Stereoselective and/or specific enzymes of alkaloid and flavonoid compound biosynthesis in plant extract.
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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Cellular motility has been an essential cellular phenomenon throughout phylogeny that has allowed organisms to survive, adapt and prosper in different environments. It is engrained in the chemoattraction and nutrient-seeking mechanisms in protozoa such as
Other than these physiological conditions, cellular motility is essential in regulating some of the physiopathological steps seen in disease. As example, it is well-documented that cellular migration is one of the prominent factors involved in the later stages of carcinogenesis and the subsequent phases of metastasis [9–11]. Cancer cell dissemination is clearly dependent upon the ability of migratory tumour cells to evade away from their initial niche, leading to the colonisation and formation of distant secondary lesions in the body [12].
\nAt the molecular level, cell migration requires the coordinated regulations, both spatial and temporal of numerous cytoskeletal proteins, to orchestrate the dynamic cellular processes needed for cells to acquire movement. In this context, the actin cytoskeleton and the closely linked myosin network play essential functions [13, 14]. The process of cellular motility can be summarised as an engineered cycle composed of three distinct phases which are, (1) formation of cellular protrusion in the forms of lammelipodia and fillopodia to initiate contact and adhesion with the external environment, (2) regulation of cell-extracellular matrix established connections, usually integrin-dependent, and (3) force generation by the actomyosin network which will control both the structure and organisation of the motile architecture [15]. I provide here a brief overview of some of the different elements and protein complexes that are regulated during this migratory cycle, focusing primarily on specific components of the actomyosin complexes.
\nA group of low-molecular weight polypeptides that has been demonstrated to have key functions in remodelling the overall actin cytoskeletal network is the S100 protein family [16]. Composed of approximately 25 members, the presence of the majority of these in different cellular systems, both in vivo and in vitro has been associated with significant changes in cellular migration. One of the most prominent members of this family to have been linked to regulate cellular motility is S100A4, a protein that has received constant attention for its significant role in promoting cancer metastasis [16–18]. Consequently, and in order to emphasis the impact of this work and strengthened its delivery, I have concentrated our attentions on actomyosin proteins/complexes that have both been demonstrated to be crucial players of the migration process but also S100A4 interactors. In doing so, this chapter aims to capture a picture of how expression of this small, calcium-binding protein may in essence remodel at different levels the actin organisation and fulfil the motility engineered cycle of protrusion, attachments and contractions.
\nMotility can be seen as a lone activity where a single cell may migrate (also known as amoeboid or mesenchymal migration [19, 20]) or is referred to as collective, if this effort is the result of concerted effort undertaken by numerous cells, either in sheet or clusters [9]. Equally important is the cell physiognomy that will be regulated in the process. Mesenchymal motility as seen during fibroblast migration leads to cellular characteristic of a more elongated spindle-like shape. In this type of migration, an actin-rich leading edge can be observed, where extension of the front leading edge is driven by actin polymerisation [21]. In amoeboid migration, cells adopt a more rounded morphology and rely on the contraction-based membrane blebbing and enriched levels of myosin II at the cell rear [22]. Both of these migratory processes have been shown to play important roles in both physiological and pathological events.
\nThe complexity of the different types of cell migration that can be used is mirrored by the number of different molecular pathways that are available to orchestrate these processes. Among them, however, the remodelling of the actin cytoskeleton and its organisation stands as an irreplaceable circuitry which is undisputably common to all. At the molecular level, this network is considered to provide the platform where physical forces will be exerted. Pushing forces generated by the assembly of filamentous actin (F-actin) will encourage the formation of cellular protrusions, such as filopodia, lamellipodia, blebbing and the most recently characterised invadopodia [23–25]. These changes in actin polymerisation and their dynamics will be directly responsible for reshaping and remodelling the underling plasma membranes.
\nActin structure and cartoon of F-actin polymerisation. (A) G-actin monomer at 1.54-Å resolution bound to ADP (PDB code 1J6Z) by Otterbein et al. [
In the early stages of assembly, also known as nucleation, actin protomers aggregate in an energetically unfavourable process to form a dimer that is more likely to dissociate. Addition of another subunit stabilises the complex and represents the nucleus, a state where actin polymerisation is now more favourable than dissociation (Figure 1). The association of monomers into a trimeric structure is seen as the rate limiting step of the whole polymerisation process as it is reversible where monomers can easily dissociate [28–30]. It is during the stage of nucleation that addition of further actin subunits is supported at both ends. Once the nucleus and newly added monomers have been locked into position by conformational changes, the process of elongation begins and the addition of actin molecules at the barbed end of the filament can be seen, resulting in the formation of structural polarised complexes (Figure 1). Whilst G-actin subunits can self-assemble, this process only occurs if the concentration of actin exceeds a critical concentration.
\nWithin cells, a growing number of binding partners, or actin-binding proteins, will act both antagonistically and agonistically to regulate the polymerisation process. Some factors will act as nucleators, such as formins and Arp2/3, facilitating the process through providing a scaffold structure which encourages de novo assembly. Others will regulate the overall structure of filaments through their remodelling in larger structures. Examples provided here will control the cross-linked state of actin filaments through the involvement of bundling regulators such as the tropomyosins and to an extent myosins. Involvements of all these factors, as well as many others that are too numerous to be listed, here, will be responsible for the remodelling of the actin cytoskeleton into different substructures seen during cell migration (Figure 2).
\nS100A4 interacting actomyosin complexes and their simplified organisation in the different protrusions of a migrating cell. (A) Actin and focal adhesion organization in a HeLa migrating cell. Staining for F-actin using Phalloidin-rhodamin (red) and paxillin with antibodies coupled to FITC (green) in a migrating HeLa cell. In this image, the actin mediated structures of the filopodium and lamellipodium/lamellum are distinctly visible at the leading edge of the cell. B and C present models for the lamellipodium/lamellum and filopodium and the respective molecular organisation within, focusing on the proteins presented in this chapter. (B) A simplified model for lamellipodium/lamellum formation. In the lamellipodium, the Arp2/3 complex via activation by WASP/WAVE complex interacts with actin filaments resulting in the nucleation of new actin filaments from the side of existing filaments. Formin proteins are also found at the barbed end of filaments. Limprin and the Rho-GTPase-Rhotekin complexes could get regulated by S100A4 to promote lamellipodia protrusions. In the lamellum, tropomyosin wrapping around the actin filaments prevents interactions with other actin binding proteins. NMMIIA regulates retrograde flow in the lamellum. At the interface of the lamellipodium–lamellum, actin is depolymerised. Interactions of S100A4 with tropomyosins and the NMMII complexes have been reported and could result in significant changes in their overall organisation. (C) A simplified model for filopodia formation. In this diagram, actin polymerisation promoted by the Arp2/3 complex leads to the branching and extension of nascent individual actin filaments in the filopodium. Recruitment of the formins to this location promotes the elongation of the filaments through the addition of actin monomers at the barbed end. Other actin bundling proteins such as fascin regulates filopodia stability through the clustering of actin filaments. Both the Limprin and the Rho-GTPase-Rhotekin complexes could be regulated by S100A4 to control filopodial protrusions.
When grown in a 2D environment, cells will encourage the formation of differential planar filamentous actin, in the form of filipodia/microvilli or sheet-like structures referred to as lamellipodia (Figure 2, [31, 32]). Whilst the former act as sensory organelles that enable cells to probe their local environment, through the formation of thin extensions that are mainly made of long, unbranched bundles, the latter is viewed as the main driving force for locomotion, through the organisation of short branched actin networks (Figure 2). In both instances, however, regulation of F-actin polymerisation, especially at their barbed end is essential, in order to control their elongation in the direction of the plasma membrane and is thought to require nucleation-promoting factors where both formins and Arp2/3 have been shown to play key functions (Figure 2, [31, 33]).
\nCartoon showing some of the regulation steps for different actin nucleating proteins. (A) Activation of the Diaphanous-related formin. Autoinhibition of the actin nucleating ability is due to the interaction of the C-terminal Diaphanous auto-regulation domain (DAD) with the N-terminal FH3 (Formin homology) domain. Rho-GTP Binding of the GTP bound Rho to the GTPase binding domain (GBD) region is thought to lead to a partial displacement of the DAD as well as relocalisation of the complex, resulting in the unfolding of the protein and the relieve of the autoinhibition (DD dimerization domain). (B) Cartoon representation of the Arp2/3 complex and nucleation of a branched filament. The Arp2/3 complex initially binds to the pointed end of the mother F-actin. Binding of the WCA domain of a nucleation promoting factor (NPF) to exposed regions of Arp2 and Arp3 allows the delivery of actin monomer and initiate the polymerisation of a nascent branched filament as elegantly demonstrated [
Taken all together, actin polymerization at the leading edge is a vital process for cellular migration, through the orchestrations of events that will ultimately lead to different cellular protrusion events. In this section, different actin polymerization factors and their functions (Arp2/3 and Formin) were briefly explored. One should remember that this is only a preferential view in regards to their potential involvements through a S100A4-dependent process and that numerous other regulators not mentioned here play equally vital roles in the process of actin remodelling and cellular migration.
\nAway from the leading edge and the protrusions of the lamellipodia and filopodia, the array of filamentous actin is seen to exist as more bundling rather than the branched sheets reported previously, mainly due to the interaction of different actin-binding proteins. This contractile network is seen as a unique structural complex, spatially posterior to the lamellipodium, and is referred to as the lamellum [61].
\nIn the spatial arrangement of the lamellum, filaments are organised in different structures, known as stress, dorsal and ventral fibres; they are the result of interaction of the actin filaments with different partners (Figure 2). It is in this context and primarily through the control of the tropomyosin and myosins that contractile forces are exerted to manipulate their overall organisation. Generation of such tensile forces is provided by the myosin network, mainly non-muscle myosin II (NMMII) which is responsible for the majority of the morphological and architectural reorganisations that promote cell movement.
\nThe overall organisation of the actin cytoskeleton can also be dictated by actin bundling and contractile motor proteins. Binding of individual filaments, actin cross-linking and motor proteins allow the formation of thicker, linear and either paralleled or antiparallel filamentous F-actin networks that can be found in all subcellular localisations. In the lamellum, the class II non-muscle myosin family has been shown to be a key regulator, participating in the bundling of actin filaments and generating mechanical forces, which result in filaments sliding and/or contractions [72, 73].
