More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
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Our breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
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“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
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Additionally, each book published by IntechOpen contains original content and research findings.
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We are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\n
Simba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\n
IntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\n
Since the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\n
Our breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n
“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\n
Additionally, each book published by IntechOpen contains original content and research findings.
\n\n
We are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n
\n\n
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"189",leadTitle:null,fullTitle:"Novel Applications of the UWB Technologies",title:"Novel Applications of the UWB Technologies",subtitle:null,reviewType:"peer-reviewed",abstract:"Ultra wideband (UWB) communication systems are characterized by high data rates, low cost, multipath immunity, and low power transmission. 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1. Introduction
Parkinson’s disease (PD) is the second most common neurodegenerative disease that affects more than 5 million people, accounting to 1-2 % of the population worldwide. It is characterized by the loss of dopaminergic neurons in the substantia nigra associated with the formation of fibrillar aggregates that are composed of α-synuclein and other proteins [1]. PD is clinical characterized by four major symptoms; tremor, bradykinesia, rigidity and postural instability. Initially PD was considered sporadic, however genetic studies in patients families revealed mutations that are segregating with PD. Nowadays, in addition to environmental factors, mutations within 6 loci (SNCA, LRRK2, PRKN, DJ1, PINK1 and ATP13A2) have been clearly demonstrated to be causative to familial PD [2-4]. Among them, SNCA and LRRK2 mutations cause autosomal dominant forms of PD [5]. Human leucine-rich-repeat kinase 2 (LRRK2) has been found to be thus far the most frequent cause of late-onset PD [6, 7]. The identification of missense mutations in LRRK2 has redefined the role of genetic variation in PD susceptibility. The mutations are found in 5-6 % of patients with familial PD, and also have been implicated with sporadic PD [8]. LRRK2 mutations initiate a penetrant phenotype with complete clinical and neurochemical overlap with idiopathic PD (IPD). Penetrance is age-related, around 75 % mutation carriers showed PD symptoms at the age of 80 [9, 10]. Tremor is more commonly observed in LRRK2 mediated PD compared to IPD [11]. Although dementia and cognitive defects are not frequently present in patients with mutations in LRRK2, LRRK2 does associate with Lewy bodies in IPD and dementia [12-14].
Figure 1.
Domain topology of human LRRK2. The labels show the segregating mutations of LRRK2 in Parkinson\'s disease (green box), cancer associated mutations (blue box) and Crohn\'s disease (yellow box).
LRRK2 belongs to the Roco family of proteins, which constitute a novel family of Ras-like G-proteins that have an unique domain architecture [15]. LRRK2 is a large and complex protein with multiple domains; Armadillo repeats (ARM), Ankyrin repeats (ANK), leucine-rich repeats (LRR), a Ras of complex (Roc), a C-terminal of Roc (COR), kinase domain and WD40 repeats (Fig. 1). Most of the PD mutations are accumulated around the central core of the protein, one is found in the LRR, two in the Roc domain (with multiple substitutions), one in the COR and two in the kinase domain [16, 17]. The multiple disease-linked mutations in LRRK2 represent a unique opportunity to explore the activation mechanism of the protein and its miss-regulation in PD. In this chapter we will focus on the effects of LRRK2 on cellular signalling, the recent progress in elucidating the activation mechanism and discuss possible ways to therapeutically target LRRK2 mediated PD.
2. Cellular function of LRRK2
Although several potential LRRK2 mediated pathways and interaction partners have been identified, yet much about the cellular functions of LRRK2 and LRRK2 mediated progression of PD remains unknown [17]. Below we highlight the evidence for a role of LRRK2 in a wide variety of these cellular pathways and discuss a possible link to other PD-related genes.
2.1. Neurite development, outgrowth and branching
LRRK2 is directly linked to neurite outgrowth. Several studies have shown that primary neurons over-expressing mutant LRRK2 have significantly reduced neurite outgrowth and branching. However, the reported reduction varies and might only be significant in long term culture [18-20]. Adult neurogenesis and neurite outgrowth is impaired in mice overexpressing G2019S LRRK2 in the subventricular zone (SVZ) and hipppocampal denate gyrus [21]. This deficiency of neurite outgrowth can be rescued by inhibiting LRRK2 kinase activity with non-specific or more specific LRRK2 inhibitors, such as staurosporin [20] or G1023 [22], respectively. A recent study analysed LRRK2 expression in neonatal and postnatal mouse embryo and showed that LRRK2 expression can be detected in E10.5 of neural tissue. At the time of neurogenesis, prominent expression is found in the ventricular and SVZ of the telencephalon [23]. LRRK2 is also expressed in adult SVZ, where neural stem cells generate neurons in adult brain [24]. Both R1441G and G2019S LRRK2 impair development of neural stem cells [25-27], whereas LRRK2 deficient cells have increased neurite development [25, 28, 29]. Although the mechanisms are yet to be identified, these data show that LRRK2 is regulating neurite-, and neural development. Interestingly, LRRK2 is not only controlling neurite development via its kinase activity, also the LRRK2 G-domain and protein-protein interaction domains play a direct and important role. Tubulin, ArfGAP1, Rac1 and DVL family proteins bind to and/or are regulated by the G domain of LRRK2 and subsequently modulate the cytoskeleton [30-34]. Wnt signalling is essential for several steps in neural development, including presynaptic assembly, signal transduction at the postsynaptic cleft and adult neurogenesis [35, 36]. Overexpression of Wnt7a or inhibition of the Wnt signalling suppressor GSK3β promotes neuron differentiation and maturation [37, 38]. LRRK2 interacts with both the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) and the downstream DVL proteins, suggesting that LRRK2 might function as a scaffold for Wnt signalling proteins [39].
2.2. Autophagy
It is generally accepted that neurodegenerative diseases are associated with dysregulation of autophagy [40]. Autophagy is the regulated self-degradation of damaged organelle, ubiquitinated proteins and protein aggregates by lysosomes. Autophagy is an adaptive response which is stimulated by stress or unfavourable conditions, such as starvation, accumulation of aggregate-prone proteins, oxidative stress, and infection [41]. Autophagy is a double-edged sword; it can promote cell survival or lead to cell death [42]. Autophagy regulates the removal of protein aggregates, which are a common symptom in neurodegenerative diseases, and thereby promotes cell survival [43-45]. Protein aggregates such as α-synuclein [46], tau [47], and huntingtin [48] are cleared by autophagy. Disruption of the autophagy related genes atg5 or atg7 in mice, results in severe impairment autophagy and neurodegeneration [49, 50]. The purkinje cells of the mutant mice are characterized by axonal dystrophic swelling and degenerate within a few weeks after birth [51, 52]. Mice with conditional knockdown of atg7 gene in the substantia nigra and cerebellum showed age-related loss of dopaminergic neurons and autophagy deficiency dependent accumulation of alpha-synuclein aggregates [53]. Expression of LRRK2 G2019S in retinoic acid differentiating SH-SY5Y neuroblastoma cells results in the accumulation of LRRK2 containing-autophagic vacuoles and shortens neuritic processes. Cells expressing wild-type LRRK2 show a similar but less severe phenotype. Disruption of atg7 and microtubule-associated protein 1A/1B-light chain 3 (lc3) in these LRRK2 mutants completely rescues the phenotype [54]. Co-localization of LRRK2 with p62 and LC3 puncta in autophagic vacuoles is reported for human brain and by several other cell culture studies [55]. Not only overexpression of wildtype and mutant LRRK2 increases accumulation of autophagic vacuoles and the induction of autophagy [56-58], also knocking down LRRK2 activity by either RNAi or with specific LRRK2 inhibitors stimulates autophagy [59]. In addition, LRRK2 activity itself is regulated by macroautophagy and chaperon-mediated autophagy (CMA). LRRK2 inhibits CMA and hinders clearance of α-synuclein by CMA [60]. The complex role of LRRK2 in autophagy is not only playing a role in Parkinson’s disease but has been linked to several other diseases as well (see below).
2.3. Mitochondrial disease
Mitochondrial dysfunction in the pathogenesis of PD has been studied extensively. Although the cellular mechanism remains largely unclear, LRRK2 seems to be important for proper mitochondrial regulation. Some reports suggest that LRRK2 partly localizes in mitochondria and several LRRK2 PD associated mutations results in impaired mitochondrial function [61]. Cells carrying the LRRK2 G2019S mutation display a general uncoupling of the oxidative phosphorylation [62]. The mitochondrial potential and intracellular ATP levels are reduced along with increased oxygen utilization [62]. Also shape and organization of the mitochondria are significantly affected as they appear elongated with an enhanced interconnectivity [63]. The increased kinase activity of LRRK2 G2019S leads to an increased AMP- activated protein kinase (AMPK) level [57]. Since, AMPK is an autophagy regulating protein, its enhanced activity results in an increased number of autophagosomes [57]. High levels of autophagy/ autophagic vacuoles lead, as described above, to a vulnerability and thus retraction and degeneration of neurons, one of the main characteristic features of PD [54]. Several other PD associated proteins, including α-synuclein, Parkin, DJ- 1, PINK1 and HTRA2 [64-66], show similar defects in mitochondria regulation, suggesting that LRRK2 and other PD associated proteins share common pathogenic pathways.
2.4. Common pathways for LRRK2 and other PD-relelated proteins?
Lewy bodies are protein aggregates found in degenerating dopaminergic neurons of PD patients. They are composed of many different proteins, including LRRK2 and α-synuclein [67, 68]. α-synuclein is a small protein (140 amino acids) that is located in presynaptic nerve terminal vesicles, plasma membrane lipid rafts and the nucleus [69-71]. Recent studies show that α-synuclein promotes SNARE-complex assembly [72, 73], and either overexpression or aggregation of α-synuclein interferes with vesicular trafficking [74-76]. Phosphorylation of α-synuclein is critical for aggregation and pathology. Since phosphorylation of α-synuclein serine residue 129 in HEK293T expressing LRRK2 is increased, it was initially proposed that α-synuclein is a direct substrate of LRRK2 [77]. However, phosphorylation of α-synuclein is normal in LRRK2-/- mice [78], suggesting that the rather weak effect of LRRK2 on α-synuclein S129 phosphorylation in cells is most likely indirect. Expression of LRRK2 and α-synuclein is co-regulated; increase of α-synuclein in mouse striatum results in increased LRRK2 transcription [79]. Both LRRK2 and α-synuclein interact with Rab5, which is important for vesicle trafficking [80, 81], suggesting LRRK2 and α-synuclein might share common pathways. Recessive mutations of Parkin, PINK1 and DJ-1 are causative to PD [82]. PTEN-induced kinase 1 (PINK1) is important for mitochondrial function and its deletion leads to increased susceptibility to oxidative stress [83, 84]. PINK1 is a cytosolic serine/threonine kinase under steady-state condition and its mitochondrial localization is stabilized by decreased mitochondrial membrane potential, an indicator of damaged mitochondria [85]. Parkin is an E3 ubiquitin ligase, which is phosphorylated and recruited to mitochondria by PINK1. The activated Parkin and PINK1 in conjugation clear damaged mitochondria via selective degradation and autophagy [85]. Co-expression of Parkin and LRRK2 G2019S in flies protects rotenone-induced neurodegeneration of dopaminergic neurons [86]. Expression of LRRK2 PD mutants in pink1-null flies enhances the phenotype [87]. In human cells, LRRK2 is found to interact with Parkin, and co-expression of the two proteins increases LRRK2 containing aggregates. Altogether, this suggests that LRRK2 and PINK1/Parkin pathway are using similar pathways for the regulation of mitochondrial function. DJ-1 is a redox sensitive protein that is linked to a large variety of function, for example Ras-dependent cell transformation, neuroprotection, transcription, apoptosis suppression, P53 signalling, chaperon and protease [88]. It protects neurons from oxidative stress, by scavenging mitochondrial peroxide through oxidation of cysteine residues, and by binding metal ions like mercury and copper [89]. In cells that are exposed to oxidizing agents and mouse brains treated with rotenone, DJ-1 converts to more acidic isoforms [90, 91]. DJ-1 deficient cells, including cell lines and primary neurons, display altered mitochondrial morphology and an increase in autophagic flux [92]. PINK1 and Parkin overexpression can rescue the mitochondrial morphology of dj-1-null cells, but vice versa DJ-1 cannot rescue the defects of PINK1 and Parkin mutants. However, DJ-1 can protect PINK1 deficient neurons from oxidative stress induced by rotenone, suggesting DJ-1 may act both upstream and parallel to the PINK1/Parkin pathway [93]. In comparison to PINK1/Parkin, LRRK2 shows a less direct relation with DJ-1, albeit it still clearly exacerbate the eye phenotype of DJ-1 overexpression / loss in Drosophila [87]. As described previously, LRRK2 is important for autophagy in neurons, thus it is tempting to speculate that LRRK2 plays a role together with PINK1/Parkin and DJ-1 in regulating mitochondrial homeostasis.
