status [83] Inhibition of 20S proteasome activity [69] Inhibition of glycolysis [83] Lysosomal pathway [61] p38 pathway [82] Ribosome interactions [2] | MAL co-localizes with mitochondria and causes release of cytochrome MAL causes loss of mitochondrial membrane potential (ΔΨm) and abnormal MPT HAMLET causes p53-independent apoptotic or apoptotic-like cell death in tumor cells BAMLET-induced cell death varies according to cell type HAMLET induces an macroautophagic response in tumor cells HAMLET accumulates in the nucleus of tumor cells HAMLET binds to histones, independent of the histone tail, resulting in chromatin structure disorder in tumor cells HAMLET causes caspase-dependent and caspase-independent chromatin condensation and acts in synergy with histone deacetylase inhibitors MAL and HAMLET facilitates tumor cell detachment Elevated expression of c-Myc oncogene sensitizes tumor cells to HAMLET-induced tumor cell death HAMLET binds to 20S proteasome subunits causing structural modifications and partial activity inhibition HAMLET binds to and reduces the activity of HK1 BAMLET activates a caspase-independent lysosomal pathway in tumor cells leading to lysosomal membrane permeabilization Indicated to be the top-scoring cell death pathway of HAMLET HAMLET binds to intact ribosomes and individual ribosome proteins |
The tumor cell death mechanisms of HAMLET and HAMLET-like complexes.
For elaboration of the specific tumor cells prone to the mentioned effect, the reader is encouraged to see the references. HK1, hexokinase 1; IMM, inner mitochondrial membrane; MAL, multimeric α-lactalbumin; MPT, mitochondrial permeability transition.
Several studies have focused on clarifying the precise role of apoptosis in the HAMLET-induced cell death of tumor cells. Initially, it was shown by the use of an anti-CD95 antibody that the CD95 receptor-mediated apoptotic pathway had no effect on the apoptosis-inducing activity of MAL [84]. It was also found that MAL co-localized with mitochondria and caused release of cytochrome
HAMLET-treated Jurkat leukemia cells and A549 lung carcinoma tumor cells exhibited classical apoptotic changes, as well as apoptosis-like changes, such as proapoptotic caspase activation, phosphatidyl serine externalization, DNA fragmentation, apoptotic body formation and compacted chromatin condensation [88-90]. However, classical apoptosis was not the cause of death, as a pan-caspase inhibitor zVAD-fmk was unable to rescue HAMLET-treated cells from dying [84,90]. This was confirmed by the finding that HAMLET-induced cell death is independent of the anti-apoptotic Bcl-2 and Bcl-xL proteins in Jurkat leukemia, K562 promyelocytic leukaemia and FL5.12 murine prolymphocytic tumor cells, as over-expression of Bcl-2 failed to prevent cell death [90]. In addition, the tumoricidal activity of HAMLET is independent of the tumor suppressor protein p53, as there was no difference in HAMLET susceptibility of tumor cells with wild-type, deleted or mutated p53 gene [2,90,91]. Analyzing the effect of BAMLET on Jurkat and THP1 cells by flow cytometry indicated that the death of Jurkat cells looked more apoptotic than the death of THP1 cells which were more necrotic, showing that the actual mechanism of cell death apparently varies between different types of cells [53].
Autophagy has been a topic of comprehensive debate concerning its function as an alternative caspase-independent type II programmed cell death pathway, in addition to serving as a survival mechanism during cellular stresses [92-95]. Macroautophagy, the only autophagic response included in type II programmed cell death, is an adaptive stress response observed in cells exposed to cellular stresses (e.g. starvation), which triggers the recycle of organelles and long-lived proteins as a nutritional source utilized to prolong cell survival [91,92, 96].
HAMLET induces a macroautophagic response in treated tumor cells, with the appearance of cytoplasmic vacuoles and double-membrane enclosed vesicles [81,91]. Furthermore, HAMLET was shown to alter the staining-pattern of LC3-GFP-transfected cells from uniform (LC3-I) to granular (LC3-II), reflecting the translocation of LC3 to autophagosomes during macroautophagy [81]. HAMLET also induced LC3-II accumulation, detected by a Western Blot, when lysosomal degradation was inhibited, which is a clear indicative of macroautophagy [81].