\nNMMII isoforms in the form of NMMIIA, NNMIIB and NMMIIC are found in most, but not all human cells and most mammals. NMMIIA and NMMIIB are expressed at similar levels in endothelial and epithelial cells. There is, however, little or no NMMIIC present in these cell subsets although it is known to be much more prominent in cells of lung and nervous tissues. Their location appears to be cell-specific and will be regulated differentially depending on the type of cell migration. Perhaps their expression patterns further reflects their function, since NMMIIA and NMMIIB play fundamental roles in mediating cell shape and matrix interactions during migration, whilst a clear role of NMMIIC in this process is still missing. As a consequence, during mesenchymal motility, NMMIIA is localised throughout the cells, in cellular protrusions and in both the lamellipodia and lamella of migrating cells [78] where, with Arp2/3-dependent actin polymerisation in the former, it results in actomyosin contraction and the retrograde flow of F-actin towards the cell body [61]. NMMIIB is predominantly found in the central and rear regions of the cell but not at the cell front [79].
\nWhilst formation of protrusions is a key element of cellular motility, it is equally critical that these newly created extensions also adhere and attach to the substratum, as their inability to do so result in their rearward movements in waves due to cellular tension [80]. Nascent adhesions are the first observable adhesive structures established in the lamellipodium [72, 81]. Their transient nature will force them to either disassemble quickly or mature into larger complexes known as focal adhesions which reside at the boundary of the lamellipodium and lamellum [82]. Actomyosin contraction is the main regulator that controls nascent adhesion enlargement [72]. This initial interaction with the extracellular environment will in turn induces activation of downstream effectors transmitted to the plasma membrane to encourage further integrin adhesion and clustering through their activation as well as changes in confirmation of extracellular matrix proteins [83]. Following on from this integrin activation, other downstream cellular pathways are also instigated; these lead to the recruitment, in a force dependent manner, of numerous framework and adaptor proteins which associate to form an adhesome [84]. Indeed mechanical stretch generated during this process induces changes in structural protein configurations, thereby encouraging binding of certain factors to other partners, as is the case for paxillin, vinculin, talin and actin, three essential component of the adhesome/adhesion complex [85, 86] (Figure 4).
\nMyosin IIA expression in Cos7 cells regulates actin fiber formation and focal adhesion maturation. (A) Regulation of the actin organisation in Cos7 cells in the presence of NMMIIA. Cos7 cells were seeded into 24 well plates and left to incubate for 24 h. Cells were washed and fresh medium without antibiotics were added into each well 4 h prior to adding transfection mixture containing either the empty PeGFP-C3 plasmid (green cells labelled as A’) or the PeGFP plasmid expressing NMMIIA (green cells labelled B’). Following a 48-h incubation, cells were fixed, permeabilised and stained either for actin (Phalloidin-rhodamine (red)) prior to mounting and viewing by epifluorescence microscopy. Note that the expression of NMMIIA leads to significant increases in stress fibres formation (B’ where both NMMIIA and actin colocalise). (B) Focal adhesion organisation in Cos7 cells in the presence of NMMIIA. Cells grown as above were transfected with an empty PeGFP-C3 plasmid (green cells labelled as C’) or the PeGFP plasmid expressing NMMIIA (green cells labelled D’) prior to fixing, permeabilisation and immunostaining for paxillin using a mouse anti-paxillin primary antibody and a secondary anti-mouse rabbit Alexa-568 secondary antibody (red), prior to mounting and viewing by epifluorescence microscopy. Note that the expression of NMMIIA leads to significant increases in formation of paxillin cluster at the end of the myosin fibres (D’ where paxillin foci are seen).
NMMII cross-linking and contractile functions to remodel the actin cytoskeleton are regulated by phosphorylation of (1) regulatory light chains (RLC), (2) heavy chains (HC) and (3) myosin’s ability to assemble into filaments. The RLC polypeptide can be specifically phosphorylated at different regulatory sites. The most prominent site is Ser19, leading, when phosphorylated, to a significant increase in ATPase activity of the head domain in the presence of actin [87]. Phosphorylation sites in the C-terminus of the myosin heavy chain have also been identified, although the true implications of such changes in ATPase activity remain unclear. Regulation of the reversible phosphorylation of specific residues is obtained through the activation of different kinases and phosphatases, depending on the residues considered. Whilst phosphorylation at residue Ser19 will be regulated by MLCK (myosin light chain kinase) and MYPT1 (myosin phosphatase target subunit 1), the most prominent examples, respectively [88, 89], the C-terminal region of the myosin heavy chain is directly targeted by kinases such as TRPM7 (transient receptor potential cation channel subfamily M member 7) and PKC (protein kinase C) [77, 90].
\nCompelling evidence also demonstrates that phosphorylation and interactions with the C-terminal region of NMMII regulate assembly of the complex into filaments. Such post-translational modifications also result in a change in overall structure. In its fully dephosphorylated form, the compact NMMII complex adopts an asymmetric state, unable to polymerise which is relaxed into an extended conformation following phosphorylation of RLC [91]. Phosphorylation of the C-terminal region of NMMII by kinases such as TRPM7 and PKC has also been shown to interfere with its abilities to form filaments [92]. Finally, it is predominantly through changes at the C-terminus, via the coiled-coil domain that NMMII assembly into filaments is controlled. Truncation experiments have demonstrated that the C-terminal region containing an ACD (assembly competence domain), as well as the C-terminal tail piece, are both important to promote correct assembly of NMMII into parallel and anti-parallel filaments [93, 94]
\nAnother key regulator of motility is the cell’s ability to orchestrate the different contraction and tension forces that are necessary to promote movement. In this section, lamellum components such as those of the NMMII and tropomyosin networks have been briefly reviewed. The overarching purpose here being once again to focalise the reader’s mind on certain complexes, which are known interactors for the S100A4 proteins and could be key players in the process of motility observed when this protein is aberrantly expressed. Other pivotal factors that regulate motility via contractions have not been mentioned here but have been addressed in numerous other reviews and chapters [23, 95–101].
\nInitially, referred to as mts1, FSP1, metastatin, p9Ka, PEL98, calvasculin, 42A and placental calcium-binding protein, S100A4 is a low-molecular weight acidic protein belonging to the S100 family. This small polypeptide is characterised, as all other members of this family, by a pair of calcium-binding helix-loop-helix regions referred to as EF-hand calcium-binding domains located at either side of the protein and separated by a hinge region [16, 102]. Over the years, S100A4 has received a large degree of interest in the field of cancer cell biology, since its expression is linked to increased motility and invasion directly promoting metastasis in animals, and it is now considered a potent marker for human metastasis and predictor for poor patient outcomes [17, 103]. Its expression is also observed in non-physiopathological states in different motile cell types in vivo, including those of the immune system (lymphocytes, macrophages and neutrophils) as well as mesenchymal fibroblastic cells. The biological implications of S100A4 expression on cellular migration are well-known [16], but the mechanisms required to attain such phenotypic changes are not fully characterised. In this part of the chapter, I will review its interactions with the different actomyosin components that have been discussed, whether actin nucleating activators, actin binding proteins or myosin regulators, highlighting how their functions are being affected in the presence of the S100A4 protein.
\nExpression of S100A4 has been correlated to significant changes in overall actin organisation and cellular extensions, with extensive increases in lamellipodia and forward protrusions [104, 105] which, in turn, are thought to result in greatly enhanced cellular motility. Similarly, S100A4 has been found to be enriched at both the leading edge and in pseudopodia of migrating cells [104, 106]. A clear molecular explanation as to how S100A4 can regulate such processes is currently lacking, but different hypotheses have been formulated in view of what is known about its different binding partners and regulatory functions.
\nRecent evidence indicates that the retrograde flow exerted by NMMII impedes extension of the leading edge and subsequent rates of protrusions because of reduced actin polymerisation [130, 131]. Therefore, a reduction in contractile forces, as observed when NMMII activity in cells is inhibited by blebbsistatin, leads to significant decreases in actin retrograde flow in the lamellum. This reduced flow leads, in turn, to subsequent increases in actin clustering into bundles at the lamellipodium–lamellum interface, and increased leading edge extension [132, 133]. The opposite experiment where activation of the NMMII complex is achieved through a Eph receptor/RhoA/ROCK signalling pathway was found to inhibit lamellipodial extension [134].
\nIt is therefore rational to suggest that one of the protrusion-promoting abilities of S100A4 may be directly linked to its ability to interfere with formation of myosin fibres and their role in protrusion formation. Experimental support for a S100A4-NMMIIA role in cellular protrusion was obtained when S100A4 overexpression in tumour cells led to significant increase in leading edge protrusive activity [104]. This change in phenotype was shown indirectly to be NMMIIA dependent since the exogenous addition of antibody targeted towards the NMMIIA-binding site mimicked the cellular behaviour [104]. Interestingly, a reverse experiment also confirmed a clear role for S100A4 in this process, since S100A4 (−/−) macrophages demonstrated large amounts of over assembled NMMIIA filaments, leading to significant lamellipodia instability and reduced persistence [135]. Because NMMIIA has been clearly demonstrated to be the preferential cytoskeletal target for S100A4 to date, it is expected that their partnership may also influence the overall organisation of the actomyosin network in the lamellipodium and lamellum where the majority of the NMMIIA pools are located.
\nWhilst S100A4 expression in cells has undoubtedly been linked to regulation of cellular protrusions, mainly increases in lamellipodia and forward protrusions, and arguably being responsible at least in part for some of the enhanced cellular motility observed, the true molecular processes responsible are yet to be fully characterized. In this section, S100A4 partners such as Rhotekin, actin or liprin possibly found at the leading edge are presented in order to provide possible explanations as to how such biological properties may be regulated and it is expected that future researches will shed new lights into the true mechanisms that are involved in this process.
\nBehind the cellular protrusion of the highly dynamic lamellipodium, the actomyosin network contributes to cell migration through contractibility and substrate adhesion [61, 72, 81]. Although direct evidence of S100A4 being localised in the lamella of migrating cells is still lacking, numerous reports have highlighted potential regulatory functions of the S100A4 within this subcellular fraction since its expression has been shown to lead to dramatic changes in numbers and organisation of focal adhesions and actin stress fibres [104, 105, 109, 122, 128, 136]. I will briefly discuss here the different properties that S100A4 encompasses towards a remodelling of this cellular architecture.
\nThis final section briefly summarizes the best characterized and known S100A4 interactor, namely NMMII, in view of their high binding affinity, as well as by the number of reports highlighting their association. Yet again, whilst we are gathering further understanding related to their association and the different regions of the proteins that are responsible, a true model as to how their interactions regulate cellular motility remains elusive both theoretically and more importantly experimentally.