2.5. LRRK2 and other diseases
Mutations in LRRK2 have been linked to several other diseases, including Crohn’s disease and cancer. Carriers of LRRK2 G2019S mutation have an increased risk of non-skin cancer [94, 95]. Knock-down of LRRK2 in different cancer cell lines by RNAi, results in decreased stability of the 4E-BP1 protein [96]. Stability of 4E-BP1 protein is dependent on its phosphorylation state; it is a known downstream target of mTOR, inhibition of mTOR leads to accumulation of dephosphorylated 4E-BP and blocks cell transformation in a Kaposi’s sarcoma model [97]. The PI3K/mTOR pathway is very frequently dysregulated in human cancer [98]. Previously, 4E-BP was identified as a direct LRRK2 kinase substrate (see section 3.3), suggesting LRRK2 might play a role in regulating 4E-BP stability and thus the oncogenic PI3K/mTOR pathway.
Genome wide association studies linked LRRK2 mutations to Crohn’s disease (CD) and leprosy [99, 100]. CD associated mutations in the LRRK2 locus are located in non-coding regions, with an exception of the polymorphism rs3761863, which is leading to M2397T substitution in the WD40 repeats of LRRK2 [99]. CD is a chronic inflammatory disorder which primarily affects the gastrointestinal tract. Patients with CD have defective macrophages and neutrophils, resulting in a deficient innate immunity [101, 102]. LRRK2 is widely expressed in many organs and tissue, including brain, kidney and spleen. In the spleen, LRRK2 is highly expressed in CD19+ B cells, whereas lower expression was detected in CD4+ or CD8+ T-cells, macrophages, and monocytes [103, 104]. In macrophages, LRRK2 expression is induced by activation of Toll-like receptors and viral transduction [103]. CD patients exhibit high concentrations of proinflammatory cytokines, including interferon-γ (IFN- γ), which induces LRRK2 expression in macrophages [105]. In cell-based reporter studies, LRRK2 is found to activate NFκB and inhibit NFAT, which both are important transcription factors in the immune system [103, 106]. Interestingly this effect is independent of LRRK2 kinase activity, since expression of both wildtype and kinase dead LRRK2 result in a similar phenotype.
3. Intramolecular LRRK2 activation mechanism
LRRK2 has two bona-fide enzymatic activities from its Roc and kinase domain. It has been shown that both a functional Roc G-domain and kinase are essential for the pathogenicity of LRRK2. Importantly, several of the pathogenic mutations in LRRK2 result in decreased GTPase activity and enhanced kinase activity, suggesting a possible PD-related gain of abnormal function [107-109]. However the exact molecular mechanisms by which these mutations enhance LRRK2 catalytic activity are not completely resolved so far. Because of the lack of sufficient high quality recombinant LRRK2 protein, important understanding of the complex regulatory mechanism of LRRK2 has come from work with related Roco family proteins.
3.1. Homologous Roco proteins as model to study the mechanism of LRRK2 mediated PD
Roco proteins constitute a novel family of complex Ras-like GTPases that have an unique domain architecture [15]. Roco proteins are characterized by the presence of a Ras-like Guanine nucleotide binding domain, called Roc (Ras of complex proteins), followed by a COR domain (C-terminal of Roc), a conserved stretch of 300-400 amino-acids with no significant homology to other described protein domains (Fig. 2). The Roc and COR domains always occurs as a pair and so far no proteins are identified containing either the Roc or COR domain alone, suggesting that these two domains might function as one inseparable unit. Roco proteins were first identified in the social amoeba Dictyostelium discoideum and are found in prokaryotes, plants and metazoa, but not in Plasmodium and yeast. Based on domain topology, the family of Roco proteins can be divided into three groups, each containing at least one mammalian member. The first group is found in mammals (MASL1), plants and in prokaryotes. These proteins contain besides a Roc and COR domain always a N-terminal stretch of leucine-rich repeats (LRR), which are supposed to be involved in protein-protein interaction. The second group of Roco proteins is present in Dictyostelium and metazoa. In these proteins the Roc domain is again preceded by LRRs and the COR domain always succeeded by a kinase domain of the MAPKKK subfamily of kinases. A subset of Roco proteins contains the metazoan tumour suppressor death-associated protein kinases (DapK) domain, which is found in many proteins with apoptotic function [110]. Although there is a high variation in additional regulatory domains among the Roco proteins, previous studies have shown that the function and regulation of the catalytic core is conserved.
Figure 2.
Domain architecture of the Roco family of proteins. The domains are leucine-rich repeat (LRR), Ras in complex domain (Roc), C-terminal of Roc domain (COR), ankyrin repeat (ANK), Kinase domain (Kinase), WD40 repeats (WD), armadillo repeat (ARM), Rho guanine nucleotide exchange factor domain (RhoGEF), Pleckstrin domain (PH), Dishevelled, Egl-10 and Pleckstrin domain (DEP), Rho GTPase activating protein domain (RhoGAP), Kelch motif (K), regulator of G protein signalling domain (RGS), N-terminal motif of RasGEF (N-GEF), Ras guanine nucleotide exchange factor domain (RasGEF), cyclic nucleotide binding domain (cNB), glucosyltransferases, Rab-like GTPase activators and myotubularins domain (GRAM), N-terminal myotubulin-related domain (myotub), protein tyrosine phosphatase domain (PTP) and death domain (DD).
Figure 3.
LRRK2 function and inhibition experiment with Dictyostelium cells. Wild-type, roco4-null and roco4-null cells expressing Roco4-LRRK2 kinase in which the kinase domain of Roco4 has been replaced with the kinase domain of LRRK2, were allowed to develop for 48 hours on nutrient-free agar. Pieces of agar were excised and photographed from the side. roco4-null cells fail to make a normal fruiting body due to defective synthesis of cellulose. The right panel shows a side view of the development of wild-type cells in the presence of the LRRK2-inhibitor H1152. Cells in the presence of 0.5 mM H1152 have the typical roco4-null phenotype. Figure modified with permission from Proc. Natl. Acad. Sci. USA, (Gilsbach et al., 2012).
3.2. Dictyostelium Roco proteins to study the LRRK2 activation mechanism
Dictyostelium discoideum is a social, soil- dwelling amoeba that feeds on bacteria. The organism is genetically tractable with the ease of making gene disruptions and inducible expression, and at the same time it can be grown to large quantities for biochemical analyses [111]. Most importantly, many key pathways are conserved between Dictyostelium and human. Therefore, Dictyostelium offers unique advantages for studying fundamental cellular processes, as well as the molecular causes of human diseases [112]. Although Dictyostelium neither has a brain nor muscle, it is, as described below, an excellent model to study the molecular basis of LRRK2-mediated PD.
Dictyostelium contains eleven Roco family members, that all belong to the second subgroup of the Roco family. They are sharing the characteristic Roc, COR and kinase domains and in addition most also have LRR (Fig. 2, [15]). Dictyostelium Roco proteins are structurally more varied than the Roco proteins found in all the other species together; various domains are additionally fused to the conserved region. Roco proteins are most likely the result of recent gene duplications, and are very homologous to mammalian LRRK2 [113]. Disruption of Dictyostelium Roco genes leads to very different phenotypes, indicating that they are involved in multiple cellular processes. They participate in processes as diverse as chemotaxis, cell division, osmotic-stress-response and development [114]. The strong and diverse phenotypes of the Dictyostelium Roco disruption mutants therefore provide a strong tool to investigate the activation mechanisms of Roco proteins. Especially the studies with Dictyostelium Roco4 gave mechanistic insight into the regulation of LRRK2 [114, 115]. Dictyostelium Roco4 has the same domain architecture as LRRK2, but in contrast to LRRK2, Roco4 is biochemically and structurally more tractable [115]. Roco4 plays an important role in the late development stage of Dictyostelium [114]. During the vegetative growth stage, single Dictyostelium cells feed on bacteria and divide by simple mitotic divisions. In times of starvation, a developmental program is initiated, which is accompanied by major changes in gene expression. As a result, single cells are able to form aggregates via cAMP- dependent chemotaxis, resulting in the development of mobile multicellular forms, called slugs [111]. Eventually, the slugs will permanently settle down, culminate and generate fruiting bodies, which consist of a cellulose containing stalk and basal disc and end in a spore head [116]. Single cell amoebae are embedded in the spore head, which are resistant to extreme temperatures or drought and can be released upon germination under more favourable environmental conditions [111]. Cells lacking roco4 undergo the characteristic streaming, aggregating and mound forming phases, however after 12 hours of starvation the cells start to display severe developmental defects. The formation of slugs and subsequent stalks and spore heads is severely delayed; 72 hours in the mutant cells, compared to 24 hours in wild-type [114]. Furthermore, roco4-null cells display aberrant fruiting body morphology as the spore heads are located on the agar surface due to a reduced cellulose level and thus instable stalks (Fig. 3, second panel). The strong developmental phenotype of roco4-null cells was used to determine essential structural elements in the protein. Remarkably, this phenotype can completely be rescued by expression of a chimeric Roco4 protein, in which its kinase domain has been replaced with the LRRK2 domain (Fig. 3, third panel) [115]. Furthermore, Roco4 kinase activity is inhibited by LRRK2 inhibitors (Fig. 3, right panel), and LRRK2 phosphorylates specific developed artificial substrates for LRRK2 in vitro [115, 117]. This shows that Roco4 has properties very much resembling those described for LRRK2, indicating that Roco4 protein thus can serve as a valid model to understand the complex structure and regulatory mechanism of LRRK2.
3.3. LRRK2 kinase activity
Protein kinases catalyze the transfer of γ-phosphate of ATP to the hydroxyl group of serine/threonine/tyrosine in peptide substrates. Due to the simplicity, stability, and reversibility, protein phosphorylation is chosen by nature for modulating protein functions. Phosphorylation allows specific and dedicated control over enzymatic activities, regulation of protein localization and the transition between the ordered and disordered states of proteins [118]. Therefore, protein kinases are essential for many biological processes such as energy metabolism, cell cycle progression, transcription and cytoskeleton rearrangement. There are more than 500 protein kinases identified in the human genome, of which the majority are serine/threonine kinases, a much smaller amount is tyrosine specific and a trace amount are atypical kinases [119].
LRRK2 kinase activity is extensively studied since its discovery, and it is found to be essential for neuronal toxicity induced by PD mutant of LRRK2 [120, 121]. LRRK2 and Roco proteins are serine/threonine specific kinases. Previously the structures of Roco4 kinase wild-type and the PD-related mutants G1179S and L1180T (G2019S and I2020T in LRRK2) were solved [115]. Like almost all kinases, Roco4 consists of a canonical, two-lobed kinase structure, with an adenine nucleotide located in the conventional nucleotide binding site [118, 122]. The N-terminal lobe is smaller, which is composed of an anti-parallel β-sheet and the large conserved αC-helix. It is followed by a linker connecting the larger C-terminal lobe, which is composed predominantly of α-helices and is containing the activation loop with the conserved DFG motif at the N-terminus [115]. The ATP binding pocket is located between the N- and C-terminal lobes and forms together with the activation segment and αC-helix the catalytic site of the kinase. In its inactive (dephosphorylated) form, the activation segment of Roco4 is disordered, and not visible in the crystal structure. In the active (phosphorylated) conformation, the αC-helix is ordered and packs against the N-terminal lobe. This conformational change between the active and inactive conformation is conserved between most kinases, and often dependent on autophosphorylation of the activation loop [118, 122-124]. In vitro kinase and in vivo rescue experiments showed that Roco4 S1187 and S1189 are essential for regulating Roco4 kinase activity. Autophosphorylation is well demonstrated in LRRK2 by numerous studies. LRRK2 contains with T2031/S2032/T2035 three potential phosphorylation sites in the activation loop. Studies using phosphospecific antibodies have shown that all three sites are phosphorylated, but like for Roco4, only the two later sites, S2032 and T2035, are important for LRRK2 activity in vivo [125]. Most other autophosphorylation sites are located in the Roc domain and kinase domain, such as S1292, T1348, T1349, T1357, T1503, T1967, T1969 [22, 126, 127]. Mutations of these residues significantly affect the enzymatic activities of LRRK2. Importantly, mutating S1292 to alanine [22] or inhibiting kinase activity with inhibitors, completely rescues neurite outgrowth in LRRK2 PD mutants. This suggests that LRRK2 kinase activity is important for both the intramolecular activation mechanism, as well, for downstream signalling. Several putative LRRK2 kinase substrates have been identified so far. LRRK2 phosphorylates 4E-BP [128] and FoxO and thereby modulates their translation and transcription activities. However, the relevance of 4E-BP phosphorylation by LRRK2 for the progression in PD is still under debate [129-131]. Phosphorylation of FoxO induces expression of the pro-apoptotic Bcl-2 protein, Bim, and the endogenous caspase-8 inhibitor, c-FLIP, leading to programmed cell death [132-134]. Therefore, FoxO may be one of the missing links between LRRK2 and cell death in neurons. [135]. Several LRRK2 substrates are linked to cytoskeleton remodelling; moesin promotes actin rearrangement in neurons [136, 137], and β-tubulin and tubulin-associated tau are important for neurite outgrowth and axonal transport [138-140].