The inhibition of macroautophagy in HAMLET-treated tumor cells by RNA interference of Beclin-1 synthesis resulted in reduced cell death and inhibition of the increase in granular LC3-GFP staining, suggesting that macroautophagy is an important response pathway in HAMLET-induced cell death [81,91]. In accordance with this finding, it was shown that mTOR, an inhibitor of macroautophagy, is inactivated in tumor cells in response to HAMLET [81,97]. An important note is that the mitochondrial damage observed in the different tumor cells of the mentioned experiments also has the potential to trigger macroautophagy in the cells [81,98,99].
A striking feature of HAMLET is the ability to move through the cytoplasm and accumulate in the nucleus of tumor cells, as initially elucidated by the study of the active human milk fraction [3,66]. Healthy, differentiated cells did not accumulate biotinylated MAL or Alexa-labeled HAMLET in the nucleus, although uptake in the cytoplasm was observed [66,67].
Through combination of
In a different study it has also been shown that monomeric Ca2+-loaded α-LA and apo-state α-LA alone can bind histone H3
HAMLET has been shown to act in synergy with histone deacetylase inhibitors, as pre-treatment of Jurkat tumor cells with these resulted in enhanced lethal effect of HAMLET and an increased hyperacetylation response [100]. Caspase-independent DNA damage and DNA fragmentation was observed after treatment, suggesting that apoptosis was not the key pathway involved in the combined effect [100]. In addition, HAMLET caused chromatin condensation, as HAMLET-treatment of stably transfected HeLa cells resulted in a decrease of nuclear size. The ability of HAMLET to induce both caspase-dependent and caspase-independent chromatin condensation pattern was found in another study, indicating that the response to HAMLET involves both classical apoptosis and caspase-independent cell death pathways [90].
The ability of HAMLET to facilitate tumor cell detachment has been described both in early and recent literature. Initially, MAL was found to possess anti-adhesive properties against bacterial attachment to alveolar type II lung carcinoma cells [1]. Subsequently, an
A major reason for studying the cytotoxic activity of HAMLET is the apparent specificity towards cancer cells. Although this specificity of cytotoxic HAMLET-induced cell death remains unclear, there have been continuous indications in many
The observed effects mentioned are
Papillomas are characterized as premalignant lesions of the skin and mucosal surfaces, caused by human papillomavirus transformation of keratinocytes [4,104]. The therapeutic treatment options are ineffective and include cryotherapy, immuno modulators, curettage, cautery, salicylic acid, CO2 laser, antimitotic agents, or photo-dynamic theraphy [106,107].
Skin papillomas were the first model selected for the examination of the
Bladder cancer treatment [2,102,105] Gliblastoma (multiforme) treatment in a rat model [68] Skin papilloma treatment [104] | Induces bladder carcinoma cell death ( Increases daily shedding of dead tumor cells into the urine Reduces tumor size or area and changes tumor character Delays progression of bladder cancer Induces apoptosis in GBM biopsy spheroids ( Reduces intracranial tumor volume Delays onset of pressure symptoms Reduces the volume of papillomas Leads to long-term resolution of lesions Similar effects of treatment in immunosuppressed patients as in immunocompetent patients |
Possible therapeutic applications of HAMLET.
The development of bladder cancers is common and remains a massive worldwide challenge, despite continuous advances in the therapeutic options available. The prevalence of bladder cancer is 1 in 4000 people, accounting for about 5% of all cancers, making it the fourth most common malignancy in the United States and the fifth most common in Europe [108]. The current treatments of bladder cancer typically involve intravesical instillation of antitumor agents such as
Early
The therapeutic potential of HAMLET was further studied in a mouse bladder carcinoma model, with MB49 carcinoma cells installed via a catheter into the bladder of anesthetized mice, followed by five intravesical installations of HAMLET [105]. The treatment resulted in significantly decreased tumor areas and delayed the progression of bladder cancer compared to controls. Furthermore, whole body imaging of Alexa Fluor 568-labeled HAMLET revealed that the uptake and retention of the complex were tumor tissue-specific.