\nControlling the actin cytoskeleton and the motility process is a key function, that when going awry, leads to significant pathological conditions. Not surprisingly, mutations or aberrant expression of all actin interacting proteins listed in this section have been liked to diseases, thought to be the result of significantly reduced cellular motility. Mutations in cytoplasmic actin have been related to autosomal dominant hearing loss [144]. Mutation or molecular mechanisms that result in changes of activity of actin-binding proteins, such as the nucleating facilitating protein complex Arp2/3 have been linked, albeit indirectly, to bacillary dysentery, as their functions are high jacked by the
I would like to apologise for the numerous studies, which have significantly improved our understanding of actin dependent processes regulating cellular motility and invasion, but could not be included in this work owing to limits on the number of references. Special thanks are given to Prof. Philip S. Rudland (the University of Liverpool) for his critical comments on the chapter and for Prof. David Poyner (Aston University) for his invaluable help with the preparation of the different actin structures used.
\nChiral inversion is the process by which enzymes modify the three-dimensional structure of a molecule by converting one enantiomer to its antipode [1]. Racemization occurs when isomerization leads in the creation of a racemic mixture. As a result, chiral inversion influences drug stability throughout drug discovery and development. Biological activity, toxicity, shelf-life and dosage of the compound are affected by the stability of the drug [2]. The process of chiral inversion is affected by a lot of variables, consequently, the strength of chiral inversion under different situations and in various substances can vary significantly. The primary elements that were acknowledged to play a vital part in the process of chiral inversion were reported to be interspecies differences and tissue types. Some recent researches have demonstrated that additional variables, such as administration route or interaction with other xenobiotics, can also impact enantiomeric conversion.
Plants create a vast diversity of physiologically active metabolites, many of which have stereochemical variants on the same molecular scaffold. These alterations in stereochemistry have a significant influence on biological function. Notably, plant stereoisomers of alkaloids and flavonoids exhibit a wide range of pharmacological effects. Alkaloids are cyclic chemical molecules with a negative oxidation state of nitrogen. They are found throughout the flora and play an important function in plant protection, sprouting, and encouraging plant development. Plants containing alkaloids are frequently employed as traditional remedies, and these chemicals typically have specific pharmacological actions. The majority of alkaloids are in a chiral form which is often appeared in products as racemic compounds, while their enantiomers have been proved to have different pharmacological actions [3]. Flavonoids are a vast category of polyphenolic chemicals with a benzo—pyrone structure that is found in all plants. Phenylpropanoid is their produce’s pathway. Recent interest in these chemicals has been sparked because of the possible health advantages of these antioxidant polyphenolic compounds [4]. The relevance of racemic flavanones stereospecific pomological disposition has been determinated and described in the last 20 years. The majority of these studies report on the measurement of flavanones in citrus fruit juices and herbs [5].
Can all chiral compounds undergo chiral inversion? Maybe no, many compounds still can be considered stable in metabolize process. Why are some enantiomers of plants inverted by enzymes and others are not attacked? The reason lies in the structure. The intent of this chapter is to provide a comprehensive, rather than an exhaustive, appraisal of chiral bio-inversion. This chapter will discuss enzymatic chiral inversion of plants in secondary metabolize and its importance create pharmacology effect. Therefrom, it helps a better understanding of chiral compounds in plants, facilitating the application for drug development from medicinal herbs.
Under selective conditions, racemization or enantiomerization defined as the chiral conversion of enantiomer into its antipode may present in many plants metabolizing. When the chiral molecule enantiomers in herbals interact with a chiral macromolecule-like enzyme, they generate a pair of diastereoisomeric complexes that vary energetically. It is not surprising, then, that the results of enzyme-mediated reactions performed on a pair of enantiomers may differ in type and/or extent. Indeed, given the structure of the enzyme-substrate complex, it is plausible to believe that enantioselectivity is the rule rather than the exception in metabolism. Likewise, the binding of a prochiral substrate to an enzyme may orient two enantiotopic groups differently about the enzyme catalytic site, causing these two groups to become diastereotopic within the enzyme-substrate complex. It’s simple to see how the production of a chiral metabolite from a prochiral substrate may result in stereoselectivity for one isomeric product [6].
At the substrate and product levels, xenobiotic metabolic reactions exhibit two forms of stereoselectivity. As a result, they can be classed according to their stereoselectivity or, if such selectivity is complete, their stereospecificity. Caution while using this latter phrase, because the ability to determination “specificity” is clearly dependent on the analytical approach of the research. The words substrate and product “stereospecificity” were initially introduced to the enzyme-mediated reduction of ketones by Prelog [7], and were later extended to drug metabolic processes by Jenner and Testa [8]. Substrate stereoselectivity is the preferred metabolism of one of two stereoisomers over the other, whereas product stereoselectivity is the preferential production of one stereoisomer over the other stereoisomers that may exist. These two “selectivities” may be so closely related that substrate-product stereoselectivity, i.e., the selective metabolism of one of a pair of enantiomers to form one of several possibly diastereoisomeric products, may also be seen. If the enantiomeric composition of medication or metabolite is detected in the analysis process, data collected from in vivo research on stereochemistry in plants must be regarded with caution (Table 1).
Plant | Enzyme | Stereoselective | Stereospecificity | Ref. |
---|---|---|---|---|
Opium poppy | 1,2-dehydroreticuline reductase | (R)-reticuline | [9] | |
Catharanthus roseus | tetrahydroalstonine synthase | (3S,19S,20S)-Tetrahydroalstonine | [10] | |
Claviceps purpurea | Dimethylallyl tryptophan synthase | L-tryptophan | [11] | |
Hyoscyamus niger | Hyoscyamine 6β-hydroxylase | L-hyoscyamine | [12] | |
Berberis koetineana | Tetrahydrobenzyliso-quinoline- | ( | [13] | |
Soybean | Chalcone isomerase | (2S)-flavanone | [14] | |
Dahlia variabilis | Flavanone 4-reductase | (2S)-flavanone | (2S, 4R)-flavan-4-ol | [15] |
Citrus unshiu | Flavonol synthase | (2R,3R)-dihydroflavonol | [16] | |
Glycyrrhiza echinata | Flavanone 2-hydroxylase | (2S)-flavanone | [17] | |
Ginko biloba Pseudotsuga menziesii | Dihydroflavonol 4-reductase | (2R,3R)-dihydroflavonol | (2R, 3S, 4S)-flavan-2,3-trans-3,4-cis-diol | [18] |
Medicago truncatula | Anthocyanidin reductase | (2R, 3R)-flavan-3-ol | [19] | |
Medicago sativa | Isoflavone reductase | (2R)-isoflavanone | [20] | |
Pisum sativum | Hydroxymaackiain-3-Omethyltransferase | (+)-6a-hydroxymaackiain | [21] | |
Desmodium uncinatum | Leucoanthocyanidin 4-reductase | flavan-2,3-trans-3,4-cisdiol | (2R, 3S)-flavan-3-ol | [22] |
Stereoselective and/or specific enzymes of alkaloid and flavonoid compound biosynthesis in plant extract.
Plants are thought to generate over 12,000 distinct alkaloids, which may be classified based on their carbon skeleton structures. Many catalytic stages in alkaloid biosynthesis in plants are catalyzed by enzymes from various protein families.
Since the discovery of morphine in 1806, the complex relationships between opium poppy and the human condition have fueled substantial study into the production of morphinan alkaloids [23]. During the 1960s, significant progress toward route elucidation was made, which supported a major theory [24] that morphine was generated by 1-benzylisoquinoline alkaloid metabolism [25]. Because only the (R)-conformer could undergo additional phenol coupling to the morphinan scaffold, (S)-reticuline emerged as the primary 1-benzylisoquinoline intermediate, with its stereochemical inversion to (R)-reticuline thought to be a critical gateway reaction [26].
The pathway makes use of opium poppy reticuline epimerase, a multi-domain protein composed of the P450 CYP82Y2 linked to an aldo-keto reductase (AKR). CYP82Y2 (1,2-dehydroreticuline synthase, DRS) catalyzes the conversion of (S)-reticuline to 1,2-dehydroreticuline, which is then converted to (R)-reticuline by the AKR module (1,2-dehydroreticuline reductase, DRR) [26]. A second P450 called CYP719B1 then tranforms (R)-reticuline into salutaridine [27, 28]. This procedure includes (R)-reticuline twisting, reorientating and oxidative C–C bond coupling stimulated by CYP719B1 (Figure 1).
Proposed chiral inversion of (S)-reticulin to (R)-reticulin catalyzed by 1,2- dehydroreticuline reductase (DRR) and 1,2-dehydroreticuline reductase (DRR) in
Catharanthus roseus, a medicinal plant, creates three of these isomers: ajmalicine (raubasine), tetrahydroalstonine, and 19-epi-ajmalicine (mayumbine) (Figure 2) [30]. These heteroyohimbines are produced from deglycosylated strictosidine (strictosidine aglycone), as are the bulk of monoterpene indole alkaloids [31]. A glucose unit removal from strictosidine by strictosidine glucosidase (SGD) leads to the formation of a reactive dialdehyde intermediate that can rearrange to generate a variety of isomers [32]. The stability of these isomers by enzyme-catalyzed reduction is thought to be the first step toward the vast chemical variety found in monoterpene indole alkaloids. The tetrahydroalstonine synthase (THAS) is a zinc-dependent medium-chain dehydrogenase/reductase (MDR) that manufactures the heteroyohimbine tetrahydroalstonine (Figure 2) [33]. Although, these studies showed that THAS is an important enzyme for the heteroyohimbine production, the mechanism by which this enzyme controls the stereoselectivity of the reduction remained unexplained. Moreover, the fact that strictosidine aglycone is also a predrug of some alkaloid scaffolds so constitutes a major branch point in the monoterpene indole alkaloid biosynthesis process [29].
Heteroyohimbine alkaloid biosynthesis. Red highlighted compounds indicate the three diastereomers identified in
Most flavonoid biosynthesis enzymes are extremely stereoselective and/or stereospecific; nonetheless, this assertion is based on just one or a few published findings for numerous enzymes. Flavonoids are produced by the phenylpropanoid pathway, which begins with the enzyme L-phenylalanine ammonia-lyase deamination of phenylalanine (PAL). D-phenylalanine is not a substrate for PAL; it is selective for the naturally occurring L-isomer of phenylalanine [34]. The process mediated by chalcone–flavanone isomerase (CHI), which sets the stereochemistry at C-2 of the flavonoid heterocyclic ring, maybe the most stereo-chemically crucial in flavonoid biosynthesis. CHI is a chemically and structurally well-characterized enzyme that creates (2S)-flavanones from chalcones (Figure 3) [14, 35].