3.4. Mechanism of increased kinase activity in LRRK2 PD mutants
The most prevalent PD mutation in the kinase domain is G2019S, which enhances kinase activity, while the PD-related mutation I2020T shows a slightly decreased activity [108, 109, 117, 121, 141]. Recently the molecular mechanism by which the G2019S mutation enhances LRRK2 was resolved using Dictyostelium Roco4. The LRRK2 G2019 and I2020 residues are conserved in Dictyostelium Roco4 and correspond to G1179 and L1180, respectively. Overlay of the solved Roco4 wild-type and the Roco4 G1179S structure didn’t show large differences in the overall structure, however closer observation revealed that S1179 makes a new hydrogen bond with R1077, thereby presumably stabilizing the activation loop and the αC-helix in their active conformation. R1077 is conserved in almost all Roco proteins and corresponds to LRRK2 R1918. Kinase activity measurement with the Roco4 double mutant G1179S/R1077A and the homologous LRRK2 double mutant G2019S/R1918A, in which the new hydrogen bond is no longer possible, confirmed the proposed mechanism since it shows wild type kinase activity [115].
The structure of the PD-related mutant L1180T showed that the T1180 side-chain points into the solvent and revealed that it is most likely not directly involved in regulating kinase activity. Importantly, the data show that the PD-related effect of LRRK2 mutations result from different defects in the LRRK2 activation mechanism and suggest that different LRRK2 mutations such as S2019 and T2020 might require different ways of inhibition for the purpose of drug development [115, 142].
3.5. The RocCOR tandem
The Roc domain of LRRK2 belongs to the family of small G-proteins. G-proteins are GTP binding proteins which switch between an active GTP- and inactive GDP-bound state. The G-domain has an universal switch mechanism that carries out the basic function of nucleotide binding and hydrolysis [143]. The universal switch mechanism between the inactive GDP and active GTP form often consist of only small structural changes in the so called switch regions [144]. Although, the two nucleotide-bound states have only a slightly different conformation, only the GTP-bound conformation possesses high affinity for effector proteins [145]. In Roco family members the G-domain always occurs in tandem with the COR domain. Studies with both LRRK2 and Dictyostelium Roco4 revealed that a functional Roc domain is essential for kinase activity, the COR domain functions as the dimerization device and disruption of Roc or the kinase domain by a single point mutation leads to the complete inactivation of the protein. These suggest that the Roc-COR tandem is regulating kinase activity and/or that the kinase is regulating the activity of Roc by autophosphorylation [146]. The cycle of “classical” small G-protein is strictly controlled by GEFs (Guanine nucleotide Exchange Factors), which catalyze the exchange from GDP to GTP, and the intrinsic low GTP hydrolysis rate is increased by GAPs (GTPase Activating Proteins) [147]. It is well established that LRRK2 and other Roco proteins are active as a dimer ([148-150], see also below). The previously solved structure of the Roco protein from the bacteria Chlorobium tepidum, revealed that COR is the dimerization device and that Roco proteins, including LRRK2, belong to the GAD class of molecular switches (G proteins activated by nucleotide dependent dimerization) [149, 151]. This class also includes proteins such as signal recognition particle, dynamin and septins [151]. It is proposed that the juxtaposition of the G domains of two monomers in the complex across the GTP-binding sites activates the GTPase reaction and thereby regulates the biological function of these proteins (Fig. 4). Since GTPase activity is regulated within the dimer complex, GTP hydrolysis by Roco proteins is not regulated by GAP’s. LRRK2 and Roco proteins have a much lower affinity (μM range) compared to other small G-proteins (nM range), and therefore most likely do not need GEFs for activation [149, 152]. The PD-related mutations, R1441C/G/H in the Roc domain and Y1699C in the COR domain, do not affect nucleotide binding, but significantly decrease GTPase activity [153, 154]. Importantly, the structure of the Chlorobium tepidum Roco protein showed that the PD-analogous mutations of the Roc and COR domain are in close proximity to each other at the dimer interface. Furthermore, these mutations are present in a region of the protein that is strongly conserved between bacteria, Dictyostelium and man. PD-mutations in the Chlorobium tepidum protein, like that of LRRK2, decrease the GTPase reaction, most likely due to altered interaction in the dimer between the Roc and COR domains [149].
3.6. Function of the N-terminus of LRRK2
The N- terminal part of LRRK2 consists of Armadillo repeats (ARM), Ankyrin repeats (ANK), and leucine-rich repeats (LRR) (Fig. 1). All these domains are commonly found in signalling proteins, in which they have a role in protein-protein interaction or assembly of large protein complexes [155]. The N-terminal segment of LRRK2 is most likely involved in regulating activity and/or localization. ARM are approximately 40 amino acid long tandem repeated sequences that form superhelix of helices. ANK consist of seven structural repeats, each repeat forms two anti-parallel helices ending with a loop or hairpin [156, 157]. LRR are defined by an 11 amino acid long consensus sequence LxxLxLxxNxL, where leucine can be replaced by isoleucine, valine or phenylalanine [155]. The LRRK2 LRR domain is composed of 13 repeats, allowing the formation of its characteristic horseshoe shaped structure due to parallel lining β- sheets with ending α- helices [139, 158, 159]. The LRR domain of LRRK2, and Dictyostelium Roco4, are not involved in Roc or kinase activation in vitro, but are absolutely essential for activity of the protein in vivo [160, 161]. Recent data suggest that the LRR are directly involved in determining input/output specificity of the Roco proteins, most likely by binding upstream proteins that activate specifically the Roco protein and/or by selectively binding of the substrate (AK unpublished data). Previously, it has been shown that 14-3-3 proteins bind to the N-terminus of LRRK2 [25]. 14-3-3 are highly conserved proteins that have been found in a variety of organisms, including mammals, plants, yeast, Drosophila, and Dictyostelium [162, 163]. In human, the 14-3-3 protein family consists of 7 structural similar yet distinct isoforms: α, β, γ, δ, ε, ζ, η [162]. The proteins exist as homo- or functional active heterodimers and are important for various signalling pathways, including neurotransmitter synthesis in mammalian brain tissue, via direct ligand binding [163, 164]. Interaction of 14-3-3 with LRRK2 is dependent on the phosphorylation of two conserved serine residues (S910, S935), situated at the N- terminal part of LRRK2 anterior to the LRR domain [158]. Since several LRRK2 specific kinase inhibitors abolish 14-3-3 binding, it is proposed that the binding is regulated by auto-phosphorylation [165, 166]. However, other studies suggest that LRRK2 interaction is dependent on a so far unidentified upstream kinase [167]. Disrupted phosphorylation of the serine residues results in strong defects in LRRK2 signalling; the protein is delocalized and accumulates in inclusion like bodies instead of being transported to the cell membrane [158, 166]. Interestingly, pathogenic PD mutants of LRRK2 display a similar dysfunctional phenotype, suggesting a direct link between LRRK2 and 14-3-3 signalling.
3.7. WD40 domain at the C-Terminus of LRRK2
LRRK2 contains a C-terminal WD40 domain. It comprises seven repeats each of which consists of antiparallel, four stranded β- sheets resulting in a circular propeller-like structure. WD40 repeats have a high positive net charge and several hydrophilic surfaces, and are therefore often involved in membrane binding and interaction with negatively charged proteins [157]. Two non-conserved mutations which are suggested to be involved in the onset of PD are found in the WD40 domain of LRRK2: G2385R and T2356I [157]. A yeast-two hybrid screen showed a direct interaction of WD40 repeats with the Roc domain [168]. In addition, LRRK2 lacking the WD40 domain has abolished abilities to form dimers, displays impaired activity and localization [169]. Together these results suggest an important role for the WD40 domain in the intramolecular regulation of LRRK2 activity.
Figure 4.
Proposed model for the function and activation mechanism of LRRK2.
3.8. LRRK2/Roco activation model
We have translated all biochemical, genetic and structural data into a model for the regulatory mechanism of LRRK2 (Fig. 4). LRRK2 is monomeric and inactive in the cytosol, but attains pre-dominantly dimeric and in the active state at the membrane [150]. These results suggest that LRRK2 cycles between a low activity monomeric state and high activity dimeric state. The previously solved structure of the Roco protein from Chlorobium tepidum revealed that COR is the dimerization device and that Roco proteins belong to the GAD class of molecular switches. In the GDP-bound inactive state the G-domains are flexible, but in the active form the G-domains come in close proximity to each other. This conformational change is transmitted to the kinase domains to allow the activation loops of the two kinase protomers to be autophosphorylated and activated. The GTPase reaction is also dependent on dimerization, because efficient catalytic machinery is formed by complementation of the active site of one protomer with that of the other protomer. In this way the GTPase reaction functions as a timing device for the activation of the kinase and the biological function of the protein. Consistently, PD-related mutations have reduced GTPase activity and enhanced kinase activity (MS in preparation, [16]). The N- and C- terminal segments are not important for kinase activity in vitro, but appear to be essential in vivo [114, 160, 161] and most likely determine the input and/or output specificity of the proteins. One of these upstream regulators might be 14-3-3, which binds in a phosphorylation dependent way to the N-terminal segment of LRRK2, thereby regulating its subcellular localization and secretion in exosomes [158, 170, 171].
4. Therapeutic targeting LRRK2
The multiple allosteric and enzymatic functions within one protein make LRRK2 an excellent therapeutic target (Fig. 5). Below we highlight the recent progress in identifying LRRK2 kinase inhibitors and discuss alternative ways of targeting LRRK2-mediated PD-disease.
Figure 5.
Strategies of LRRK2 inhibition.
4.1. LRRK2 kinase as a therapeutic target
Kinases are one of the most potent classes of drug targets and have been effectively used in the treatment of cancer, immunological, neurological and infectious diseases [172]. The majority of inhibitors directly target the ATP binding site. They are divided into three groups; most of the inhibitors reported are type I inhibitors, which target the active conformation and directly compete with ATP for the binding pocket. Type II inhibitors also bind in the ATP binding pocket resulting in a change from the active DFG-in into an inactive DFG-out conformation. Type III inhibitors directly target the DFG – out conformation. One of the approved kinase inhibitors for renal cell carcinoma treatment is Sunitinib (Sutent(®), Pfizer Inc.). It is a tyrosine kinase inhibitor which has several targets and inhibits tumor cell proliferation, and angiogenesis [173]. LRRK2 kinase activity is critically linked to clinical effects, and the most prevalent PD mutation, LRRK2 G2019S in the kinase domain, enhances kinase activity by 2-4 folds [108, 141]. Therefore LRRK2 kinase inhibitors are an intensively pursued class of drug targets. Several non selective inhibitors were found to inhibit LRRK2 with their IC50 values in nanomolar range, including staurosporin, K252A and Su-11248 (Sunitinib) [141, 174]. Several ROCK inhibitors have also been found to inhibit LRRK2 with similar efficiencies (low micromolar range), such as isoquinolinesulfonamides hydroxyfasudil and H1152, and the structurally unrelated Y-27632. Noteworthy, not all ROCK inhibitors inhibit LRRK2; isoquinolinesulfonamides do not inhibit LRRK2 as effective as ROCK and the aminofurazan ROCK inhibitor GSK269962A cannot inhibit LRRK2 [175]. Despite a high degree of conservation in the ATP binding site of kinases, it is possible to develop highly selective kinase inhibitors [172]. LRRK2-IN-1 is the first one discovered by compound-centric high throughput library screening [165]. It inhibits both wild-type (IC50 = 13 nM) and G2019S mutant (IC50 = 6 nM) of LRRK2, and shows high selectivity. Among a panel of 442 kinases, only 12 kinases were inhibited, with up to 10 µM of LRRK2-IN-1. LRRK2-IN-1 also inhibits LRRK2 activity in human cells, however dephosphorylation of LRRK2 can only be observed in the kidney and not in the brain of the mice received intraperitoneal injection of the inhibitor, suggesting that this potent and selective LRRK2 inhibitor is incapable of crossing the blood brain barrier [165].
The recently identified LRRK2 inhibitors, HG-10-102-01 [176] and GNE-7915 [177] are selective and brain penetrant [178]. However, long-term inhibition of LRRK2 with these inhibitors leads, similar to disrupting LRRK2 in mice, to kidney abnormality [179-181]. Developing kinase inhibitors specific to PD mutants of LRRK2, not affecting wild-type, might therefore be the most promising approach. The previous solved structure of the Roco4 kinase PD mutant and Roco4 kinase in complex with the LRRK2 inhibitor H1152 might be instrumental in this process [115]. Although current available LRRK2 kinase inhibitor can not be used for PD treatment yet [178], they provide an excellent tool to study PD in vitro and in vivo and form a good starting point to develop better PD drugs.
4.2. Alternative therapeutic approaches
Although most attention has concentrated on targeting LRRK2 kinase activity so far, only for the G2019S consistently an increased kinase activity has been reported. All other pathogenic mutations show inconsistent-, modest- or no effect on kinase activity. This suggests that different PD mutations in LRRK2 have a different defect in the activation mechanism and might require different ways of inhibition for the purpose of drug development (Fig. 5). The LRRK2 mutations in the Roc (R1441C/G/H), and COR (Y1699C) domain have a decreased GTPase activity [153, 154], suggesting GTPase activity forms a good therapeutic target. Since Ras is the most common oncogene in human cancer, many studies have focussed on identifying Ras inhibitors. Targeting the G-domain could be done by using small compounds that bind to the nucleotide binding site and resemble the GDP bound off state or increase the GTPase reaction. Due to the high nucleotide affinity and the high cytosolic concentration, it has been very challenging to identify a therapeutic target of Ras. However, since LRRK2 has a much lower nucleotide affinity and the GTPase activity is regulated by dimerization, the LRRK2 G-domain may provide a better therapeutic target.