Gliomas are a heterogeneous group of intracranial neoplasms originating from neuroglial cells, which accounts for over 60% of all primary brain tumors and have an unfavorable prognosis [110-113]. Glioblastoma multiforme (GBM), grade IV on the current WHO grading-scale for tumors in the central nervous system, is the most malignant of the gliomas, showing a mean survival time of less than a year [113,114]. The current treatment is only palliative, involving surgery, radiotherapy and chemotherapy [115].
HAMLET has been shown to induce apoptosis in GBM biopsy spheroids
The development of the mammary gland through puberty, pregnancy and lactation has been intensively studied and much is known about the factors responsible for regulating the processes. When suckling stops, the gland goes into involution, and despite much research little is known regarding the factors involved in this remodeling of the gland.
Milk synthesis occurs in mammary epithelial organized in small hollow “balls” called alveoli. It is known that the accumulation of milk in the alveoli results in down regulation of protein synthesis as well as reduction in the number of secretory cells by apoptosis [117]. It is also believed that local factors secreted into the milk are responsible for the effect, but molecular details of such compounds are lacking. A protein called FIL (Feedback Inhibitor of Lactation) from milk has been isolated and partly characterized [118], but at present its existence is unconfirmed.
Some sea animals have a special lactation cycle due to long periods of foraging trips away from the offspring. Remarkably, despite the absence of suckling for many days no apoptosis occurs in the mammary gland of e.g. Cape fur seals, and this phenotype has been correlated with lack of α-LA in their milk [119]. The possibility that α-LA either alone or in a complex with fatty acids is involved in the regulation of involution has been suggested as apoptotic cell death in the mammary gland was enhanced by the introducing of HAMLET in the gland of lactating mice [103].
The milk protein alpha-lactalbumin (α-LA) is one of the most studied proteins with respect to structure and function and has been a model for investigating intermediate folding conformations generally called molten globule states. It has a well-described function as part of the enzyme lactose synthetase, where α-LA is one component of the two-polypeptide enzyme. The other part is a non-specific galactosyl transferase, which in complex with α-LA becomes highly specific for forming lactose from UDP-galactose and glucose.
In the late nineties an entirely different activity of α-LA was discovered. When α-LA is in a partly unfolded conformation it can form a complex with oleic acid (OA) where the complex shows cell-killing activity specific for cancer cells. This partly unfolded conformation of α-LA can be obtained by removing a tightly bound calcium ion, leaving the protein in the apo-state capable of interacting directly with OA and thereby forming the cytotoxic complex. The complex between human α-LA and OA has been called HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) and similar complexes can be formed with α-LA from other species.
In cell culture systems HAMLET shows cytotoxic activity in µM concentrations but the activity varies greatly between cell types. The exact mechanism of cell-killing is not clear, but HAMLET has been shown to interact with numerous cell organelles including the nucleus, lysozymes, mitochondria, proteasomes and ribosomes. Apoptosis, autophagy and chromatin structure disorder are three different cytotoxic pathways described when HAMLET is added to cell cultures. It is therefore likely that different cells will show different death mechanisms dependent on the experimental conditions.
When the cytotoxic activity of α-LA/OA complexes are measured in a dose-response manner, it is characteristic that very steep curves are obtained where as little as a four-fold dilution can result in no activity compared to 100% cell death in the undiluted solution. This underlines the importance of defining the experimental conditions exactly when measuring cytotoxic activity as small changes in concentration might lead to contradictory conclusions. This aspect is especially important when the activity of HAMLET is compared between healthy differentiated normal cells and tumor cells. According to numerous reports HAMLET kills tumor cells as well as undifferentiated cells but leave normal cells untouched. This has recently been questioned as it was found that both normal white blood cells and fully developed erythrocytes were highly sensitive to the cell-killing activity.
The potential of HAMLET as a therapeutic agent has been investigated in three different models. First, skin papillomas were treated in a double-blinded study showing positive results compared to the controls, secondly, patients with bladder cancer indicated reduction in tumor size when the bladder was flushed with a solution of HAMLET, and finally, in a glioblastoma rat model HAMLET treatment resulted in a decrease of the intracranial tumor volume. This suggests that tumor cells in some cases might be more sensitive to HAMLET when compared with the healthy cells from which the tumors originate.