General outline of the flavonoid pathway (PAL: Phenylalanine ammonia-lyase, CHS: Chalcone synthase, CHI: Chalcone isomerase, FHT: Flavanone 3β-hydroxylase, FNS Ι: Flavone synthase Ι, FLS: Flavonols synthase, DFR: Dihydroflavonols reductase, ANS: Anthocyanidin synthase). Chiral inversion in flavonoid metabolizes was highlighted by red frame.
Unlike other flavonoid enzymes such as PAL or CHI, the 2-oxoglutarate-dependent dioxygenases flavonol synthase (FLS) and anthocyanidin synthase (ANS) have wide substrate and product selectivities in vitro (both take flavanone, dihydroflavonol, and leucoanthocyanidin as substrates). Prescott et al. have reported a detailed structural and in vitro research on recombinant flavonol synthase from Arabidopsis thaliana, with a focus on the stereochemistry of substrate and product, have provided information on how they catalyze reactions with their real substrates in vivo [36]. FLS and ANS prefer substrates with natural C-2 and C-3 stereochemistry [(i.e. (2R,3R)- dihydroquercetin for FLS and (2R,3S, 4R/S)- leucoanthocyanin for ANS], but hydroxylate both (2R)- and (2S)-naringenin equally well in vitro, indicating that the C-3 hydroxyl group is important in biasing substrate selectivity [37].
The flavan-3-ols (+)-catechin and (−)-epicatechin serve as the foundation for proanthocyanidins (condensed tannins), a family of molecules of great interest due to their effects on animal health [38]. The C-2 and C-3 stereochemistries of (+)-catechin (2,3-trans) are identical to those of flavonoid pathway intermediates, and a pathway leading from (2R, 3S, 4S)-leucoanthocyanidin to (+)-catechin, catalyzed by leucoanthocyanidin reductase (LAR), has been illustrated and affirmed by the cloning of a leucoanthocyanidin reducta [22]. LAR belongs to the Reductase–Epimerase–Dehydrogenase protein family, which also includes isoflavone reductase and similar homologs (Figure 4) [39].
The pro-anthocyanidin pathway showing the LAR reaction.
The process catalyzed by anthocyanidin reductase (ANS) and anthocyanidin reductase (ANR) leads from leucocyanidin to (−)-epicatechin [40]. By operating on an achiral intermediate, ANR, an enzyme with limited sequence similarity to dihydroflavonol reductase, can introduce the 2,3-cis stereochemistry (anthocyanidin). Mechanisms for this reaction have been hypothesized, and it is plausible that more ANR-like enzymes with the potential to introduce different stereochemistries exist (Figure 5) [41].
Pathway for CT biosynthesis placing BAN immediately downstream of ANS.
Chiral inversion is always mediated by enzymes and varies with solvent, pH and temperature. When a molecule has two or more elements of chirality, one of which is configurationally labile, enantiomerization can occur. Many studies have been reported about the chiral compounds inversion such as: evodiamine in Evodia rutaecarpa [42], ephedrine and atropine (Figures 6 and 7) [43].
Structures of (A): (1R,2S)-(−)-ephedrine and (1S,2R)-(+)-ephedrine; (B); (S)-(−)- hyoscyamine and (R)-(+)-hyoscyamine.
Chemical structure of (1a) R-(−)-evodiamine, (1b) S-(+) evodiamine.
Chiral inversion is always mediated by enzymes. One of the most valuable synthetic features of enzymes is their ability to discriminate between enantiomers of racemic substrates [44]. The ratio of stereoisomers is changed mainly by stereospecificity and stereoselectivity of enzymes transformation. The stereoselectivity and stereospecificity of enzymes change dramatically the ratio of drug enantiomers and metabolites enantiomers in biological systems. The enzyme-mediated chiral inversion can be affected by determining expression, substrate affinity and activity of the enzyme. The difference of species and tissue can be different in the rate of the chiral inversion occursion as well as of the routes and mechanisms of inversion [2].
On another hand, the development of strategies that improves the stereoselectivity of enzyme-catalyzed resolutions has been researching. Modification of the substrate, recycling of the product and changing of the reaction conditions are the three most common ways. From now, even enzymes with modest stereoselectivity can be used successfully [44]. Configurational stability depends mainly on the structure and the conditions, especially with solvent, pH and temperature [2].
According to Ngoc Van Thi Nguyen et al. (2013) research, extraction conditions are also can affect the enantiomerization while this study investigated the optimization of the extraction procedure, more specifically the solvent, pH and temperature [42].
In the metabolic chiral inversion research, avoiding spontaneous or chemical racemization of enantiomers is one of the important things [2]. The organic solvent characterism is one other parameter that can significantly interfere with this chiral inversion [45]. The study of Yang SK [46] has shown that racemization half-lives t1/2 of enantiomeric oxazepam were 4.8 min in methanol, while it was 840 min in diethyl ether, and 5000 min in hexane, 4500 min in acetonitrile, etc.
Based on the result of the study of Glass Amanda M. et al. (2012), the data collectively prove that pH has a minute effect on the chiral inversion rate (Figure 8) [48].
Time-dependent changes of D-luciferin substrate. Luciferin racemization under various pHs of 150 mM GTA buffer, under ddH2O, and under a medium was monitored for 12 days. The results are highlighted by colors: pH 5 (purple), pH 6 (blue), pH 7 (orange), pH 8 (wine red), pH 8.5 (green), ddH2O (pink) and DMEM (brown). Even under acidic to neutral conditions, obvious racemization that could not be ignored for long-term experiments were observed. The best condition for inhibiting racemization to maintain D-luciferin optical purity was dissolution in ddH2O [
The pH effect on proton extraction to give the enolate-form of CoA-thioester resulting in chiral inversion [47]. Chiral inversion and sufficient emission intensity were observed at basic pH 8 and 8.9, respectively, whereas only little emission was observed under neutral to acidic conditions.
Enzyme activity is also affected by temperature, which can lead to the chiral inversion efficiency. The research of the effect of temperature on enzyme activity showed that the hydrogen peroxidase activity’s best temperature is 41°C. When this condition is decreased to 37° C, the enzyme activity decreased. Continuing to decrease to 9°C can decrease dramatically the activity of the enzyme. The influence on enzyme flexibility is because of the temperature effect on hydrogen bonds and covalent (Figure 9) [49].
The effect of temperature on enzyme activity [
One of the three majorities of racemic pharmaceuticals are the racemic drugs that only have one eutomer, but the distomer could be transformed into its bioactive antipode by chiral inversion in the body (Table 2) [60].
Plant | Stereoisomer compound | Pharmacological effect | Test model | Ref. |
---|---|---|---|---|
Huperzia serrata | Huperzine A and B | Anticholinesterase activity | Acetylcholinesterase (AChE) inhibitory assay | [50] |
Narcissus jonquilla quail | Jonquailine | Anticancer | Human cancer cell line: A549; OE21; Hs683 U373;SKMEL B16F10 | [51] |
Uncaria rhynchophylla | Speciophylline | Antiplasmodial activity | [52] | |
Isatis indigotica | Isatindigotindoline | Inhibitory effects on β-amyloid aggregation | Thioflavin T (ThT)-binding assay | [53] |
Centaurea maculosa | Trans-flavan-3-ol (+)-catechin | Antibacterial | [54] | |
Citrus fruit | Narirutin, naringin, hesperidin and neohesperidin | Antioxidant | DPPH assy | [55] |
Psidium guajava | Quercetin-3-O-α-L-arabinopyranoside | anti-Streptococcus mutans activity | [56] | |
Rhus retinorrhoea | Persicogenin | Anticancer | MCF-7, HeLa, and HT-29 cells | [57] |
Silybum marianum | Silibinin A and Silibinin B | Anticancer | MDA-MB-468 breast cancer cells of the control mice | [58] |
Leucosceptrum canum | S-(+)- and R-(−)-leucoflavonines | Aticholinesterase activity | Acetylcholinesterase (AChE) inhibitory assay | [59] |
Pharmacologic effect of stereoisomer compound in plant extract.
Based on many studies about unnatural alkaloid enantiomers, and the results reviewed here the pharmacological effect of natural isomers is enantioselective. However, unnatural enantiomers also have a pharmacological effect of their own which can be discovered in the future. Morphinans of the unnatural (+)-series, in contrast to the (−)-series which are chemically connected with natural morphine, were found to be do not have pharmacological effects as analgesics in vivo, instead, presented useful antitussive properties (Figure 10) [62].
Biosynthesis of morphine in plants. * These metabolic conversions are highly stereoselective [
(+)- and (−)-spondomine-racemic and dimeric indole alkaloids have been reported in the study of Tian-Yun Jin (2021) [63], especially, (+)-spondomine displayed cytotoxic against the K562 cell line and exhibited Wnt and HIF1. Moreover, all of them were found to be active in promoted angiogenesis and moderate antiinflammation.
Oleracein E (OE) (8,9-dihydroxy-1,5,6,10b-tetrahydro-2H25 pyrrolo[2,1-a]isoquinoline-3-one), an alkaloid possessing tetrahydroisoquinoline and pyrrolidone skeletons. It was reported to have a lot of pharmacological effects such as: anti-bacterial, anti-inflammatory, anti-aging, anti-hypoxia, anti-oxidant, skeleton-relaxant, hypolipidaemic, analgesic, hypoglycemic, cognition-improvement and neuroprotective functions, especially the optical isomer of (+)-oleracein E (OE) called (−)-trolline has remarkable antibacterial as well as moderate antiviral activity against influenza viruses A and B [64].
According to Blair, Lachlan M. (2016) [65], (−)-Foveoglin A (5) exhibited cytotoxicity against a panel of cancer cell lines, while (+)-isofoveoglin (7) and (−)-cyclofoveoglin (8) were weakly cytotoxic, and (+)-foveoglin B (6) was inactive (Figures 11 and 12).
Aglain and aglaforbesin flavoalkaloids 1–7, 10–12 [
Aglain and aglaforbesin flavoalkaloids 8, 9 [
Characterize the stereoselective pharmacokinetics of pinocembrin and pinostrobin and their bioactivity in some in vitro investigation with relevant roles in heart disease, colon cancer, and diabetes etiology and pathophysiology [66]. These investigations have revealed that chiral differences in the chemical structure of these compounds result in significant pharmacodynamic differences. Pinocembrin and pinostrobin demonstrated concentration-dependent alpha amylase inhibitory activity. While pinocembrin also has anti-inflammatory antioxidant in the pure S-enantiomer and racemate.