The N- and C-terminal segments of LRRK2 contain several protein-protein interaction domains which are involved in regulating kinase activity, oligomerization, and/or localization (Fig 5). As described above, LRRK2 cycles between a low active monomeric cytosolic state and high active dimeric membrane bound state. The regulation of LRRK2 membrane association is not well understood, but probably includes dimerization, post-translational modification and protein-protein interactions [158, 170, 182]. 14-3-3 proteins bind in a phosphorylation dependent manner to the N-terminus of LRRK2, which is important for LRRK2 localization and activity [25]. All purified or co-immunoprecipitated LRRK2 fragments are dimeric [148], and LRRK2 kinase activity seems to be dependent on dimerization [150, 170]. Active LRRK2 is a constitutive dimer by high affinity interaction of the COR domains, suggesting that in the cytosol the dimerization is most likely covered by regulatory proteins. Importantly, since LRRK2 activation is dependent on membrane localization and dimerization, inhibiting either of these properties may be a good therapeutic approach.
5. Conclusion
The multiple disease-linked mutations and enzyme functions within one protein make LRRK2 an excellent therapeutic target. Since several PD mutants result in an increase in LRRK2 kinase activity, the focus so far has been to develop kinase domain inhibitors as potential PD therapeutics. However, alternative approaches that target other domains of LRRK2, localization, dimerization, or allosteric modulation of the kinase domain may have significantly improved therapeutic benefits. To explore these potential therapeutic approaches, it will be essential to completely understand the molecular activation mechanism, identify upstream and downstream regulators, and characterize the cellular function of LRRK2. Work with model organism and biochemical and structural characterization of related Roco proteins from lower organisms might be important in this enterprise.
Acknowledgments
This work is supported by the Michael J. Fox foundation for Parkinson’s research and a NWO-VIDI grant to AK. We want to thank Bernd Gilsbach for his input in this chapter.
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Kortholt",authors:[{id:"40511",title:"Dr",name:"Arjan",middleName:null,surname:"Kortholt",fullName:"Arjan Kortholt",slug:"arjan-kortholt",email:"A.Kortholt@rug.nl",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"170519",title:"Dr.",name:"Franz Y",middleName:null,surname:"Ho",fullName:"Franz Y Ho",slug:"franz-y-ho",email:"franzkrystian@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"170520",title:"Dr.",name:"K.E.",middleName:null,surname:"Rosenbusch",fullName:"K.E. Rosenbusch",slug:"k.e.-rosenbusch",email:"k.e.rosenbusch@rug.nl",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Cellular function of LRRK2",level:"1"},{id:"sec_2_2",title:"2.1. Neurite development, outgrowth and branching",level:"2"},{id:"sec_3_2",title:"2.2. Autophagy",level:"2"},{id:"sec_4_2",title:"2.3. Mitochondrial disease",level:"2"},{id:"sec_5_2",title:"2.4. Common pathways for LRRK2 and other PD-relelated proteins?",level:"2"},{id:"sec_6_2",title:"2.5. LRRK2 and other diseases",level:"2"},{id:"sec_8",title:"3. Intramolecular LRRK2 activation mechanism",level:"1"},{id:"sec_8_2",title:"3.1. Homologous Roco proteins as model to study the mechanism of LRRK2 mediated PD",level:"2"},{id:"sec_9_2",title:"3.2. Dictyostelium Roco proteins to study the LRRK2 activation mechanism",level:"2"},{id:"sec_10_2",title:"3.3. LRRK2 kinase activity",level:"2"},{id:"sec_11_2",title:"3.4. Mechanism of increased kinase activity in LRRK2 PD mutants",level:"2"},{id:"sec_12_2",title:"3.5. The RocCOR tandem",level:"2"},{id:"sec_13_2",title:"3.6. Function of the N-terminus of LRRK2",level:"2"},{id:"sec_14_2",title:"3.7. WD40 domain at the C-Terminus of LRRK2",level:"2"},{id:"sec_15_2",title:"3.8. LRRK2/Roco activation model",level:"2"},{id:"sec_17",title:"4. Therapeutic targeting LRRK2",level:"1"},{id:"sec_17_2",title:"4.1. LRRK2 kinase as a therapeutic target",level:"2"},{id:"sec_18_2",title:"4.2. Alternative therapeutic approaches",level:"2"},{id:"sec_20",title:"5. Conclusion",level:"1"},{id:"sec_21",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Lees A.J., Hardy J., and Revesz T. (2009). Parkinson\'s disease. Lancet 373: 2055-2066.'},{id:"B2",body:'Bekris L.M., Mata I.F., and Zabetian C.P. (2010). The genetics of Parkinson disease. J. Geriatr. Psychiatry Neurol. 23: 228-242.'},{id:"B3",body:'Satake W., Nakabayashi Y., Mizuta I., Hirota Y., Ito C., Kubo M., Kawaguchi T., Tsunoda T., Watanabe M., Takeda A. et al. (2009). Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson\'s disease. Nat. Genet. 41: 1303-1307.'},{id:"B4",body:'Singleton A.B., Farrer M.J., and Bonifati V. (2013). The genetics of Parkinson\'s disease: progress and therapeutic implications. 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Chem. 55: 9416-9433.'},{id:"B178",body:'Chen H., Chan B.K., Drummond J., Estrada A.A., Gunzner-Toste J., Liu X., Liu Y., Moffat J., Shore D., Sweeney Z.K. et al. (2012). Discovery of selective LRRK2 inhibitors guided by computational analysis and molecular modeling. J. Med. Chem. 55: 5536-5545.'},{id:"B179",body:'Herzig M.C., Kolly C., Persohn E., Theil D., Schweizer T., Hafner T., Stemmelen C., Troxler T.J., Schmid P., Danner S. et al. (2011). LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice. Hum. Mol. Genet. 20: 4209-4223.'},{id:"B180",body:'Ness D., Ren Z., Gardai S., Sharpnack D., Johnson V.J., Brennan R.J., Brigham E.F., and Olaharski A.J. (2013). Leucine-rich repeat kinase 2 (LRRK2)-deficient rats exhibit renal tubule injury and perturbations in metabolic and immunological homeostasis. PLoS. One. 8: e66164.'},{id:"B181",body:'Tong Y., Giaime E., Yamaguchi H., Ichimura T., Liu Y., Si H., Cai H., Bonventre J.V., and Shen J. (2012). Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway. Mol. Neurodegener. 7: 2.'},{id:"B182",body:'Berger Z., Smith K.A., and LaVoie M.J. (2010). Membrane localization of LRRK2 is associated with increased formation of the highly active LRRK2 dimer and changes in its phosphorylation. Biochemistry 49: 5511-5523.'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"F.Y. Ho",address:null,affiliation:'
Department of Biochemistry, University of Groningen, Groningen, The Netherlands
Department of Cell Biochemistry, University of Groningen, Groningen, The Netherlands
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1. Introduction
Honey consumption has a very old history for humans. It has been used as a sweetener and flavoring in countless food and beverages. Since ancient times, honey has been known for its nutritious and therapeutic aspects. The most important components of honey are carbohydrates, which are found in the form of fructose, glucose, disaccharides, and oligosaccharides, and components such as maltose, isomaltose, maltulose, sucrose provide the sweet taste to honey. It also contains enzymes such as amylase, oxidase peroxide, catalase and acid phosphorylase, including anderosis and panoz. Also, honey is rich in amino acids, minerals, antioxidants and various phytochemicals [1]. Many of the reported biological properties of honey, such as antioxidant, antibacterial, antifungicidal, anti-inflammatory, hypotensive, antiproliferative, hepato-protective properties of these components are associated with presence of these properties. However, the composition of honey largely depends on a number of factors, such as flower source, geographical region, climatic conditions, harvesting season, processing and storage conditions. There are studies that report that honey, administered alone or in combination with traditional therapy, may be useful in the treatment of chronic diseases that are commonly associated with oxidative stress and the state of inflammation [2]. Honey is classified according to various criteria. In this classification, honey is classified as secretion honey (such as pine honey, oak honey, fir honey, leaf honey) and flower honey (linden honey, cotton honey, trirose honey, thyme honey, mashed honey, acacia honey, heather honey, etc.). According to the form of marketing, framed comb honey, natural comb honey, partial comb honey, cut-comb honey, strained honey, crystallized honey, creamed honey, pressed honey, chunk honey (strained with comb or comb with strained), filtered honey and baker’s honey. According to the moisture content, honey is classified as grade 1 honeys (humidity below 17.8%), grade 2 honeys (humidity up to 18.6%) and grade 3 honeys (humidity up to 20%). According to their color, honey is classified as white, golden, amber and dark. The color of honey can vary from light water white to black warehouse [3]. The physical and chemical properties, antimicrobial effects, which are of great importance for public health, and GMP and HACCP systems applied in the production process and microbiological dangers will be addressed in this section.
1.1 Physical and chemical properties of honey
Honey contains about 200 substances and is a nutrient consisting of substances such as carbohydrates, water, enzymes, free amino acids, essential minerals, vitamins, phenolic compounds, volatile compounds (monoterpenes, benzene derivatives) and some other solids. Carbohydrates in honey are mainly monosaccharides, glucose and fructose. This is followed by disaccharides and trisaccharides. They contribute mainly to the energy value. Proteins include enzymes such as invertase, diastase, glucose oxidase, catalase, peroxidase and acid phosphatase, and their content varies from 0.1% to 3.3% depending on the type of honey. It contains essential and non-essential amino acids, but the most common amino acid in honey is proline, which accounts for 1% of honey components [2]. Honey contains tocopherol (E), anti-hemorrhagic vitamin (K), ascorbic acid (C), thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5) and a small amount of vitamin pyridoxine (B6). Vitamins of the B complex and vitamin C are mainly derived from pollen and can be affected by commercial and industrial processes such as filtration or oxidation reactions [4].
Honey has a slight acid reaction due to about 0.57% organic acids. Acids contribute to the aroma and antimicrobial activity of honey. The predominant acid in honey is gluconic acid, it is followed by aspartic citric, acetic, formic, fumaric, galacturonic, malonic, formic, acetoglutaric, glutamic, butyric, glutaric, propionic, pyruvic, glioxia, 2-hydroxybutyric, a-hydroxiglutaric, isocyric, lactic, malic, methylmalonic, kynic, succinic, tartaric, oxalic acid [2]. The mineral content in honey ranges from 0.04% in light honey and 0.2% in dark honey. Potassium is the most abundant element. But the main bioactive molecules contained in honey are represented by polyphenols. Polyphenols are a heterogeneous chemical compound that can be divided into flavonoids (flavonols, flavones, flavanols, flavanones, anthocyanin, calcones and isoflavones) and non-flavonoid (phenolic acids). The profile of polyphenolic compounds in honey is thoroughly studied and includes vanillin, caffeic, syringing, p-gamic, ferulic, ellagic, 3-hydroxybenzoic, chlorogenic, genistic, gallic and benzoic acids and contains different phenolic acids, such as different flavonoids, mainly quercetin, kaempferol, myricetin, chrysin, galangin, hesperetin. The amount and type of polyphenols largely depends on the flower source or the variety of honey. In addition, it is known that there is a strong relationship between antioxidant activity and total phenolic content [5].
1.2 The importance of honey in terms of health and its antimicrobial effect
Honey is a food that has been used in therapeutic treatments for thousands of years. Among other useful properties to health, this product has been reported as a promising agent for wound healing, including leg ulcers and eyes, skin disorders by in vitro and clinical studies. In studies on New Zealand manuka honey, unique to the New Zealand, positive effects were observed on the viability of potentially useful Lactobacillus reuter and Bifidobacterium longum found in the human intestine. Moreover, it was found that Salmonella enterica Typhimurium, an enteric pathogenic bacterial type, showed a 65% reduction in their proliferation. In this sense, it has been established that manuka honey has a beneficial effect on the intestine by producing acid metabolites that reduce the intestinal pH and prevent pathogenic colonization and hence support the growth of bifidobacteria and lactic acid bacteria. Honey has been reportedly able to modulate oxidative stress and also has anti-proliferative, pro-apoptotic, anti-inflammatory and anti-metastatic properties. The anticancer effect of honey is connected to the presence of natural bioactive compounds, mainly such as pinobanksin, pinocembrin, luteolin, chrysin, salicylic acid and 3.4 dihydroxybenzoic acid [6, 7]. Some of the vitamins contained in honey are ascorbic acid, pantothenic acid, niacin and riboflavin. Moreover, it is a food that also contains minerals such as calcium, copper, iron, magnesium, manganese, phosphorus, potassium and zinc. Its rich variety of vitamins and minerals also plays a role in increasing the antioxidant characteristics of honey. The presence of free radicals and reactive oxygen types is responsible for pathogenesis of aging, as well as cellular dysfunction, metabolic and cardiovascular diseases. Consumption of foods rich in antioxidants can protect against these pathological changes, preventing the pathogenesis of chronic ailments [8].