It has been theorized that HAMLET could be naturally formed in the digestive system of breast-fed children, due to low pH conditions of the stomach, serving the function as a natural scavenger and selective cytotoxic killer of cancerous cells in early infancy. The development of normal epithelia cells in the digestive system could also be affected. Obviously, many dairy products contains α-LA in fairly high concentrations and numerous production techniques, such as acid pH and heat treatment, facilitate the formation of partly unfolded α-LA making the protein ready to bind fatty acids and other similar compounds. To what degree such complexes in fact are formed in dairy products remains to be seen.
Fascioliasis is an ancient food-borne neglected zoonotic disease of medical importance caused by some species of macroscopic and leaf-like digenetic trematodes in the genus
Since every continent is infested with these trematodes, 180 million people are at risk, while an estimated 2.4 million people living in more than 70 countries of the world are suffering from the scourge of fascioliasis [1, 5]. Meanwhile, it has been estimated that
Recently, there has been a significant increase in the global prevalence of human fascioliasis [1, 7] with a strong correlation with a high infection rate among ruminant definitive hosts [8].
A broad range of cosmopolitan freshwater snails in the family Limnaeidae are responsible for the transmission of fascioliasis. For instance,
Liver flukes have a complex life cycle with a wide range of mammalian definitive hosts [9]. Humans are accidental definitive host of
The number of eggs extruded by each adult worm per day varies from one definitive host to the other. Report has shown that as much as 25,000 eggs, 12,000 eggs, and 2,150 eggs could be extruded in sheep, cow, and black rats, respectively [16, 17]. Elsewhere, it has been reported that an individual liver fluke could extrude about 40,000 eggs per day [9]. These unembryonated eggs are transported in the bile medium to the small intestine, where they mix up with feces [18]. In ruminant definitive hosts, they are passed out in the pasture and undergo a period of embryonation under suitable ambient temperature and humidity.
Since freshwater body is crucial to the development of the larval stages of liver flukes [18], hatching takes place in response to external stimuli of light, temperature, and humidity [9, 19, 20]. The emerging free-swimming ciliated miracidia are genetically configured to locate a suitable Limnaeid snail intermediate host via thin films of water [21], in less than 24 hours through positive chemotactic and phototactic movements [9]. By means of their piercing stylets and proteolytic enzymes, they mechanically invade their snail hosts’ body wall and tissues [20, 22] and develop into sporocysts. The sporocysts further metamorphose into mother rediae, which develop into the daughter rediae. The metamorphosis in the snail host culminates in the emergence of cercariae, which are capable of passively infecting suitable vertebrate hosts and humans who drink infested water [18, 23, 24, 25]. Relative humidity above 65%, annual rainfall >100 mm, and ambient temperature of between 25 and 30°C have been reported as the factors that are suitable for the growth and shedding of cercariae [26, 27].
Finally, the cercariae locate the wet leaves of herbaceous plants by negative geotactic movement, encyst, and metamorphose into metacercariae. When ingested by suitable ruminant definitive hosts during grazing, the cyst is digested by the hosts’ enzyme and the metacercariae migrate to the duodenum where they re-encyst [18, 28]. Figure 1 below shows a summary of the life cycle of liver flukes.
Life cycle of liver flukes.
Fascioliasis is endemic in every continent of the world with the exception of Antarctica (Figure 1). The disease is being reported from Africa, Asia, the Caribbean, Europe, parts of Latin America, Middle East, and Oceania [29]. High transmission rate of human fascioliasis has been reported from the Andean highlands of Bolivia, Peru, the Nile valley, the Caspean sea basin, East Asia, and South East Asia [30].
In sub-Saharan Africa (SSA), fascioliasis has been reported in West Africa [12, 31], East Africa [32], and South African countries [33, 34]. However, it has also been reported in Egypt (outside SSA), North Africa [35, 36].
The distribution of fascioliasis in Nigeria covers every geo-political zone. There have been reports from North West [37, 38], North Central [39, 40], North East [41, 42], South West [43, 44], South South [45, 46] and South East [47, 48].
In 1939, Eugene Pavlovsky, a Russian Academician propounded the theory of disease focality, which suggests that some disease-causing organisms (pathogens) naturally occur in specific ecosystems [49, 50]. This implies that the population of the pathogens is an integral part of that natural landscape [51]. Characteristically, pathogens are transmitted in such settings irrespective of the presence of humans. Consequently, humans become accidental definitive hosts when their ecological niche overlaps with suitable hosts from such landscapes and they become infected after establishing contact [52]. Researchers have found out that the epidemiology of fascioliasis has a strong link with the ecology of the settings where the disease is transmitted [30].