Racemic liquiritigenin is proved to be a dose-dependent inhibition of alpha-amylase enzyme whereas its pure enantiomers did not have this bioactivity. Racemic liquiritigenin showed moderate antiproliferative activity on an HT-29 cancer cell line that was also dose-dependent and had inhibitory effects on the cyclooxygenase-2 enzyme [67].
Racemic liquiritigenin, which was dose-dependent, has been proved its moderate antiproliferative activity on a cancer cell line_ HT-29, and inhibitory effects on the cyclooxygenase-2 enzyme [67]. The nature type of naringenin, hesperetin and hesperidin is S - enantiomer, but both R and S enantiomers can have biological activities such as: antitumor, antioxidant and anti-inflammatory [68]. The two enantiomers of equol: R-(+)-equol and S-(−)-equol have been researched in antitumor activity which shown a significant decrease in the number of palpable tumors presented in animals feeding R-(+)-equol compared to the S-(−)-equol’s result (Figure 13).
Chemical structure of daidzein (a) and its metabolites (b and c).
Chiral inversion is always mediated by enzymes and varies with solvent, pH and temperature. Considerable attention should be paid to the mechanism of the inversion reaction and its pharmacological and toxicological results. Recent advances in chiral analysis for the herbal plants in clinical research & forensic toxicology by experiments in which one enantiomer was given to the experiment subjects in a specific situation. Demonstration of metabolic chiral inversion demonstration may give an answer for the development of a new pharmaceutical entity. Understanding more about the factors facilitating such interconversions may considerably aid herbal plant development thanks to this feature determination at an early stage and thereby reducing bioanalytical and toxicology workload.
The authors would like to express their hearty gratitude to Can Tho University of Medicine and Pharmacy. We also thank all of our colleagues for their excellent assistance.
The authors declare no conflict of interest.
IntechOpen aims to guarantee that original material is published while at the same time giving significant freedom to our Authors. We uphold a flexible Copyright Policy, guaranteeing that there is no transfer of copyright to the publisher and Authors retain exclusive copyright to their Work.
',metaTitle:"Publication Agreement - Monograph",metaDescription:"IntechOpen aims to guarantee that original material is published while at the same time giving significant freedom to our authors. For that matter, we uphold a flexible copyright policy meaning that there is no transfer of copyright to the publisher and authors retain exclusive copyright to their work.",metaKeywords:null,canonicalURL:"/page/publication-agreement-monograph",contentRaw:'[{"type":"htmlEditorComponent","content":"When submitting a manuscript, the Author is required to accept the Terms and Conditions set out in our Publication Agreement – Monographs/Compacts as follows:
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\\n\\nPolicy last updated: 2018-09-11
\\n"}]'},components:[{type:"htmlEditorComponent",content:'When submitting a manuscript, the Author is required to accept the Terms and Conditions set out in our Publication Agreement – Monographs/Compacts as follows:
\n\nCORRESPONDING AUTHOR'S GRANT OF RIGHTS
\n\nSubject to the following Article, the Author grants to IntechOpen, during the full term of copyright, and any extensions or renewals of that term, the following:
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\n\nThe Author, on his or her own behalf and on behalf of any of the Co-Authors, reserves the following rights in the Work but agrees not to exercise them in such a way as to adversely affect IntechOpen's ability to utilize the full benefit of this Publication Agreement: (i) reprographic rights worldwide, other than those which subsist in the typographical arrangement of the Work as published by IntechOpen; and (ii) public lending rights arising under the Public Lending Right Act 1979, as amended from time to time, and any similar rights arising in any part of the world.
\n\nThe Author, and any Co-Author, confirms that they are, and will remain, a member of any applicable licensing and collecting society and any successor to that body responsible for administering royalties for the reprographic reproduction of copyright works.
\n\nSubject to the license granted above, copyright in the Work and all versions of it created during IntechOpen's editing process, including all published versions, is retained by the Author and any Co-Authors.
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\n\nAll rights granted to IntechOpen in this Article are assignable, sublicensable or otherwise transferrable to third parties without the specific approval of the Author or Co-Authors.
\n\nThe Author, on his/her own behalf and on behalf of the Co-Authors, will not assert any rights under the Copyright, Designs and Patents Act 1988 to object to derogatory treatment of the Work as a consequence of IntechOpen's changes to the Work arising from the translation of it, corrections and edits for house style, removal of problematic material and other reasonable edits as determined by IntechOpen.
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Several examples taken from scientific journals and monographs are selected dealing with linearity, calibration, heteroscedastic data, errors in the model, transforming data, time‐order analysis and non‐linear calibration curves.",book:{id:"5832",slug:"uncertainty-quantification-and-model-calibration",title:"Uncertainty Quantification and Model Calibration",fullTitle:"Uncertainty Quantification and Model Calibration"},signatures:"Julia Martin, David Daffos Ruiz de Adana and Agustin G. Asuero",authors:[{id:"190870",title:"Dr.",name:"Agustín G.",middleName:null,surname:"Asuero",slug:"agustin-g.-asuero",fullName:"Agustín G. Asuero"},{id:"190871",title:"Dr.",name:"Julia",middleName:null,surname:"Martín",slug:"julia-martin",fullName:"Julia Martín"},{id:"203694",title:"Mr.",name:"David",middleName:null,surname:"Daffos Ruiz De Adana",slug:"david-daffos-ruiz-de-adana",fullName:"David Daffos Ruiz De Adana"},{id:"203695",title:"Mr.",name:"Alberto",middleName:null,surname:"Romero Gracia",slug:"alberto-romero-gracia",fullName:"Alberto Romero Gracia"}]},{id:"55003",title:"Uncertainty Quantification and Reduction of Molecular Dynamics Models",slug:"uncertainty-quantification-and-reduction-of-molecular-dynamics-models",totalDownloads:1439,totalCrossrefCites:2,totalDimensionsCites:5,abstract:"Molecular dynamics (MD) is an important method underlying the modern field of Computational Materials Science. Without requiring prior knowledge as inputs, MD simulations have been used to study a variety of material problems. However, results of molecular dynamics simulations are often associated with errors as compared with experimental observations. These errors come from a variety of sources, including inaccuracy of interatomic potentials, short length and time scales, idealized problem description and statistical uncertainties of MD simulations themselves. This chapter specifically devotes to the statistical uncertainties of MD simulations. In particular, methods to quantify and reduce such statistical uncertainties are demonstrated using a variety of exemplar cases, including calculations of finite temperature static properties such as lattice constants, cohesive energies, elastic constants, dislocation energies, thermal conductivities, surface segregation and calculations of kinetic properties such as diffusion parameters. We also demonstrate that when the statistical uncertainties are reduced to near zero, MD can be used to validate and improve widely used theories.",book:{id:"5832",slug:"uncertainty-quantification-and-model-calibration",title:"Uncertainty Quantification and Model Calibration",fullTitle:"Uncertainty Quantification and Model Calibration"},signatures:"Xiaowang Zhou and Stephen M. Foiles",authors:[{id:"201277",title:"Dr.",name:"Xiaowang",middleName:null,surname:"Zhou",slug:"xiaowang-zhou",fullName:"Xiaowang Zhou"},{id:"205437",title:"Dr.",name:"Stephen M.",middleName:null,surname:"Foiles",slug:"stephen-m.-foiles",fullName:"Stephen M. Foiles"}]},{id:"54841",title:"State‐of‐the‐Art Nonprobabilistic Finite Element Analyses",slug:"state-of-the-art-nonprobabilistic-finite-element-analyses",totalDownloads:1647,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The finite element analysis of a mechanical system is conventionally performed in the context of deterministic inputs. However, uncertainties associated with material properties, geometric dimensions, subjective experiences, boundary conditions, and external loads are ubiquitous in engineering applications. The most popular techniques to handle these uncertain parameters are the probabilistic methods, in which uncertainties are modeled as random variables or stochastic processes based on a large amount of statistical information on each uncertain parameter. Nevertheless, subjective results could be obtained if insufficient information unavailable and nonprobabilistic methods can be alternatively employed, which has led to elegant procedures for the nonprobabilistic finite element analysis. In this chapter, each nonprobabilistic finite element analysis method can be decomposed as two individual parts, i.e., the core algorithm and preprocessing procedure. In this context, four types of algorithms and two typical preprocessing procedures as well as their effectiveness were described in detail, based on which novel hybrid algorithms can be conceived for the specific problems and the future work in this research field can be fostered.",book:{id:"5832",slug:"uncertainty-quantification-and-model-calibration",title:"Uncertainty Quantification and Model Calibration",fullTitle:"Uncertainty Quantification and Model Calibration"},signatures:"Wang Lei, Qiu Zhiping and Zheng Yuning",authors:[{id:"196882",title:"Prof.",name:"Zhiping",middleName:null,surname:"Qiu",slug:"zhiping-qiu",fullName:"Zhiping Qiu"},{id:"198421",title:"Dr.",name:"Lei",middleName:null,surname:"Wang",slug:"lei-wang",fullName:"Lei Wang"},{id:"204754",title:"Dr.",name:"Yuning",middleName:null,surname:"Zheng",slug:"yuning-zheng",fullName:"Yuning Zheng"}]},{id:"55556",title:"An Improved Wavelet‐Based Multivariable Fault Detection Scheme",slug:"an-improved-wavelet-based-multivariable-fault-detection-scheme",totalDownloads:1542,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"Data observed from environmental and engineering processes are usually noisy and correlated in time, which makes the fault detection more difficult as the presence of noise degrades fault detection quality. Multiscale representation of data using wavelets is a powerful feature extraction tool that is well suited to denoising and decorrelating time series data. In this chapter, we combine the advantages of multiscale partial least squares (MSPLSs) modeling with those of the univariate EWMA (exponentially weighted moving average) monitoring chart, which results in an improved fault detection system, especially for detecting small faults in highly correlated, multivariate data. Toward this end, we applied EWMA chart to the output residuals obtained from MSPLS model. It is shown through simulated distillation column data the significant improvement in fault detection can be obtained by using the proposed methods as compared to the use of the conventional partial least square (PLS)‐based Q and EWMA methods and MSPLS‐based Q method.",book:{id:"5832",slug:"uncertainty-quantification-and-model-calibration",title:"Uncertainty Quantification and Model Calibration",fullTitle:"Uncertainty Quantification and Model Calibration"},signatures:"Fouzi Harrou, Ying Sun and Muddu Madakyaru",authors:[{id:"197090",title:"Dr.",name:"Fouzi",middleName:null,surname:"Harrou",slug:"fouzi-harrou",fullName:"Fouzi