Various parameters such as low water activity, high sugar content, acidity and hydrogen peroxide (H2O2) content, phytochemicals, peptides, non-peroxidase glycoeptides and proteins make up the antibacterial potential of honey. Water activity of honey varies from 0.56–0.62. These values might be considered low enough to prevent the development of bacteria or other microorganisms [9]. Although previously it was believed that the only responsible agent for the antibacterial effect of diluted honey was H2O2 and that this antibacterial effect can be completely eliminated through catalysis, it has been found out that bacteria can also be affected via the existence of pythochemical elements present in honey [10]. As it suppresses the activities of bacteria causing infections in urinary systems, such as E. coli and Proteus species and Streptococcus faecalis, diluted honey is used to treat urinary system infections and it inhibits toxin production [11]. Undiluted honey hinders the reproduction and development of bacteria due to the content of sugar, which exerts osmotic pressure on bacterial cells and causes water to flow out of bacterial cells through osmosis. Thus, the cells shrink due to dehydration, and they cannot remain alive in hypertonic sugar solution. The optimal pH necessary for the development of most microorganisms ranges from 6.5–7.5. The pH value of honey is between 3.2–4.5, and this value is a very distinctive feature of its antibacterial activity. This acidity is caused by the presence of certain important organic acids, especially gluconic acid - in 0.5% (a/h) concentration. Glycogenic acid is produced from glucose oxidation by an endogenous enzyme of glucose oxidase and is an extremely powerful antibacterial agent. In undiluted pure honey, low pH can contribute to antibacterial action, but when the product is diluted pH alone is not enough to prevent the development of bacteria [9]. The formation of H2O2 is a dominant mechanism in which honey exerts bacteriostatic and bactericidal activity. It provides antibacterial activity of honey and is produced enzymatically. The enzyme glucose oxidase is inherently inactive in honey due to low pH conditions, and glucose oxidase is activated when honey is diluted. However, it is known that concentrations of H2O2 are adversely affected by various minor components, such as nectar, pollen, and yeast. It has also been reported as having high sensitivity to light and light sources [12]. Honey contains relatively small amounts of proteins, whose molecular weights range from 20 to 80 kDa, ranging from approximately 0.1% to 0.5%. These proteins contain many enzymes involved in sugar metabolism, such as alpha and beta glucosidase, glucose oxidase and amylase. Numerous studies have shown that important royal jelly proteins have antimicrobial and anticancer activity and anti-inflammatory potential [13].
Honey shows antibacterial activity against a large number of bacteria in different environments. Natural components of honey have antifungal, antiviral, antibacterial activities. It has been reported that the antibacterial activity of honey is also likely to depend on the pasture, climatic conditions, and also on the natural composition of flower nectar. Honey has excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), often associated with wound and burn infections, and Pseudomonas spp. Many studies have shown that honey is also effective against hemolytic streptococci and vancomycin resistant enterococci. Twenty-one kinds of honey tested for antibacterial activity against Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa), and it has been established that they have a positive effect due to H2O2 and polyphenolic content levels. The effectiveness of free radical cleansing is observed in all kinds of honey. In addition, honey tested by freezing, drying and powdering has been reported to show antioxidant activity in each form [9, 14]. Flavonoids contained in the natural composition of honey is also known to be effective against microorganisms that are present in the tissue of chronic wounds, in particular S. aureus, P. aeruginosa, as well as Escherichia coli (E. coli). Flavonoids are often recommended as a natural source to control chronic inflammatory diseases, the incidence of which increases significantly. Despite the fact that the topical application of honey for medicinal purposes is old, there are a small number of studies that address its anti-inflammatory activity at the cellular level. Although flavonoids are small components of honey, their anti-inflammatory effect is extraordinary compared to other natural compounds [15]. Honey was found to have a preventive effect on about 60 bacteria such as, Bacillus anthracis, Corynebacterium diptheriae, Haemophilus influenzae, Klebsiella pneumoniae, Shigella, Mycobacterium tuberculosis, and many aerob and anaerob bacterial types. In vitro studies of Helicobacter pylori in the human digestive system have shown that when using honey, its activity decreases by 20%. It has been reported that honey can be used in combination with antibiotics to produce a synergistic effect of bactericidal activity against Helicobacter pylori. The main difference of honey with antibiotics is that it does not develop antibiotic-resistant bacteria, so it can be used continuously without such risk [16].
2. Other beekeeping products
2.1 Pollen
Pollen is the only source of protein found in nature for bees. The amino acids contained in its composition are isolosin, arginine, lysine, histidine, leucine, methionine, treonine, phenylalanine, tryptophan and valine. It is essential for adequate development of their muscles, tissues, secretory glands and other organs in the upbringing of honeybees and its young stages. It is a nutritional source rich in vitamins, proteins, sterols, minerals and lipids. It has been reported that pollen collected by honeybees may have differences in their general chemical composition as a result of supplying from different plants [17].
2.2 Nectar
Bees have two stomach and they use one of them to perform normal body functions whereas the other to store the nectar they collect. In order to collect nectar found in flowers, bees use rod-like, tubular long tongues. It has been reported that bees can contain about 70 mg of nectar in the stomach they store nectar, and that they should visit 100 to 1500 different flowers to fully fill their honey stomach [17].
2.3 Propolis
Propolis is recognized as a therapeutic agent due to several reported functional effectiveness. It is known that honey contains phenolic compounds. Propolis contains a higher content of phenolic compounds than honey and shows significantly higher antimicrobial and antioxidant activities. Today it is used in industry as a component of confectionery, biopharmaceuticals and cosmetics. It is gaining popularity as a natural preservative and helps to improve shelf life and consumer health as a source of bioactive compounds for food and drinks. However, propolis has a strong and bitter taste, which changes the sensory properties of food due to the high concentration of phenolic compounds. Therefore, the acceptance of foods containing propolis by consumers must be determined by its propolis concentration, which has to be carefully researched so as not to adversely change the sensory properties of such foods [18].
2.4 Bee milk
The importance of bee milk, one of bee products, was noticed in the 1600s and was given the name “Royal Jelly”, which means excellent food in English. Bee milk is secreted from the upper jaw (mandibular) and throat glands (hypopharyngeal) of young worker bees of 5–15 days of age. All larvae only in their first three-day period, and the larvae that will become the queen bee are fed with royal jelly during the entire larval and adult periods. Bee milk can be described as food with a peculiar smell and a bitter taste and a mush-like form with bone-like color. It is collected from the cells of larvae of 3–4 days of age of the future queen, or from the cells of queen bees where larvae of 1–2 days are laid after 48–72 hours. It is quite flowing and has yogurt-like consistency but is a homogeneous substance. It has a light beige and yellowish whitish color, a sharp phenolic smell and a distinctive sour taste. Its density is approximately 1.1 g/cm3 and is soluble in water [19].
3. Microbiological risks in honey and honey products
Although honey is considered a low-risk food due to its antimicrobial and bacteriostatic effects, studies disprove this view. In addition to primary contamination, staff, tools and equipment used in beekeeping and honey production are also a potential source of secondary contamination. In addition, honey, which has the potential to contain many microorganisms as a result of cross-contamination, is among the important nutrients and can indirectly threaten public health. Despite the fact that some types of honey contain H2O2 and benzoic acid and phenolic compounds such as some flavonoids, it can constitute risks for consumer health due to minimal hygiene rules. It is reported that pathogens can be found as causative agents in honey produced without food safety systems. Food-borne pathogens are recognized as an important risk factor for public health in developed and developing countries due to their spread around the world. Viruses, bacteria, fungi, parasites and mites are the most common disease factors in beekeeping. Fecal-oral route is an important way of transmission of these diseases. Agents that pollute bees through water and food can be transmitted to larvae by infected bees. Another contamination that may occur in honey is secondary contamination caused by secondary contamination sources such as personnel, tools and equipment [20].
The presence of strains Bettsya alvei, Acosphaera apis and Acosphaera major in honey production can be indicative of improper beehive management practices. Different types of microorganisms such as Acinetobacter spp., Bacillus spp., Clostridium spp., Corynebacterium spp., Pseudomonas spp. are bacteria that are widely found in the soil. Brochothrix spp., Citrobacter spp., Enterobacter spp., Erwinia spp., Flavobacterium spp., Lactobacillus spp., Lactococcus spp., Leuconostoc spp., Listeria spp. and Pediococcus spp. are other bacteria that are likely to be found in plants and plant products. On the other hand, among yeast strains Saccharomyces, Schizosaccharomyces and Torula species predominate in high humidity sugars. Bacterial spores, especially Bacillus and Clostridium, can be seen in honey. Clostridium is an indicator organism that provides evidence of contamination or pollution in honey. Clostridium botulinum (C. botulinum) spores are usually found at low levels in honey. The presence of clostridium spores can be dangerous, especially for children under one year of age. It is known that infant botulism is mainly caused by the consumption of honey contaminated with C. botulinum [21, 22]. C. botulinum forms 4 different types of neuroparalytic diseases in humans. In addition to infant botulism, they are classified as food-borne botulism, wound botulism, and yet unclassified latent botulism. The most important of them is infant botulism, which occurs in newborn babies of 3–20 weeks. Infant botulism is diagnosed with isolation of C. botulinum and toxin in feces. Decreases in sucking and swallowing reflexes of infants can be observed, which is very rarely fatal [23].
One of the animal products that have been the focus of food warnings due to the presence of chemical hazards such as antibiotics or pesticides in recent years are honey and honey products. The source of these residues in honey is mainly due to bee parasites, such as European offspring rot (Streptococcus pluton) or American offspring rot (Bacillus larvae) and are veterinary drugs that are necessary to treat bacterial diseases. It is known that chemical residues caused by these drugs used to eliminate microbiological risks, lead to such adverse conditions on human health as allergic reactions, bacterial resistance, along with changes of reproductive toxicity [24, 25].
4. HACCP in honey production
Food safety can be ensured by systematic implementation of all activities in line with a plan. The Hazard Analysis Critical Control Points (HACCP) system, as a preventive system for ensuring food safety, controls production at various points throughout the food production, thereby ensuring that the final product complies with legislation. Preliminary Requirement Program must be created first in order to establish the HACCP system in any food business. In this context, the deficiencies of the infrastructure and processes such as water, energy, warehouse, cleaning and sanitation, personnel, environment and equipment hygiene, personnel training and pest control should be addressed. However, it is necessary to plan the process management by writing down the procedures. The processes that need to be addressed afterwards can be sorted as follows; identification of the HACCP team and a clear definition of the task descriptions by making the managerial organization chart, determination of food safety policy by business management, making an understandable description of the products to be produced, determination of the intended usage method, preparation of a flow diagram and placement plan by HACCP team and verification of this plan at site, analyzing hazards and risks, identification of critical control points, making up of critical limits and monitoring procedures, determination of corrective activities for cases where it is necessary, and the proving or verification of the effectiveness of the system [26].
Codex Alimentarius Standard and the European Commission allows nomenclature for honeys produced from certain botanical sources if the product comes from the specified origin and has anticipated physicochemical, organoleptic and microscopic properties. The fact that there are different varieties of honey and each has its own production steps, leads to an increase in the limits that need to be controlled. For the import of food products of animal origin, such as honey, EU legislation requires a number of health and national residue monitoring procedures such as HACCP during the production and processing of honey. These requirements are known to be independent of whether honey is organic or traditional. Thus, imported products are intended to meet the standards required for production and trade within EU member countries. Costs, lack of qualified personnel, misinterpretation of EU legislation, lack of laboratory in international standards and improper infrastructure are the main obstacles to being accredited by the EU [27, 28].
Although honey is a product that is part of the low-risk group due to its high sugar content, it should be carefully examined for physical, chemical and biological hazards. In general, the hygiene of the processing area, tool and equipment and personnel in contact with food should be observed as it should be in all food enterprises. Physical hazards such as soil, plant materials, glass materials, tools and equipment are defined as potential hazards to honey. Traces of pesticides and herbicide, beekeeping drugs and antibiotics are chemical hazards. Soil originated C. botulinum, the most important biological danger in honey production, is eliminated by the provision of hygienic conditions in the production of honey [29].
General hygiene rules should be applied effectively to prevent physical, chemical, and microbiological hazards. In hives, legally approved preservatives should be used. Insects and mice should be kept away from hives. During transportation, the vehicles should be cleaned well, in case of the presence of dirt left from the previous use. It is necessary to effectively clean the equipment and work area before and after use. Persons involved in the process should wear a separate clothing to protect the product from contamination caused by clothing or individuals. Especially before and after use, cleaning control of filters must be carried out effectively. In the HACCP plan, the purpose of conducting hazard analysis must be effectively controlled. All potential hazards in each step of the workflow process must be identified and the risk and severity of each identified hazard should be assessed. At this point, it is also necessary to determine the sources of dangers. In a study, corrective activities to prevent and/or eliminate hazards were determined and two critical controls points, “filtration/unloading” and “packaging” were pointed out. Examples of forms used in each HACCP plan and all procedures of the HACCP plan must be provided and monitored [26, 30].