Pavlovsky’s theory explains why fascioliasis is categorized as a focal infectious disease [29]. It could be transmitted independent of human presence. Drawing analogy from Pavlovsky’s theory, there are three important elements that play key roles in the transmission pattern of fascioliasis. These are the snail intermediate hosts, ruminant vertebrate hosts, and humans who are the accidental hosts (see Figure 2 below).
Global distribution of fascioliasis. Source: Reprinted from [
The transmission patterns of fascioliasis vary in different epidemiological settings [30]. In the last 20 years, some researchers proposed that the patterns of the disease can be classified as fascioliasis due to influx of immigrants, human endemic/non-human (animal) endemic areas, native or isolated cases, and the three human degrees of endemicity. The fourth classification is further grouped as hypoendemic [prevalence rate < 1% while Arithmetic Mean Intensity of Infection (AMII) < 50 eggs/gram of feces], mesoendemic [prevalence rate of 1–10% while AMII 50–300 eggs/gram of feces], and hyper-endemic [prevalence rate > 10% while AMII >300 eggs/gram of feces]. In mesoendemic settings, school-age children (SAC) [5–15 years] may have higher prevalence rates while in hyper-endemic settings, SAC usually record higher prevalence rates [54, 55].
The role of climate in the ecology of disease-causing organisms cannot be overemphasized. In fact, climate is regarded as a basic concept of ecology. Climate triggers environmental changes [56], which in turn affect the ecosystems where parasites are transmitted, reproduced, and complete their life cycles. Because life cycles, transmission rates, and pattern
Factors that predispose humans and animals to infectious diseases are referred to as risk factors. At different times and locations, many researchers have carried out spatial regression analysis of environmental variables to determine the risk factors of fascioliasis in humans and domestic ruminants. Consequently, significant associations have been described between fascioliasis and streams, wetlands, pastures [60], raising more than five sheep, dog ownership, familiarity with aquatic plants, drinking alfalfa juice, dizzy spells, history of jaundice, peripheral eosinophilia, presence of
Meanwhile, gender, age, epidemiological settings (rural, urban, or rural-urban), feeding habit, familial, and social factors have been reported as the major risk factors of fascioliasis among humans [55].
In areas that are hyper-endemic for human fascioliasis (e.g., Egypt and Bolivia), females have reportedly recorded higher prevalence and intensity rates [55, 63, 64].
All age groups have been found to be at risk of infection with fascioliasis but school-age children (5–15 years) have the highest prevalence and intensity [30, 64].
People from low-middle income countries are more likely to suffer from fascioliasis. However, inhabitants from developed countries could be infected when they feed on imported infested plants that elude quarantine measures [30]. During field trips, urban inhabitants could be at a high risk of infection due to fascioliasis [55].
Source of food and water consumed is an important epidemiological factor of human fascioliasis. Uncontrolled markets of vegetables (like carrot, cucumber, cabbage, onions, tomatoes, spinach, etc.) coupled with drinking infested water or beverages/juice made from local plants could predispose humans to infection since liver flukes have affinity for all plants. Reports have also shown that consumption of raw liver plays a vital role in infection transmission [55, 65].
Information on the prevalence of fascioliasis in Nigeria is more available compared to the intensity of infection: researchers seem to report the former more than the latter.