Harrou"}]}],onlineFirstChaptersFilter:{topicId:"613",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82166",title:"Evaluation of Principal Component Analysis Variants to Assess Their Suitability for Mobile Malware Detection",slug:"evaluation-of-principal-component-analysis-variants-to-assess-their-suitability-for-mobile-malware-d",totalDownloads:10,totalDimensionsCites:0,doi:"10.5772/intechopen.105418",abstract:"Principal component analysis (PCA) is an unsupervised machine learning algorithm that plays a vital role in reducing the dimensions of the data in building an appropriate machine learning model. It is a statistical process that transforms the data containing correlated features into a set of uncorrelated features with the help of orthogonal transformations. Unsupervised machine learning is a concept of self-learning method that involves unlabelled data to identify hidden patterns. PCA converts the data features from a high dimensional space into a low dimensional space. PCA also acts as a feature extraction method since it transforms the ‘n’ number of features into ‘m’ number of principal components (PCs; m < n). Mobile Malware is increasing tremendously in the digital era due to the growth of android mobile users and android applications. Some of the mobile malware are viruses, Trojan horses, worms, adware, spyware, ransomware, riskware, banking malware, SMS malware, keylogger, and many more. To automate the process of detecting mobile malware without human intervention, machine learning methods are applied to discover the malware more precisely. Specifically, unsupervised machine learning helps to uncover the hidden patterns to detect anomalies in the data. In discovering hidden patterns of malware, PCA is an important dimensionality reduction technique that can be applied to transform the features into PCs containing important feature values. So, by implementing PCA, the correlated features are transformed into uncorrelated features automatically to explore the anomalies in the data effectively. This book chapter explains all the variants of the PCA, including all linear and non-linear methods of PCA and their suitability in applying to mobile malware detection. A case study on mobile malware detection with variants of PCA using machine learning techniques in CICMalDroid_2020 dataset has been experimented. Based on the experimental results, for the given dataset, normal PCA is suitable to detect the malware data points and forms an optimal cluster.",book:{id:"11201",title:"Advances in Principal Component Analysis",coverURL:"https://cdn.intechopen.com/books/images_new/11201.jpg"},signatures:"Padmavathi Ganapathi, Shanmugapriya Dhathathri and Roshni Arumugam"},{id:"81645",title:"Determining an Adequate Number of Principal Components",slug:"determining-an-adequate-number-of-principal-components",totalDownloads:11,totalDimensionsCites:0,doi:"10.5772/intechopen.104534",abstract:"The problem of choosing the number of PCs to retain is analyzed in the context of model selection, using so-called model selection criteria (MSCs). For a prespecified set of models, indexed by k=1,2,…,K, these model selection criteria (MSCs) take the form MSCk=nLLk+anmk, where, for model k,LLk is the maximum log likelihood, mk is the number of independent parameters, and the constant an is an=lnn for BIC and an=2 for AIC. The maximum log likelihood LLk is achieved by using the maximum likelihood estimates (MLEs) of the parameters. In Gaussian models, LLk involves the logarithm of the mean squared error (MSE). The main contribution of this chapter is to show how to best use BIC to choose the number of PCs, and to compare these results to ad hoc procedures that have been used. Findings include the following. These are stated as they apply to the eigenvalues of the correlation matrix, which are between 0 and p and have an average of 1. For considering an additional PCk + 1, with AIC, inclusion of the additional PCk + 1 is justified if the corresponding eigenvalue λk+1 is greater than exp−2/n. For BIC, the inclusion of an additional PCk + 1 is justified if λk+1>n1/n, which tends to 1 for large n. Therefore, this is in approximate agreement with the average eigenvalue rule for correlation matrices, stating that one should retain dimensions with eigenvalues larger than 1.",book:{id:"11201",title:"Advances in Principal Component Analysis",coverURL:"https://cdn.intechopen.com/books/images_new/11201.jpg"},signatures:"Stanley L. Sclove"},{id:"81542",title:"On the Use of Modified Winsorization with Graphical Diagnostic for Obtaining a Statistically Optimal Classification Accuracy in Predictive Discriminant Analysis",slug:"on-the-use-of-modified-winsorization-with-graphical-diagnostic-for-obtaining-a-statistically-optimal",totalDownloads:14,totalDimensionsCites:0,doi:"10.5772/intechopen.104539",abstract:"In predictive discriminant analysis (PDA), the classification accuracy is only statistically optimal if each group sample is normally distributed with different group means, and each predictor variance is similar between the groups. This can be achieved by accounting for homogeneity of variances between the groups using the modified winsorization with graphical diagnostic (MW-GD) method. The MW-GD method involves the identification and removal of legitimate contaminants in a training sample with the aim of obtaining a true optimal training sample that can be used to build a predictive discriminant function (PDF) that will yield a statistically optimal classification accuracy. However, the use of this method is yet to receive significant attention in PDA. An alternative statistical interpretation of the graphical diagnostic information associated with the method when confronted with the challenge of differentiating between a variable shape in the groups of the 2-D area plot remains a problem to be resolved. Therefore, this paper provides a more comprehensive analysis of the idea and concept of the MW-GD method, as well as proposed an alternative statistical interpretation of the informative graphical diagnostic associated with the method when confronted with the challenge of differentiating between a variable shape in the groups of the 2-D area plot.",book:{id:"11201",title:"Advances in Principal Component Analysis",coverURL:"https://cdn.intechopen.com/books/images_new/11201.jpg"},signatures:"Augustine Iduseri"},{id:"81460",title:"Spatial Principal Component Analysis of Head-Related Transfer Functions and Its Domain Dependency",slug:"spatial-principal-component-analysis-of-head-related-transfer-functions-and-its-domain-dependency",totalDownloads:15,totalDimensionsCites:0,doi:"10.5772/intechopen.104449",abstract:"In this chapter, the Principal Component Analysis (PCA) was adopted to spatial variation of Head-Related Transfer Function (HRTF) or its corresponding inverse Fourier Transform, called Head-Related Impulse Response (HRIR), in order to compactly represent their spatial variation. This is called the Spatial PCA (SPCA). The SPCA was carried out for a database of HRTFs in all directions by selecting the domain as one of the HRIRs, the complex HRTFs, the frequency amplitudes of HRTFs, log-amplitudes of HRTFs, and complex logarithm of HRTFs. The minimum phase approximation was incorporated for the frequency amplitudes and log-amplitudes of HRTFs. Comparison of the accuracies in both time and frequency domains taking into account their influence on subjective evaluation showed that the log-amplitudes and complex logarithm of HRTFs are suitable for the SPCA of HRTFs.",book:{id:"11201",title:"Advances in Principal Component Analysis",coverURL:"https://cdn.intechopen.com/books/images_new/11201.jpg"},signatures:"Shouichi Takane"},{id:"81407",title:"Space-Time-Parameter PCA for Data-Driven Modeling with Application to Bioengineering",slug:"space-time-parameter-pca-for-data-driven-modeling-with-application-to-bioengineering",totalDownloads:28,totalDimensionsCites:0,doi:"10.5772/intechopen.103756",abstract:"Principal component analysis is a recognized powerful and practical method in statistics and data science. It can also be used in modeling as a dimensionality reduction tool to achieve low-order models of complex multiphysics or engineering systems. Model-order reduction (MOR) methodologies today are an important topic for engineering design and analysis. Design space exploration or accelerated numerical optimization for example are made easier by the use of reduced-order models. In this chapter, we will talk about the use of higher-order singular value decompositions (HOSVD) applied to spatiotemporal problems that are parameterized by a set of design variables or physical parameters. Here we consider a data-driven reduced order modeling based on a design of computer experiment: from high-dimensional computational results returned by high-fidelity solvers (e.g. finite element ones), the HOSVD allows us to determine spatial, time and parameters principal components. The dynamics of the system can then be retrieved by identifying the low-order discrete dynamical system. As application, we will consider the dynamics of deformable capsules flowing into microchannels. The study of such fluid-structure interaction problems is motivated by the use of microcapsules as innovative drug delivery carriers through blood vessels.",book:{id:"11201",title:"Advances in Principal Component Analysis",coverURL:"https://cdn.intechopen.com/books/images_new/11201.jpg"},signatures:"Florian De Vuyst, Claire Dupont and Anne-Virginie Salsac"},{id:"81414",title:"Prediction Analysis Based on Logistic Regression Modelling",slug:"prediction-analysis-based-on-logistic-regression-modelling",totalDownloads:14,totalDimensionsCites:0,doi:"10.5772/intechopen.103090",abstract:"The chapter aims to show an application of logistic regression modelling for prediction analysis in the offshore industry. The different variables shown in dynamic positioning incident reports are analysed and processed using logistic regression modelling. The results of the models are then analysed, showing which data influence the loss of positioning and human errors and how the model can be interpreted. Afterwards, and based on the obtained models, operational limits can be proposed to reduce downtimes and thus improve the safety of the operations and the productivity of the offshore operations when using dynamic positioning systems.",book:{id:"11201",title:"Advances in Principal Component Analysis",coverURL:"https://cdn.intechopen.com/books/images_new/11201.jpg"},signatures:"Zaloa Sanchez-Varela"}],onlineFirstChaptersTotal:12},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:11,numberOfPublishedChapters:91,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:332,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:11,numberOfPublishedChapters:142,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:124,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:22,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:12,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:"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"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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",coverUrl:"https://cdn.intechopen.com/series/covers/23.jpg",latestPublicationDate:"August 17th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:0,editor:{id:"280770",title:"Dr.",name:"Katherine K.M.",middleName:null,surname:"Stavropoulos",slug:"katherine-k.m.