5. Conclusions
HACCP system, which is successfully implemented in the food industry, is the most effective quality system in terms of the supply of safe products. The purpose of the use of HACCP system is to provide reliable food to the consumer with the desired characteristics and quality. Honey production, which is suitable to be affected by climatic conditions, should be made systematic and controllable by removing traditional methods that are difficult to trace. In this context, the creation of honey workflow process, determining potential hazards, and analyzing hazards, taking necessary precautions, recording the system, providing internationally reliable product guarantee is of great importance for public health as well as for the economies of countries. Effective implementation of the HACCP system in enterprises is inevitable so that retrospective monitoring and recall models can be used in the event of any negativity. In the production processes of foods with high nutritional value as honey, all necessary food safety requirements must be met to protect and improve public health.
\n',keywords:"honey production, microbiological risks, HACCP",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/77920.pdf",chapterXML:"https://mts.intechopen.com/source/xml/77920.xml",downloadPdfUrl:"/chapter/pdf-download/77920",previewPdfUrl:"/chapter/pdf-preview/77920",totalDownloads:176,totalViews:0,totalCrossrefCites:0,dateSubmitted:"July 5th 2021",dateReviewed:"July 13th 2021",datePrePublished:"August 23rd 2021",datePublished:null,dateFinished:"August 7th 2021",readingETA:"0",abstract:"Honey has been considered as a very important and superior nutrient in human nutrition since ancient times due to its ability to be consumed by humans without processing, easy digestibility, nutritional properties and biological benefits. Although honey contains many desired bioactive and antibacterial substances, which may be sufficient for antimicrobial activity, it cannot be produced in sufficient quantities due to low water activity under normal conditions. This causes various food and bee-borne spores/non-spores pathogens going viral. Hence, it may cause the risk of parasitological and fungal agents to be found. In honey production, “Hazard Analysis Critical Control Point (HACCP)” must be applied meticulously and completely. Current technologies in honey production will be explained in this section.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/77920",risUrl:"/chapter/ris/77920",signatures:"Emek Dümen, Nadide Gizem Tarakçı and Gözde Ekici",book:{id:"11025",type:"book",title:"A Glance at Food Processing Applications",subtitle:null,fullTitle:"A Glance at Food Processing Applications",slug:null,publishedDate:null,bookSignature:"Dr. Isıl Var and Dr. Sinan Uzunlu",coverURL:"https://cdn.intechopen.com/books/images_new/11025.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-83969-768-5",printIsbn:"978-1-83969-767-8",pdfIsbn:"978-1-83969-769-2",isAvailableForWebshopOrdering:!0,editors:[{id:"202803",title:"Dr.",name:"Isıl",middleName:null,surname:"Var",slug:"isil-var",fullName:"Isıl Var"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1 Physical and chemical properties of honey",level:"2"},{id:"sec_2_2",title:"1.2 The importance of honey in terms of health and its antimicrobial effect",level:"2"},{id:"sec_4",title:"2. Other beekeeping products",level:"1"},{id:"sec_4_2",title:"2.1 Pollen",level:"2"},{id:"sec_5_2",title:"2.2 Nectar",level:"2"},{id:"sec_6_2",title:"2.3 Propolis",level:"2"},{id:"sec_7_2",title:"2.4 Bee milk",level:"2"},{id:"sec_9",title:"3. Microbiological risks in honey and honey products",level:"1"},{id:"sec_10",title:"4. HACCP in honey production",level:"1"},{id:"sec_11",title:"5. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'Meo SA, Al-Asiri SA, Mahesar AL, Ansari MJ. Role of honey in modern medicine. Saudi Journal of Biological Sciences. 2017;24:975-978. DOI: http://dx.doi.org/10.1016/j.sjbs.2016.12.010'},{id:"B2",body:'Terzo S, Mulè F, Amato A. Honey and obesity-related dysfunctions: a summary on health benefits. Journal of Nutritional Biochemistry. 2020;82:108401. DOI: https://doi.org/10.1016/j.jnutbio.2020.108401'},{id:"B3",body:'Doğan H. Determination of chemical, physical and antimicrobial properties of nectar honeys [thesis]. Atatürk University; 2014'},{id:"B4",body:'Cianciosi D, Forbes-Hernández TY, Afrin S, Gasparrini M, Reboredo-Rodriguez P, Manna PP, Zhang J, Lamas LB, Florez SM, Toyos PA, Quiles JL, Giampieri F, Battino M. Phenolic compounds in honey and their associated health benefits: A review. Molecules. 2018; 23:2322. DOI:10.3390/molecules23092322'},{id:"B5",body:'Miguel MG, Antunes MD, Falerio ML. Honey as a Complementary Medicine. Integrative Medicine Insights. 2017; 12:1-15. DOI: https://doi.org/10.1177/117863371770286'},{id:"B6",body:'Seraglio SKT, Schulz M, Gonzaga VL, Fett R, Costa ACO. Current status of the gastrointestinal digestion effects on honey: A comprehensive review. Food Chemistry. 2021; 357: 129807. DOI: https://doi.org/10.1016/j.foodchem.2021.129807'},{id:"B7",body:'Afrin S, Haneefa SM, Fernandez-Cabezudo MJ, Giampieri F, Al-Ramadi BK, Battino M. Therapeutic and preventive properties of honey and its bioactive compounds in cancer: an evidence-based review. Nutrition Research Reviews. 2020;33(1):50-76. DOI: https://doi.org/10.1017/S0954422419000192'},{id:"B8",body:'Ajibola A, Chamunorwa JP, Erlwanger KH. Nutraceutical values of natural honey and its contribution to human health and wealth. Nutrition & Metabolism. 2012;9(1):1-12'},{id:"B9",body:'Almasaudi S. The antibacterial activities of honey. Saudi Journal of Biological Sciences. 2021;28:2188-2196. DOI: https://doi.org/10.1016/j.sjbs.2020.10.017'},{id:"B10",body:'Albaridi NA. Antibacterial Potency of Honey. International Journal of Microbiology. 2019. DOI: https://doi.org/10.1155/2019/2464507'},{id:"B11",body:'Eteraf-Oskouei T, Najafi M. Traditional and Modern Uses of Natural Honey in Human Diseases: A Review. Iranian Journal of Basic Medical Sciences. 2013; 16(6): 731-742'},{id:"B12",body:'Brudzynski K. A current perspective on hydrogen peroxide production in honey. A review. Food Chemistry. 2020;332:127229. DOI: https://doi.org/10.1016/j.foodchem.2020.127229'},{id:"B13",body:'Tonks AJ, Cooper RA, Jones KP, Blair S, Parton J, Tonks A. Honey stimulates inflammatory cytokine production from monocytes. Cytokine 2003;21:242-247. DOI: doi:10.1016/S1043-4666(03)00092-9'},{id:"B14",body:'Stagos D, Solitsiotis N, Tsadila C, Papaeconomou S, Arvanitis C, Ntontos A, Karkanta F, Adamou-Androulaki S, Petrotos K, Spandidos DA, Kouretas D, Mossialos D. Antibacterial and antioxidant activity of different types of honey derived from Mount Olympus in Greece. International Journal Of Molecular Medicine. 2018 42:726-734. DOI: 10.3892/ijmm.2018.3656'},{id:"B15",body:'Silva B, Biluca FC, Gonzaga LV, Fett R, Dalmarco EM, Caon T, Costa ACO. In vitro anti-inflammatory properties of honey flavonoids: A review. Food Research International. 2021;14:110086. DOI: https://doi.org/10.1016/j.foodres.2020.110086'},{id:"B16",body:'Ilia G, Simulescu V, Merghes P, Varan N. The health benefits of honey as an energysource with antioxidant, antibacterial andantiseptic effects. Science & Sports. DOI: https://doi.org/10.1016/j.scispo.2020.10.005'},{id:"B17",body:'Sahin G. Research on the chemıcal composıtıon of some honey [thesis]. Ankara University; 2019'},{id:"B18",body:'Osés SM, Pascual-Maté A, Fernández-Muiño MA, López-Díaz TM, Sancho MT. Bioactive properties of honey with propolis. Food Chemistry. 2016;196:1215-1223. http://dx.doi.org/10.1016/j.foodchem.2015.10.050'},{id:"B19",body:'Akyol E, Baran Y. Arı sütünün yapısı, insanlar ve arılar için önemi. Uludag Bee Journal. 2015; 15(1):16-21'},{id:"B20",body:'Bayrakal GM, Ekici G, Akkaya H, Sezgin FH, Dümen E. Detection and Molecular Examination of Pathogens in Honey and Bees in the Northern Marmara Region, Turkey. Journal of Kafkas University of Veterinary Faculty. 2020;26(3):313-319. DOI: 10.9775/kvfd.2019.22845'},{id:"B21",body:'Finola MS, Lasagno MC, Marioli JM. Microbiological and chemical characterization of honeys from central Argentina. Food Chemistry. 2007;100:1649-1653. DOI:10.1016/j.foodchem.2005.12.046'},{id:"B22",body:'Vázquez-Quinones CR, Moreno-Terrazas R, Natividad-Bonifacio I, Quinones-Ramírez EI, Vázquez-Salinas C. Microbiological assessment of honey in México. Revista Argentina De Microbiologia. 2018;50(1):75-80. DOI: https://doi.org/10.1016/j.ram.2017.04.005'},{id:"B23",body:'Nevas M, Lindström M, Hörman A, Keto-Timonen R, Korkeala H. Contamination routes of Clostridium botulinum in the honey production environment. Environmental Microbiology. 2006;8(6):1085-1094. DOI:10.1111/j.1462-2920.2006.01000.x'},{id:"B24",body:'Juan-Borras M, Periche A, Domenech E, Escriche I. Routine quality control in honey packaging companies as a key to guarantee consumer safety. The case of the presence of sulfonamides analyzed with LC-MS-MS. Food Control. 2015;50:243-249. DOI: http://dx.doi.org/10.1016/j.foodcont.2014.08.021'},{id:"B25",body:'El-Nahhal Y. Pesticide residues in honey and their potential reproductive toxicity. Science of the Total Environment. 2020;741:139953. DOI: https://doi.org/10.1016/j.scitotenv.2020.139953'},{id:"B26",body:'Suna S, Özcan Sinir G, Anlar D. Bal Üretim Prosesinde HACCP Uygulaması. Arıcılık Araştırma Dergisi. Arıcılık Araştırma Dergisi. 2013;5(10):17-21'},{id:"B27",body:'Bogdanov S, Fluri P, Imdorf A, Charrierre JD, Kilchenmann V. Self control sytstem for the production of high quality honey: The Swiss example. Apimondia Journal. 2005;40:28-33'},{id:"B28",body:'Oddo LP, Bogdanov S. Determination of honey botanical origin: problems and issues. Apidologie. 2004;35:2-3. DOI: 10.1051/apido:2004044'},{id:"B29",body:'Al-Waili N, Salom K, Al-Ghamdi A, Ansari MJ. Antibiotic, Pesticide, and Microbial Contaminants of Honey: Human Health Hazards. The ScientificWorld Journal. 2012;9: 930849. DOI:10.1100/2012/930849'},{id:"B30",body:'Mutinelli F, Costa C, Lodesani M, Baggio A, Medrzycki P, Formato G, Porrini C. Honey bee colony losses in Italy. Journal of Apicultural Research 2010;49(1):119-120. DOI: 10.3896/IBRA.1.49.1.24'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Emek Dümen",address:null,affiliation:'
Food Hygiene and Technologies, Faculty of Veterinary, Istanbul University-Cerrahpasa, Turkey
Faculty of Health Sciences, Department of Nutrition and Dietetics, Istanbul Kultur University, Turkey
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In order to help Authors identify appropriate funding agencies and institutions, we have created a list, based on extensive research on various OA resources (including ROARMAP and SHERPA/JULIET) of organizations that have funds available. Before consulting our list we encourage you to petition your own institution or organization for Open Access funds or check the specifications of your grant with your funder to ascertain if publication costs are included. Where you are in receipt of a grant you should clarify:
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She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:43,paginationItems:[{id:"82374",title:"The Potential of the Purinergic System as a Therapeutic Target of Natural Compounds in Cutaneous Melanoma",doi:"10.5772/intechopen.105457",signatures:"Gilnei Bruno da Silva, Daiane Manica, Marcelo Moreno and Margarete Dulce Bagatini",slug:"the-potential-of-the-purinergic-system-as-a-therapeutic-target-of-natural-compounds-in-cutaneous-mel",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82103",title:"The Role of Endoplasmic Reticulum Stress and Its Regulation in the Progression of Neurological and Infectious Diseases",doi:"10.5772/intechopen.105543",signatures:"Mary Dover, Michael Kishek, Miranda Eddins, Naneeta Desar, Ketema Paul and Milan Fiala",slug:"the-role-of-endoplasmic-reticulum-stress-and-its-regulation-in-the-progression-of-neurological-and-i",totalDownloads:5,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"82212",title:"Protein Prenylation and Their Applications",doi:"10.5772/intechopen.104700",signatures:"Khemchand R. 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Currently, he is a professor of Orthodontics. He holds a Certificate of Advanced Study type A in Technology of Biomaterials used in Dentistry (1995); Certificate of Advanced Study type B in Dento-Facial Orthopaedics (1997) from the Faculty of Dental Surgery, University Denis Diderot-Paris VII, France; Diploma of Advanced Study (DESA) in Biocompatibility of Biomaterials from the Faculty of Medicine and Pharmacy of Casablanca (2002); Certificate of Clinical Occlusodontics from the Faculty of Dentistry of Casablanca (2004); University Diploma of Biostatistics and Perceptual Health Measurement from the Faculty of Medicine and Pharmacy of Casablanca (2011); and a University Diploma of Pedagogy of Odontological Sciences from the Faculty of Dentistry of Casablanca (2013). 