In a recent cross-sectional study conducted in North Central Nigeria where 686 fecal samples were collected from cattle in 11 villages, 110 were found to test positive for the eggs of
Meanwhile, a study carried out in South-South Nigeria revealed a fascioliasis prevalence (due to
Nevertheless, in the North-East, a fascioliasis (without distinction) prevalence of 28.2% was reported where 262 gall bladders of White Fulani cattle were examined [42]. In a recent longitudinal study carried out in another part of North-East, Nigeria, where 7640 samples of feces and gall bladders were collected from slaughtered cattle, sheep, and goats in seven local government areas, 3092 were positive for the eggs and adults of
Moreover, a cross-sectional study on bovine fascioliasis in southwestern Nigeria where 905 samples of feces were screened for the eggs and adult of both species shows the predominance of
Furthermore, a cross-sectional survey carried out in North-West Nigeria reported a prevalence of 27.68% after fecal and bile samples were examined from 224 cattle [37]. Another cross-sectional survey of slaughtered cattle, sheep, and goats carried out in similar zone reported a prevalence of 29.6% for
Finally, a longitudinal study carried out in South-East 8 years ago reported a prevalence of 17.2% after fecal and liver samples from 367 slaughtered sheep were examined for the presence of
The pattern of the prevalence rate of fascioliasis in Nigeria has proven the focal nature of the disease irrespective of the class of ruminant animals examined.
Oriental forms of liver flukes cause cholangiocarcinoma, a type of liver cancer that is peculiar to areas where
The parasitological means of examining fecal samples for the presence of liver flukes’ eggs is the use of microscope [68]. Eggs become visible after 8–10 weeks post infection. This, however, varies from one host species to another. The limitation of this method is that the sensitivity of the Fecal Egg Count (FEC) may be undermined by factors like the age of the host, quantity of water in each fecal sample, and how representative the number of aliquots is per fecal sample examined [70]. Furthermore, a report has shown that in definitive hosts suffering from the acute phase of the disease, adverse effects of fascioliasis become evident much earlier before the pre-patent period [71]. Consequently, at necropsy, quantitative fecal examination and finding the hepatic fluke load will grossly downplay the severity of the disease [69, 72].
Quite a number of relatively cheap antibody detection indirect enzyme-linked immunosorbent assays (ELISA) with high sensitivity and specificity have been developed. Most of these techniques are based on excretory-secretory products and cathepsin L proteases [70, 73].
Increase in parasite-specific IgG (which becomes detectable after 4 weeks post infection) is peculiar to infection with fascioliasis [74]. The limitation of this technique is that after many months of successful treatment, antibodies could remain in serum, giving a false impression that the infection status is positive [70].
Excellent specificity and sensitivity has been reported for a serodiagnostic technique developed in 2011 for human fascioliasis. SeroFluke, as it is called, is a lateral flow test which has fared better compared with ELISA test (MM3-SERO) [70, 75].
Nonetheless, report has shown the superiority of antigen detection to that of antibody in the diagnosis of human fascioliasis. Coproantigens (antigens in fecal samples) are preferred to antigenemia (the presence of antigens in blood) because in the latter, circulating antigens disappear soon in the serum of patients. Besides, most of them appear in form of immune complex which are not freely detectable [76].
Less than a decade ago, a nested-PCR was developed to boost the sensitivity and specificity of current diagnostic techniques with the view that the fascioliasis could be detected in the feces of sheep 2 weeks post infection. This method entails the amplification of a 423 bp fragment of the Cytochrome C Oxidase 1 gene [70, 77]. Interestingly, similar result was achieved a year later in lesser time by amplifying a 292 bp fragment of ITS2 gene [70, 78]. Because molecular diagnosis using PCR is not readily available everywhere and as well undermined by irreproducibility of published methods, loop-mediated isothermal amplification (LAMP) has been introduced as an alternative. LAMP has proven to be more specific and sensitive by detecting fascioliasis 1 week post infection in sheep within a much shorter time—about 2½ times faster than PCR [70, 79].
Chemotherapeutic approach has been in practice in fascioliasis control for 20 years. Based on its effectiveness, it has been predicted that the
The single dose of 10 mg/kg body weight is effective against the adult in the bile ducts and on immature flukes migrating through the liver [80, 85]. However, TCZ resistance has been reported in animals [87, 88] and in humans [89]. Reports have shown that drug resistance could frustrate fascioliasis control programmes [18]. Besides, TCZ is not commercially available because it is solely distributed by Novartis Pharma. Inc. (Basel, Switzerland). Consequently, it is not recommended for mass administration of medicines (MAM) [80, 90]. The unavailability of the drug, specifically to treat fascioliasis, has been reported to result in outbreaks of the disease more than a decade ago [91].
Periodic antihelmintic use at 12–13 week intervals is effective against both mature and immature flukes. By this strategic control measure, intensity of infection with liver flukes significantly reduces over time. In the tropics where incidence of fascioliasis occurs all year round, annual treatment of up to four times is recommended [82, 92].