-stavropoulos",fullName:"Katherine K.M. Stavropoulos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRdFuQAK/Profile_Picture_2022-05-24T09:03:48.jpg",biography:"Katherine Stavropoulos received her BA in Psychology from Trinity College, in Connecticut, USA and her Ph.D. in Experimental Psychology from the University of California, San Diego. She completed her postdoctoral work at the Yale Child Study Center with Dr. James McPartland. Dr. Stavropoulos’ doctoral dissertation explored neural correlates of reward anticipation to social versus nonsocial stimuli in children with and without autism spectrum disorders (ASD). She has been a faculty member at the University of California, Riverside in the School of Education since 2016. Her research focuses on translational studies to explore the reward system in ASD, as well as how anxiety contributes to social challenges in ASD. She also investigates how behavioral interventions affect neural activity, behavior, and school performance in children with ASD. She is also involved in the diagnosis of children with ASD and is a licensed clinical psychologist in California. She is the Assistant Director of the SEARCH Center at UCR and is a faculty member in the Graduate Program in Neuroscience.",institutionString:null,institution:{name:"University of California, Riverside",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:2,paginationItems:[{id:"89",title:"Education",coverUrl:"https://cdn.intechopen.com/series_topics/covers/89.jpg",isOpenForSubmission:!1,editor:{id:"260066",title:"Associate Prof.",name:"Michail",middleName:null,surname:"Kalogiannakis",slug:"michail-kalogiannakis",fullName:"Michail Kalogiannakis",profilePictureURL:"https://mts.intechopen.com/storage/users/260066/images/system/260066.jpg",biography:"Michail Kalogiannakis is an Associate Professor of the Department of Preschool Education, University of Crete, and an Associate Tutor at School of Humanities at the Hellenic Open University. He graduated from the Physics Department of the University of Crete and continued his post-graduate studies at the University Paris 7-Denis Diderot (D.E.A. in Didactic of Physics), University Paris 5-René Descartes-Sorbonne (D.E.A. in Science Education) and received his Ph.D. degree at the University Paris 5-René Descartes-Sorbonne (PhD in Science Education). His research interests include science education in early childhood, science teaching and learning, e-learning, the use of ICT in science education, games simulations, and mobile learning. He has published over 120 articles in international conferences and journals and has served on the program committees of numerous international conferences.",institutionString:"University of Crete",institution:{name:"University of Crete",institutionURL:null,country:{name:"Greece"}}},editorTwo:{id:"422488",title:"Dr.",name:"Maria",middleName:null,surname:"Ampartzaki",slug:"maria-ampartzaki",fullName:"Maria Ampartzaki",profilePictureURL:"https://mts.intechopen.com/storage/users/422488/images/system/422488.jpg",biography:"Dr Maria Ampartzaki is an Assistant Professor in Early Childhood Education in the Department of Preschool Education at the University of Crete. Her research interests include ICT in education, science education in the early years, inquiry-based and art-based learning, teachers’ professional development, action research, and the Pedagogy of Multiliteracies, among others. She has run and participated in several funded and non-funded projects on the teaching of Science, Social Sciences, and ICT in education. She also has the experience of participating in five Erasmus+ projects.",institutionString:"University of Crete",institution:{name:"University of Crete",institutionURL:null,country:{name:"Greece"}}},editorThree:null},{id:"90",title:"Human Development",coverUrl:"https://cdn.intechopen.com/series_topics/covers/90.jpg",isOpenForSubmission:!0,editor:{id:"191040",title:"Dr.",name:"Tal",middleName:null,surname:"Dotan Ben-Soussan",slug:"tal-dotan-ben-soussan",fullName:"Tal Dotan Ben-Soussan",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBf1QAG/Profile_Picture_2022-03-18T07:56:11.jpg",biography:"Tal Dotan Ben-Soussan, Ph.D., is the director of the Research Institute for Neuroscience, Education and Didactics (RINED) – Paoletti Foundation. Ben-Soussan leads international studies on training and neuroplasticity from neurophysiological and psychobiological perspectives. As a neuroscientist and bio-psychologist, she has published numerous articles on neuroplasticity, movement and meditation. She acts as an editor and reviewer in several renowned journals and coordinates international conferences integrating theoretical, methodological and practical approaches on various topics, such as silence, logics and neuro-education. 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He is currently a professor at the Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU). From 2010 to 2012, he was the dean of the Graduate School of Biomedical Science. Since 2012, he has served as the vice dean of the Graduate School of Medical and Dental Sciences. He has been the director of the IBB since 2020. Dr. Kagechika’s major research interests are the medicinal chemistry of retinoids, vitamins D/K, and nuclear receptors. 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Prof. Emeje’s several international fellowships include the prestigious Raman fellowship. He has published more than 150 articles and patents. He is also the head of R&D at NIPRD and holds a visiting professor position at Nnamdi Azikiwe University, Nigeria. He has a postgraduate certificate in Project Management from Walden University, Minnesota, as well as a professional teaching certificate and a World Bank certification in Public Procurement. Prof. Emeje was a national chairman of academic pharmacists in Nigeria and the 2021 winner of the May & Baker Nigeria Plc–sponsored prize for professional service in research and innovation.",institutionString:"National Institute for Pharmaceutical Research and Development",institution:{name:"National Institute for Pharmaceutical Research and Development",country:{name:"Nigeria"}}},{id:"436430",title:"Associate Prof.",name:"Mesut",middleName:null,surname:"Işık",slug:"mesut-isik",fullName:"Mesut Işık",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/436430/images/19686_n.jpg",biography:null,institutionString:null,institution:{name:"Bilecik University",country:{name:"Turkey"}}},{id:"268659",title:"Ms.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/268659/images/8143_n.jpg",biography:"Dr. Zhan received his undergraduate and graduate training in the fields of preventive medicine and epidemiology and statistics at the West China University of Medical Sciences in China during 1989 to 1999. He received his post-doctoral training in oncology and cancer proteomics for two years at the Cancer Research Institute of Human Medical University in China. In 2001, he went to the University of Tennessee Health Science Center (UTHSC) in USA, where he was a post-doctoral researcher and focused on mass spectrometry and cancer proteomics. Then, he was appointed as an Assistant Professor of Neurology, UTHSC in 2005. He moved to the Cleveland Clinic in USA as a Project Scientist/Staff in 2006 where he focused on the studies of eye disease proteomics and biomarkers. He returned to UTHSC as an Assistant Professor of Neurology in the end of 2007, engaging in proteomics and biomarker studies of lung diseases and brain tumors, and initiating the studies of predictive, preventive, and personalized medicine (PPPM) in cancer. In 2010, he was promoted to Associate Professor of Neurology, UTHSC. Currently, he is a Professor at Xiangya Hospital of Central South University in China, Fellow of Royal Society of Medicine (FRSM), the European EPMA National Representative in China, Regular Member of American Association for the Advancement of Science (AAAS), European Cooperation of Science and Technology (e-COST) grant evaluator, Associate Editors of BMC Genomics, BMC Medical Genomics, EPMA Journal, and Frontiers in Endocrinology, Executive Editor-in-Chief of Med One. He has\npublished 116 peer-reviewed research articles, 16 book chapters, 2 books, and 2 US patents. His current main research interest focuses on the studies of cancer proteomics and biomarkers, and the use of modern omics techniques and systems biology for PPPM in cancer, and on the development and use of 2DE-LC/MS for the large-scale study of human proteoforms.",institutionString:null,institution:{name:"Xiangya Hospital Central South University",country:{name:"China"}}},{id:"40482",title:null,name:"Rizwan",middleName:null,surname:"Ahmad",slug:"rizwan-ahmad",fullName:"Rizwan Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/40482/images/system/40482.jpeg",biography:"Dr. Rizwan Ahmad is a University Professor and Coordinator, Quality and Development, College of Medicine, Imam Abdulrahman bin Faisal University, Saudi Arabia. Previously, he was Associate Professor of Human Function, Oman Medical College, Oman, and SBS University, Dehradun. Dr. Ahmad completed his education at Aligarh Muslim University, Aligarh. He has published several articles in peer-reviewed journals, chapters, and edited books. His area of specialization is free radical biochemistry and autoimmune diseases.",institutionString:"Imam Abdulrahman Bin Faisal University",institution:{name:"Imam Abdulrahman Bin Faisal University",country:{name:"Saudi Arabia"}}},{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/41865/images/system/41865.jpg",biography:"Farid A. Badria, Ph.D., is the recipient of several awards, including The World Academy of Sciences (TWAS) Prize for Public Understanding of Science; the World Intellectual Property Organization (WIPO) Gold Medal for best invention; Outstanding Arab Scholar, Kuwait; and the Khwarizmi International Award, Iran. He has 250 publications, 12 books, 20 patents, and several marketed pharmaceutical products to his credit. He continues to lead research projects on developing new therapies for liver, skin disorders, and cancer. Dr. Badria was listed among the world’s top 2% of scientists in medicinal and biomolecular chemistry in 2019 and 2020. He is a member of the Arab Development Fund, Kuwait; International Cell Research Organization–United Nations Educational, Scientific and Cultural Organization (ICRO–UNESCO), Chile; and UNESCO Biotechnology France",institutionString:"Mansoura University",institution:{name:"Mansoura University",country:{name:"Egypt"}}},{id:"329385",title:"Dr.",name:"Rajesh K.",middleName:"Kumar",surname:"Singh",slug:"rajesh-k.-singh",fullName:"Rajesh K. Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329385/images/system/329385.png",biography:"Dr. Singh received a BPharm (2003) and MPharm (2005) from Panjab University, Chandigarh, India, and a Ph.D. (2013) from Punjab Technical University (PTU), Jalandhar, India. He has more than sixteen years of teaching experience and has supervised numerous postgraduate and Ph.D. students. He has to his credit more than seventy papers in SCI- and SCOPUS-indexed journals, fifty-five conference proceedings, four books, six Best Paper Awards, and five projects from different government agencies. He is currently an editorial board member of eight international journals and a reviewer for more than fifty scientific journals. He received Top Reviewer and Excellent Peer Reviewer Awards from Publons in 2016 and 2017, respectively. He is also on the panel of The International Reviewer for reviewing research proposals for grants from the Royal Society. He also serves as a Publons Academy mentor and Bentham brand ambassador.",institutionString:"Punjab Technical University",institution:{name:"Punjab Technical University",country:{name:"India"}}},{id:"142388",title:"Dr.",name:"Thiago",middleName:"Gomes",surname:"Gomes Heck",slug:"thiago-gomes-heck",fullName:"Thiago Gomes Heck",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/142388/images/7259_n.jpg",biography:null,institutionString:null,institution:{name:"Universidade Regional do Noroeste do Estado do Rio Grande do Sul",country:{name:"Brazil"}}},{id:"336273",title:"Assistant Prof.",name:"Janja",middleName:null,surname:"Zupan",slug:"janja-zupan",fullName:"Janja Zupan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/336273/images/14853_n.jpeg",biography:"Janja Zupan graduated in 2005 at the Department of Clinical Biochemistry (superviser prof. dr. Janja Marc) in the field of genetics of osteoporosis. Since November 2009 she is working as a Teaching Assistant at the Faculty