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He also obtained an MSc in Molecular and Genetic Medicine, and a Ph.D. in Clinical Immunology and Human Genetics from the University of Sheffield, UK. He also completed a short-term fellowship in Pediatric Clinical Immunology and Bone Marrow Transplantation at Newcastle General Hospital, England. Dr. Rezaei is a Full Professor of Immunology and Vice Dean of International Affairs and Research, at the School of Medicine, Tehran University of Medical Sciences, and the co-founder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Dr. Rezaei has directed more than 100 research projects and has designed and participated in several international collaborative projects. He is an editor, editorial assistant, or editorial board member of more than forty international journals. He has edited more than 50 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1,100 scientific papers in international journals.",institutionString:"Tehran University of Medical Sciences",institution:{name:"Tehran University of Medical Sciences",country:{name:"Iran"}}},{id:"180733",title:"Dr.",name:"Jean",middleName:null,surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/180733/images/system/180733.png",biography:"Dr. Jean Engohang-Ndong was born and raised in Gabon. After obtaining his Associate Degree of Science at the University of Science and Technology of Masuku, Gabon, he continued his education in France where he obtained his BS, MS, and Ph.D. in Medical Microbiology. He worked as a post-doctoral fellow at the Public Health Research Institute (PHRI), Newark, NJ for four years before accepting a three-year faculty position at Brigham Young University-Hawaii. Dr. Engohang-Ndong is a tenured faculty member with the academic rank of Full Professor at Kent State University, Ohio, where he teaches a wide range of biological science courses and pursues his research in medical and environmental microbiology. Recently, he expanded his research interest to epidemiology and biostatistics of chronic diseases in Gabon.",institutionString:"Kent State University",institution:{name:"Kent State University",country:{name:"United States of America"}}},{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",biography:"Emmanuel Drouet, PharmD, is a Professor of Virology at the Faculty of Pharmacy, the University Grenoble-Alpes, France. As a head scientist at the Institute of Structural Biology in Grenoble, Dr. Drouet’s research investigates persisting viruses in humans (RNA and DNA viruses) and the balance with our host immune system. He focuses on these viruses’ effects on humans (both their impact on pathology and their symbiotic relationships in humans). He has an excellent track record in the herpesvirus field, and his group is engaged in clinical research in the field of Epstein-Barr virus diseases. He is the editor of the online Encyclopedia of Environment and he coordinates the Universal Health Coverage education program for the BioHealth Computing Schools of the European Institute of Science.",institutionString:null,institution:{name:"Grenoble Alpes University",country:{name:"France"}}},{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},{id:"332819",title:"Dr.",name:"Chukwudi Michael",middleName:"Michael",surname:"Egbuche",slug:"chukwudi-michael-egbuche",fullName:"Chukwudi Michael Egbuche",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/332819/images/14624_n.jpg",biography:"I an Dr. Chukwudi Michael Egbuche. I am a Senior Lecturer in the Department of Parasitology and Entomology, Nnamdi Azikiwe University, Awka.",institutionString:null,institution:{name:"Nnamdi Azikiwe University",country:{name:"Nigeria"}}},{id:"284232",title:"Mr.",name:"Nikunj",middleName:"U",surname:"Tandel",slug:"nikunj-tandel",fullName:"Nikunj Tandel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284232/images/8275_n.jpg",biography:'Mr. Nikunj Tandel has completed his Master\'s degree in Biotechnology from VIT University, India in the year of 2012. He is having 8 years of research experience especially in the field of malaria epidemiology, immunology, and nanoparticle-based drug delivery system against the infectious diseases, autoimmune disorders and cancer. He has worked for the NIH funded-International Center of Excellence in Malaria Research project "Center for the study of complex malaria in India (CSCMi)" in collaboration with New York University. The preliminary objectives of the study are to understand and develop the evidence-based tools and interventions for the control and prevention of malaria in different sites of the INDIA. Alongside, with the help of next-generation genomics study, the team has studied the antimalarial drug resistance in India. Further, he has extended his research in the development of Humanized mice for the study of liver-stage malaria and identification of molecular marker(s) for the Artemisinin resistance. At present, his research focuses on understanding the role of B cells in the activation of CD8+ T cells in malaria. Received the CSIR-SRF (Senior Research Fellow) award-2018, FIMSA (Federation of Immunological Societies of Asia-Oceania) Travel Bursary award to attend the IUIS-IIS-FIMSA Immunology course-2019',institutionString:"Nirma University",institution:{name:"Nirma University",country:{name:"India"}}},{id:"334383",title:"Ph.D.",name:"Simone",middleName:"Ulrich",surname:"Ulrich Picoli",slug:"simone-ulrich-picoli",fullName:"Simone Ulrich Picoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334383/images/15919_n.jpg",biography:"Graduated in Pharmacy from Universidade Luterana do Brasil (1999), Master in Agricultural and Environmental Microbiology from Federal University of Rio Grande do Sul (2002), Specialization in Clinical Microbiology from Universidade de São Paulo, USP (2007) and PhD in Sciences in Gastroenterology and Hepatology (2012). She is currently an Adjunct Professor at Feevale University in Medicine and Biomedicine courses and a permanent professor of the Academic Master\\'s Degree in Virology. She has experience in the field of Microbiology, with an emphasis on Bacteriology, working mainly on the following topics: bacteriophages, bacterial resistance, clinical microbiology and food microbiology.",institutionString:null,institution:{name:"Universidade Feevale",country:{name:"Brazil"}}},{id:"229220",title:"Dr.",name:"Amjad",middleName:"Islam",surname:"Aqib",slug:"amjad-aqib",fullName:"Amjad Aqib",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229220/images/system/229220.png",biography:"Dr. Amjad Islam Aqib obtained a DVM and MSc (Hons) from University of Agriculture Faisalabad (UAF), Pakistan, and a PhD from the University of Veterinary and Animal Sciences Lahore, Pakistan. Dr. Aqib joined the Department of Clinical Medicine and Surgery at UAF for one year as an assistant professor where he developed a research laboratory designated for pathogenic bacteria. Since 2018, he has been Assistant Professor/Officer in-charge, Department of Medicine, Manager Research Operations and Development-ORIC, and President One Health Club at Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan. He has nearly 100 publications to his credit. His research interests include epidemiological patterns and molecular analysis of antimicrobial resistance and modulation and vaccine development against animal pathogens of public health concern.",institutionString:"Cholistan University of Veterinary and Animal Sciences",institution:null},{id:"62900",title:"Prof.",name:"Fethi",middleName:null,surname:"Derbel",slug:"fethi-derbel",fullName:"Fethi Derbel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62900/images/system/62900.jpeg",biography:"Professor Fethi Derbel was born in 1960 in Tunisia. He received his medical degree from the Sousse Faculty of Medicine at Sousse, University of Sousse, Tunisia. He completed his surgical residency in General Surgery at the University Hospital Farhat Hached of Sousse and was a member of the Unit of Liver Transplantation in the University of Rennes, France. He then worked in the Department of Surgery at the Sahloul University Hospital in Sousse. Professor Derbel is presently working at the Clinique les Oliviers, Sousse, Tunisia. His hospital activities are mostly concerned with laparoscopic, colorectal, pancreatic, hepatobiliary, and gastric surgery. He is also very interested in hernia surgery and performs ventral hernia repairs and inguinal hernia repairs. He has been a member of the GREPA and Tunisian Hernia Society (THS). During his residency, he managed patients suffering from diabetic foot, and he was very interested in this pathology. For this reason, he decided to coordinate a book project dealing with the diabetic foot. Professor Derbel has published many articles in journals and collaborates intensively with IntechOpen Access Publisher as an editor.",institutionString:"Clinique les Oliviers",institution:null},{id:"300144",title:"Dr.",name:"Meriem",middleName:null,surname:"Braiki",slug:"meriem-braiki",fullName:"Meriem Braiki",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/300144/images/system/300144.jpg",biography:"Dr. Meriem Braiki is a specialist in pediatric surgeon from Tunisia. She was born in 1985. She received her medical degree from the University of Medicine at Sousse, Tunisia. She achieved her surgical residency training periods in Pediatric Surgery departments at University Hospitals in Monastir, Tunis and France.\r\nShe is currently working at the Pediatric surgery department, Sidi Bouzid Hospital, Tunisia. Her hospital activities are mostly concerned with laparoscopic, parietal, urological and digestive surgery. She has published several articles in diffrent journals.",institutionString:"Sidi Bouzid Regional Hospital",institution:null},{id:"229481",title:"Dr.",name:"Erika M.",middleName:"Martins",surname:"de Carvalho",slug:"erika-m.-de-carvalho",fullName:"Erika M. de Carvalho",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/229481/images/6397_n.jpg",biography:null,institutionString:null,institution:{name:"Oswaldo Cruz Foundation",country:{name:"Brazil"}}},{id:"186537",title:"Prof.",name:"Tonay",middleName:null,surname:"Inceboz",slug:"tonay-inceboz",fullName:"Tonay Inceboz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/186537/images/system/186537.jfif",biography:"I was graduated from Ege University of Medical Faculty (Turkey) in 1988 and completed his Med. PhD degree in Medical Parasitology at the same university. I became an Associate Professor in 2008 and Professor in 2014. I am currently working as a Professor at the Department of Medical Parasitology at Dokuz Eylul University, Izmir, Turkey.\n\nI have given many lectures, presentations in different academic meetings. I have more than 60 articles in peer-reviewed journals, 18 book chapters, 1 book editorship.\n\nMy research interests are Echinococcus granulosus, Echinococcus multilocularis (diagnosis, life cycle, in vitro and in vivo cultivation), and Trichomonas vaginalis (diagnosis, PCR, and in vitro cultivation).",institutionString:"Dokuz Eylül University",institution:{name:"Dokuz Eylül University",country:{name:"Turkey"}}},{id:"71812",title:"Prof.",name:"Hanem Fathy",middleName:"Fathy",surname:"Khater",slug:"hanem-fathy-khater",fullName:"Hanem Fathy Khater",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/71812/images/1167_n.jpg",biography:"Prof. Khater is a Professor of Parasitology at Benha University, Egypt. She studied for her doctoral degree, at the Department of Entomology, College of Agriculture, Food and Natural Resources, University of Missouri, Columbia, USA. She has completed her Ph.D. degrees in Parasitology in Egypt, from where she got the award for “the best scientific Ph.D. dissertation”. She worked at the School of Biological Sciences, Bristol, England, the UK in controlling insects of medical and veterinary importance as a grant from Newton Mosharafa, the British Council. Her research is focused on searching of pesticides against mosquitoes, house flies, lice, green bottle fly, camel nasal botfly, soft and hard ticks, mites, and the diamondback moth as well as control of several parasites using safe and natural materials to avoid drug resistances and environmental contamination.",institutionString:null,institution:{name:"Banha University",country:{name:"Egypt"}}},{id:"99780",title:"Prof.",name:"Omolade",middleName:"Olayinka",surname:"Okwa",slug:"omolade-okwa",fullName:"Omolade Okwa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/99780/images/system/99780.jpg",biography:"Omolade Olayinka Okwa is presently a Professor of Parasitology at Lagos State University, Nigeria. She has a PhD in Parasitology (1997), an MSc in Cellular Parasitology (1992), and a BSc (Hons) Zoology (1990) all from the University of Ibadan, Nigeria. She teaches parasitology at the undergraduate and postgraduate levels. She was a recipient of a Commonwealth fellowship supported by British Council tenable at the Centre for Entomology and Parasitology (CAEP), Keele University, United Kingdom between 2004 and 2005. She was awarded an Honorary Visiting Research Fellow at the same university from 2005 to 2007. \nShe has been an external examiner to the Department of Veterinary Microbiology and Parasitology, University of Ibadan, MSc programme between 2010 and 2012. She is a member of the Nigerian Society of Experimental Biology (NISEB), Parasitology and Public Health Society of Nigeria (PPSN), Science Association of Nigeria (SAN), Zoological Society of Nigeria (ZSN), and is Vice Chairperson of the Organisation of Women in Science (OWSG), LASU chapter. She served as Head of Department of Zoology and Environmental Biology, Lagos State University from 2007 to 2010 and 2014 to 2016. She is a reviewer for several local and international journals such as Unilag Journal of Science, Libyan Journal of Medicine, Journal of Medicine and Medical Sciences, and Annual Research and Review in Science. \nShe has authored 45 scientific research publications in local and international journals, 8 scientific reviews, 4 books, and 3 book chapters, which includes the books “Malaria Parasites” and “Malaria” which are IntechOpen access publications.",institutionString:"Lagos State University",institution:{name:"Lagos State University",country:{name:"Nigeria"}}},{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/273100/images/system/273100.jpeg",biography:"Dr. Vijay Bhaskar Reddy Gayam is currently practicing as an internist at Interfaith Medical Center in Brooklyn, New York, USA. He is also a Clinical Assistant Professor at the SUNY Downstate University Hospital and Adjunct Professor of Medicine at the American University of Antigua. He is a holder of an M.B.B.S. degree bestowed to him by Osmania Medical College and received his M.D. at Interfaith Medical Center. His career goals thus far have heavily focused on direct patient care, medical education, and clinical research. He currently serves in two leadership capacities; Assistant Program Director of Medicine at Interfaith Medical Center and as a Councilor for the American\r\nFederation for Medical Research. As a true academician and researcher, he has more than 50 papers indexed in international peer-reviewed journals. He has also presented numerous papers in multiple national and international scientific conferences. His areas of research interest include general internal medicine, gastroenterology and hepatology. He serves as an editor, editorial board member and reviewer for multiple international journals. His research on Hepatitis C has been very successful and has led to multiple research awards, including the 'Equity in Prevention and Treatment Award” from the New York Department of Health Viral Hepatitis Symposium (2018) and the 'Presidential Poster Award” awarded to