In Nigeria, some parts have reported seasonal trends in fascioliasis while some Southern parts of the country have reported an all-year-round occurrence [93]. A recent 46- year meta-analysis of the prevalence and distribution of helminthes of veterinary and zoonotic importance in Nigeria has identified failure of control programmes in the area of strategic deworming, snail host control, and adequate sanitation as the reason for the highest pooled prevalence in southwestern Nigeria [38]. Some authorities recommend that cattle be dewormed regularly [94], while others recommend treatment upon onset of clinical fascioliasis. Meanwhile, two or three annual treatments have been proposed: at the start of the rainy season, mid rainy season, and at the start of the dry season [95]. Currently, the anthelminthic drugs in use in Nigeria include: albendazole, nitroxynil, clorsulon and levamisole. However, a report has shown that the drug of choice against fascioliasis (triclabendazole) is not available for use in Nigeria [82].
The emerging drug-resistant strains of liver flukes have led to the need for vaccine development. Despite the immense effort of researchers in this regard, no commercial vaccine is available yet [96]. Cysteine proteases produced by every stage in the life cycle of the liver flukes are common virulence mediators [97], which mediate biological functions like excystment, tissue invasion, and immune evasion [98].
Adult fluke cathepsin L and newly excysted juvenile (NEJ) cathepsin B are the prominent proteolytic enzymes of their respective excretory secretory (ES) materials [97]. Cathepsin L5 and cathepsin B synthesized by
Recombinant protein expression is critical to the assessment of cysteine protein vaccine potential [97]. The yeast expression system has been a useful tool for the functional expression of cathepsin L1 and L2 [102], cathepsin L5, and cathepsin B [101].
A larger part of these vaccine candidates was first isolated as native proteins from adult worm ES products. Several of these early antigens, including cathepsin L proteases, glutathione S-transferase (GST), and fatty acid binding protein (FABP) significantly reduced worm burden, egg output, and liver pathology in cattle and sheep [96, 103].
Fascioliasis has been established as an important foodborne disease of veterinary and zoonotic importance. Climate change, emerging drug resistance, and the development of new parasite strains through hybridization are the current challenges that could potentially alter the epidemiology of the disease in the nearest future [70]. To this end, researchers need to step up their effort to produce promising vaccines that offer maximum protection to farm animals and humans and as well contribute immensely to global elimination of the disease by reducing its prevalence and intensity. Government of countries in the tropics and subtropics should endeavor to provide more funds for researchers.
The authors sincerely appreciate the effort of Mr. Osuntuyi Mabayoje Pius who did the art work on the Life Cycle of liver flukes. We extend our gratitude to the World Health Organization for granting us the permission to use the map of the world showing the global distribution of fascioliasis under the request ID 312094.
The authors do not have any conflicts of interest to declare.
At IntechOpen, we not only specialize in the publication of Book Chapters as part of our Edited Volumes, but also the publication and dissemination of longer manuscripts, known as Long Form Monographs. Monographs allow Authors to focus on presenting a single subject or a specific aspect of that subject and publish their research in detail.
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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:null},{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. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{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:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}},{id:"441116",title:"Dr.",name:"Jovanka M.",middleName:null,surname:"Voyich",slug:"jovanka-m.-voyich",fullName:"Jovanka M. Voyich",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Montana State University",country:{name:"United States of America"}}},{id:"330412",title:"Dr.",name:"Muhammad",middleName:null,surname:"Farhab",slug:"muhammad-farhab",fullName:"Muhammad Farhab",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agriculture Faisalabad",country:{name:"Pakistan"}}},{id:"349495",title:"Dr.",name:"Muhammad",middleName:null,surname:"Ijaz",slug:"muhammad-ijaz",fullName:"Muhammad Ijaz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Veterinary and Animal Sciences",country:{name:"Pakistan"}}}]}},subseries:{item:{id:"2",type:"subseries",title:"Prosthodontics and Implant Dentistry",keywords:"Osseointegration, Hard tissue, Peri-implant soft tissue, Restorative materials, Prosthesis design, Prosthesis, Patient satisfaction, Rehabilitation",scope:"