of Pharmacy, Department of Clinical Biochemistry. In 2011 she completed part of her research and PhD work at Institute of Genetics and Molecular Medicine, University of Edinburgh. She finished her PhD entitled The influence of the proinflammatory cytokines on the RANK/RANKL/OPG in bone tissue of osteoporotic and osteoarthritic patients in 2012. From 2014-2016 she worked at the Institute of Biomedical Sciences, University of Aberdeen as a postdoctoral research fellow on UK Arthritis research project where she gained knowledge in mesenchymal stem cells and regenerative medicine. She returned back to University of Ljubljana, Faculty of Pharmacy in 2016. She is currently leading project entitled Mesenchymal stem cells-the keepers of tissue endogenous regenerative capacity facing up to aging of the musculoskeletal system funded by Slovenian Research Agency.",institutionString:null,institution:{name:"University of Ljubljana",country:{name:"Slovenia"}}},{id:"357453",title:"Dr.",name:"Radheshyam",middleName:null,surname:"Maurya",slug:"radheshyam-maurya",fullName:"Radheshyam Maurya",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/357453/images/16535_n.jpg",biography:null,institutionString:null,institution:{name:"University of Hyderabad",country:{name:"India"}}},{id:"418340",title:"Dr.",name:"Jyotirmoi",middleName:null,surname:"Aich",slug:"jyotirmoi-aich",fullName:"Jyotirmoi Aich",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038Ugi5QAC/Profile_Picture_2022-04-15T07:48:28.png",biography:"Biotechnologist with 15 years of research including 6 years of teaching experience. Demonstrated record of scientific achievements through consistent publication record (H index = 13, with 874 citations) in high impact journals such as Nature Communications, Oncotarget, Annals of Oncology, PNAS, and AJRCCM, etc. Strong research professional with a post-doctorate from ACTREC where I gained experimental oncology experience in clinical settings and a doctorate from IGIB where I gained expertise in asthma pathophysiology. A well-trained biotechnologist with diverse experience on the bench across different research themes ranging from asthma to cancer and other infectious diseases. An individual with a strong commitment and innovative mindset. Have the ability to work on diverse projects such as regenerative and molecular medicine with an overall mindset of improving healthcare.",institutionString:"DY Patil Deemed to Be University",institution:null},{id:"349288",title:"Prof.",name:"Soumya",middleName:null,surname:"Basu",slug:"soumya-basu",fullName:"Soumya Basu",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035QxIDQA0/Profile_Picture_2022-04-15T07:47:01.jpg",biography:"Soumya Basu, Ph.D., is currently working as an Associate Professor at Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India. With 16+ years of trans-disciplinary research experience in Drug Design, development, and pre-clinical validation; 20+ research article publications in journals of repute, 9+ years of teaching experience, trained with cross-disciplinary education, Dr. Basu is a life-long learner and always thrives for new challenges.\r\nHer research area is the design and synthesis of small molecule partial agonists of PPAR-γ in lung cancer. She is also using artificial intelligence and deep learning methods to understand the exosomal miRNA’s role in cancer metastasis. Dr. Basu is the recipient of many awards including the Early Career Research Award from the Department of Science and Technology, Govt. of India. She is a reviewer of many journals like Molecular Biology Reports, Frontiers in Oncology, RSC Advances, PLOS ONE, Journal of Biomolecular Structure & Dynamics, Journal of Molecular Graphics and Modelling, etc. She has edited and authored/co-authored 21 journal papers, 3 book chapters, and 15 abstracts. She is a Board of Studies member at her university. She is a life member of 'The Cytometry Society”-in India and 'All India Cell Biology Society”- in India.",institutionString:"Dr. D.Y. Patil Vidyapeeth, Pune",institution:{name:"Dr. D.Y. Patil Vidyapeeth, Pune",country:{name:"India"}}},{id:"354817",title:"Dr.",name:"Anubhab",middleName:null,surname:"Mukherjee",slug:"anubhab-mukherjee",fullName:"Anubhab Mukherjee",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y0000365PbRQAU/ProfilePicture%202022-04-15%2005%3A11%3A18.480",biography:"A former member of Laboratory of Nanomedicine, Brigham and Women’s Hospital, Harvard University, Boston, USA, Dr. Anubhab Mukherjee is an ardent votary of science who strives to make an impact in the lives of those afflicted with cancer and other chronic/acute ailments. He completed his Ph.D. from CSIR-Indian Institute of Chemical Technology, Hyderabad, India, having been skilled with RNAi, liposomal drug delivery, preclinical cell and animal studies. He pursued post-doctoral research at College of Pharmacy, Health Science Center, Texas A & M University and was involved in another postdoctoral research at Department of Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute, Santa Monica, California. In 2015, he worked in Harvard-MIT Health Sciences & Technology as a visiting scientist. He has substantial experience in nanotechnology-based formulation development and successfully served various Indian organizations to develop pharmaceuticals and nutraceutical products. He is an inventor in many US patents and an author in many peer-reviewed articles, book chapters and books published in various media of international repute. Dr. Mukherjee is currently serving as Principal Scientist, R&D at Esperer Onco Nutrition (EON) Pvt. Ltd. and heads the Hyderabad R&D center of the organization.",institutionString:"Esperer Onco Nutrition Pvt Ltd.",institution:null},{id:"319365",title:"Assistant Prof.",name:"Manash K.",middleName:null,surname:"Paul",slug:"manash-k.-paul",fullName:"Manash K. Paul",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/319365/images/system/319365.png",biography:"Manash K. Paul is a scientist and Principal Investigator at the University of California Los Angeles. He has contributed significantly to the fields of stem cell biology, regenerative medicine, and lung cancer. His research focuses on various signaling processes involved in maintaining stem cell homeostasis during the injury-repair process, deciphering the lung stem cell niche, pulmonary disease modeling, immuno-oncology, and drug discovery. He is currently investigating the role of extracellular vesicles in premalignant lung cell migration and detecting the metastatic phenotype of lung cancer via artificial intelligence-based analyses of exosomal Raman signatures. Dr. Paul also works on spatial multiplex immunofluorescence-based tissue mapping to understand the immune repertoire in lung cancer. Dr. Paul has published in more than sixty-five peer-reviewed international journals and is highly cited. He is the recipient of many awards, including the UCLA Vice Chancellor’s award and the 2022 AAISCR-R Vijayalaxmi Award for Innovative Cancer Research. He is a senior member of the Institute of Electrical and Electronics Engineers (IEEE) and an editorial board member for several international journals.",institutionString:"University of California Los Angeles",institution:{name:"University of California Los Angeles",country:{name:"United States of America"}}},{id:"311457",title:"Dr.",name:"Júlia",middleName:null,surname:"Scherer Santos",slug:"julia-scherer-santos",fullName:"Júlia Scherer Santos",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/311457/images/system/311457.jpg",biography:"Dr. Júlia Scherer Santos works in the areas of cosmetology, nanotechnology, pharmaceutical technology, beauty, and aesthetics. Dr. Santos also has experience as a professor of graduate courses. Graduated in Pharmacy, specialization in Cosmetology and Cosmeceuticals applied to aesthetics, specialization in Aesthetic and Cosmetic Health, and a doctorate in Pharmaceutical Nanotechnology. Teaching experience in Pharmacy and Aesthetics and Cosmetics courses. She works mainly on the following subjects: nanotechnology, cosmetology, pharmaceutical technology, aesthetics.",institutionString:"Universidade Federal de Juiz de Fora",institution:{name:"Universidade Federal de Juiz de Fora",country:{name:"Brazil"}}},{id:"219081",title:"Dr.",name:"Abdulsamed",middleName:null,surname:"Kükürt",slug:"abdulsamed-kukurt",fullName:"Abdulsamed Kükürt",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/219081/images/system/219081.png",biography:"Dr. Kükürt graduated from Uludağ University in Turkey. He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals. He is currently working on the protective activity of phenolic compounds in disorders associated with oxidative stress and inflammation.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Dr.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",slug:"md.-faheem-haider",fullName:"Md. Faheem Haider",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329248/images/system/329248.jpg",biography:"Dr. Md. Faheem Haider completed his BPharm in 2012 at Integral University, Lucknow, India. In 2014, he completed his MPharm with specialization in Pharmaceutics at Babasaheb Bhimrao Ambedkar University, Lucknow, India. He received his Ph.D. degree from Jamia Hamdard University, New Delhi, India, in 2018. He was selected for the GPAT six times and his best All India Rank was 34. Currently, he is an assistant professor at Integral University. Previously he was an assistant professor at IIMT University, Meerut, India. He has experience teaching DPharm, Pharm.D, BPharm, and MPharm students. He has more than five publications in reputed journals to his credit. Dr. Faheem’s research area is the development and characterization of nanoformulation for the delivery of drugs to various organs.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/system/329795.png",biography:"Dr. Mohd Aftab Siddiqui is an assistant professor in the Faculty of Pharmacy, Integral University, Lucknow, India, where he obtained a Ph.D. in Pharmacology in 2020. He also obtained a BPharm and MPharm from the same university in 2013 and 2015, respectively. His area of research is the pharmacological screening of herbal drugs/natural products in liver cancer and cardiac diseases. He is a member of many professional bodies and has guided many MPharm and PharmD research projects. Dr. Siddiqui has many national and international publications and one German patent to his credit.",institutionString:"Integral University",institution:null}]}},subseries:{item:{id:"9",type:"subseries",title:"Biotechnology - Biosensors, Biomaterials and Tissue Engineering",keywords:"Biotechnology, Biosensors, Biomaterials, Tissue Engineering",scope:"The Biotechnology - Biosensors, Biomaterials and Tissue Engineering topic within the Biomedical Engineering Series aims to rapidly publish contributions on all aspects of biotechnology, biosensors, biomaterial and tissue engineering. We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics can include but are not limited to: Biotechnology such as biotechnological products and process engineering; Biotechnologically relevant enzymes and proteins; Bioenergy and biofuels; Applied genetics and molecular biotechnology; Genomics, transcriptomics, proteomics; Applied microbial and cell physiology; Environmental biotechnology; Methods and protocols. Moreover, topics in biosensor technology, like sensors that incorporate enzymes, antibodies, nucleic acids, whole cells, tissues and organelles, and other biological or biologically inspired components will be considered, and topics exploring transducers, including those based on electrochemical and optical piezoelectric, thermal, magnetic, and micromechanical elements. Chapters exploring biomaterial approaches such as polymer synthesis and characterization, drug and gene vector design, biocompatibility, immunology and toxicology, and self-assembly at the nanoscale, are welcome. 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