him by the American College of Gastroenterology (2018). He was also awarded 'Outstanding Clinician in General Medicine” by Venus International Foundation for his extensive research expertise and services, perform over and above the standard expected in the advancement of healthcare, patient safety and quality of care.",institutionString:"Interfaith Medical Center",institution:{name:"Interfaith Medical Center",country:{name:"United States of America"}}},{id:"93517",title:"Dr.",name:"Clement",middleName:"Adebajo",surname:"Meseko",slug:"clement-meseko",fullName:"Clement Meseko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/93517/images/system/93517.jpg",biography:"Dr. Clement Meseko obtained DVM and PhD degree in Veterinary Medicine and Virology respectively. He has worked for over 20 years in both private and public sectors including the academia, contributing to knowledge and control of infectious disease. Through the application of epidemiological skill, classical and molecular virological skills, he investigates viruses of economic and public health importance for the mitigation of the negative impact on people, animal and the environment in the context of Onehealth. \r\nDr. Meseko’s field experience on animal and zoonotic diseases and pathogen dynamics at the human-animal interface over the years shaped his carrier in research and scientific inquiries. He has been part of the investigation of Highly Pathogenic Avian Influenza incursions in sub Saharan Africa and monitors swine Influenza (Pandemic influenza Virus) agro-ecology and potential for interspecies transmission. He has authored and reviewed a number of journal articles and book chapters.",institutionString:"National Veterinary Research Institute",institution:{name:"National Veterinary Research Institute",country:{name:"Nigeria"}}},{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",country:{name:"India"}}},{id:"94928",title:"Dr.",name:"Takuo",middleName:null,surname:"Mizukami",slug:"takuo-mizukami",fullName:"Takuo Mizukami",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94928/images/6402_n.jpg",biography:null,institutionString:null,institution:{name:"National Institute of Infectious Diseases",country:{name:"Japan"}}},{id:"233433",title:"Dr.",name:"Yulia",middleName:null,surname:"Desheva",slug:"yulia-desheva",fullName:"Yulia Desheva",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/233433/images/system/233433.png",biography:"Dr. Yulia Desheva is a leading researcher at the Institute of Experimental Medicine, St. Petersburg, Russia. She is a professor in the Stomatology Faculty, St. Petersburg State University. She has expertise in the development and evaluation of a wide range of live mucosal vaccines against influenza and bacterial complications. Her research interests include immunity against influenza and COVID-19 and the development of immunization schemes for high-risk individuals.",institutionString:'Federal State Budgetary Scientific Institution "Institute of Experimental Medicine"',institution:null},{id:"238958",title:"Mr.",name:"Atamjit",middleName:null,surname:"Singh",slug:"atamjit-singh",fullName:"Atamjit Singh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/238958/images/6575_n.jpg",biography:null,institutionString:null,institution:null},{id:"333753",title:"Dr.",name:"Rais",middleName:null,surname:"Ahmed",slug:"rais-ahmed",fullName:"Rais Ahmed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333753/images/20168_n.jpg",biography:null,institutionString:null,institution:null},{id:"252058",title:"M.Sc.",name:"Juan",middleName:null,surname:"Sulca",slug:"juan-sulca",fullName:"Juan Sulca",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252058/images/12834_n.jpg",biography:null,institutionString:null,institution:null},{id:"191392",title:"Dr.",name:"Marimuthu",middleName:null,surname:"Govindarajan",slug:"marimuthu-govindarajan",fullName:"Marimuthu Govindarajan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/191392/images/5828_n.jpg",biography:"Dr. M. Govindarajan completed his BSc degree in Zoology at Government Arts College (Autonomous), Kumbakonam, and MSc, MPhil, and PhD degrees at Annamalai University, Annamalai Nagar, Tamil Nadu, India. He is serving as an assistant professor at the Department of Zoology, Annamalai University. His research interests include isolation, identification, and characterization of biologically active molecules from plants and microbes. He has identified more than 20 pure compounds with high mosquitocidal activity and also conducted high-quality research on photochemistry and nanosynthesis. He has published more than 150 studies in journals with impact factor and 2 books in Lambert Academic Publishing, Germany. He serves as an editorial board member in various national and international scientific journals.",institutionString:null,institution:null},{id:"274660",title:"Dr.",name:"Damodar",middleName:null,surname:"Paudel",slug:"damodar-paudel",fullName:"Damodar Paudel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274660/images/8176_n.jpg",biography:"I am DrDamodar Paudel,currently working as consultant Physician in Nepal police Hospital.",institutionString:null,institution:null},{id:"241562",title:"Dr.",name:"Melvin",middleName:null,surname:"Sanicas",slug:"melvin-sanicas",fullName:"Melvin Sanicas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241562/images/6699_n.jpg",biography:null,institutionString:null,institution:null},{id:"337446",title:"Dr.",name:"Maria",middleName:null,surname:"Zavala-Colon",slug:"maria-zavala-colon",fullName:"Maria Zavala-Colon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Puerto Rico, Medical Sciences Campus",country:{name:"United States of America"}}},{id:"338856",title:"Mrs.",name:"Nur Alvira",middleName:null,surname:"Pascawati",slug:"nur-alvira-pascawati",fullName:"Nur Alvira Pascawati",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universitas Respati Yogyakarta",country:{name:"Indonesia"}}},{id:"441116",title:"Dr.",name:"Jovanka M.",middleName:null,surname:"Voyich",slug:"jovanka-m.-voyich",fullName:"Jovanka M. 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Novel computational algorithms for image analysis, scene understanding, biometrics, deep learning and their software or hardware implementations for natural and medical images, robotics, VR/AR, applications are some research directions relevant to this topic.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",hasOnlineFirst:!0,hasPublishedBooks:!1,annualVolume:11420,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. 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\r\n\tIn general, the harsher the environmental conditions in an ecosystem, the lower the biodiversity. Changes in the environment caused by human activity accelerate the impoverishment of biodiversity.
\r\n
\r\n\tBiodiversity refers to “the variability of living organisms from any source, including terrestrial, marine and other aquatic ecosystems and the ecological complexes of which they are part; it includes diversity within each species, between species, and that of ecosystems”.
\r\n
\r\n\tBiodiversity provides food security and constitutes a gene pool for biotechnology, especially in the field of agriculture and medicine, and promotes the development of ecotourism.
\r\n
\r\n\tCurrently, biologists admit that we are witnessing the first phases of the seventh mass extinction caused by human intervention. It is estimated that the current rate of extinction is between a hundred and a thousand times faster than it was when man first appeared. The disappearance of species is caused not only by an accelerated rate of extinction, but also by a decrease in the rate of emergence of new species as human activities degrade the natural environment. The conservation of biological diversity is "a common concern of humanity" and an integral part of the development process. Its objectives are “the conservation of biological diversity, the sustainable use of its components, and the fair and equitable sharing of the benefits resulting from the use of genetic resources”.
\r\n
\r\n\tThe following are the main causes of biodiversity loss:
\r\n
\r\n\t• The destruction of natural habitats to expand urban and agricultural areas and to obtain timber, minerals and other natural resources.
\r\n
\r\n\t• The introduction of alien species into a habitat, whether intentionally or unintentionally which has an impact on the fauna and flora of the area, and as a result, they are reduced or become extinct.
\r\n
\r\n\t• Pollution from industrial and agricultural products, which devastate the fauna and flora, especially those in fresh water.
\r\n
\r\n\t• Global warming, which is seen as a threat to biological diversity, and will become increasingly important in the future.
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\r\n\tThe environment is subject to severe anthropic effects. Among them are those associated with pollution, resource extraction and overexploitation, loss of biodiversity, soil degradation, disorderly land occupation and planning, and many others. These anthropic effects could potentially be caused by any inadequate management of the environment. However, ecosystems have a resilience that makes them react to disturbances which mitigate the negative effects. It is critical to understand how ecosystems, natural and anthropized, including urban environments, respond to actions that have a negative influence and how they are managed. It is also important to establish when the limits marked by the resilience and the breaking point are achieved and when no return is possible. The main focus for the chapters is to cover the subjects such as understanding how the environment resilience works, the mechanisms involved, and how to manage them in order to improve our interactions with the environment and promote the use of adequate management practices such as those outlined in the United Nations’ Sustainable Development Goals.
\r\n\tPollution is caused by a wide variety of human activities and occurs in diverse forms, for example biological, chemical, et cetera. In recent years, significant efforts have been made to ensure that the environment is clean, that rigorous rules are implemented, and old laws are updated to reduce the risks towards humans and ecosystems. However, rapid industrialization and the need for more cultivable sources or habitable lands, for an increasing population, as well as fewer alternatives for waste disposal, make the pollution control tasks more challenging. Therefore, this topic will focus on assessing and managing environmental pollution. It will cover various subjects, including risk assessment due to the pollution of ecosystems, transport and fate of pollutants, restoration or remediation of polluted matrices, and efforts towards sustainable solutions to minimize environmental pollution.
\r\n\tWater is not only a crucial substance needed for biological life on Earth, but it is also a basic requirement for the existence and development of the human society. Owing to the importance of water to life on Earth, early researchers conducted numerous studies and analyses on the liquid form of water from the perspectives of chemistry, physics, earth science, and biology, and concluded that Earth is a "water polo". Water covers approximately 71% of Earth's surface. However, 97.2% of this water is seawater, 21.5% is icebergs and glaciers, and only 0.65% is freshwater that can be used directly by humans. As a result, the amount of water reserves available for human consumption is limited. The development, utilization, and protection of freshwater resources has become the focus of water science research for the continued improvement of human livelihoods and society.
\r\n
\r\n\tWater exists as solid, liquid, and gas within Earth’s atmosphere, lithosphere, and biosphere. Liquid water is used for a variety of purposes besides drinking, including power generation, ecology, landscaping, and shipping. Because water is involved in various environmental hydrological processes as well as numerous aspects of the economy and human society, the study of various phenomena in the hydrosphere, the laws governing their occurrence and development, the relationship between the hydrosphere and other spheres of Earth, and the relationship between water and social development, are all part of water science. Knowledge systems for water science are improving continuously. Water science has become a specialized field concerned with the identification of its physical, chemical, and biological properties. In addition, it reveals the laws of water distribution, movement, and circulation, and proposes methods and tools for water development, utilization, planning, management, and protection. Currently, the field of water science covers research related to topics such as hydrology, water resources and water environment. It also includes research on water related issues such as safety, engineering, economy, law, culture, information, and education.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/41.jpg",keywords:"Water, Water resources, Freshwater, Hydrological processes, Utilization, Protection"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 24th, 2022",hasOnlineFirst:!0,numberOfOpenTopics:4,numberOfPublishedChapters:314,numberOfPublishedBooks:31,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},subseries:[{id:"14",title:"Cell and Molecular Biology",keywords:"Omics (Transcriptomics; Proteomics; Metabolomics), Molecular Biology, Cell Biology, Signal Transduction and Regulation, Cell Growth and Differentiation, Apoptosis, Necroptosis, Ferroptosis, Autophagy, Cell Cycle, Macromolecules and Complexes, Gene Expression",scope:"The Cell and Molecular Biology topic within the IntechOpen Biochemistry Series aims to rapidly publish contributions on all aspects of cell and molecular biology, including aspects related to biochemical and genetic research (not only in humans but all living beings). We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics include, but are not limited to: Advanced techniques of cellular and molecular biology (Molecular methodologies, imaging techniques, and bioinformatics); Biological activities at the molecular level; Biological processes of cell functions, cell division, senescence, maintenance, and cell death; Biomolecules interactions; Cancer; Cell biology; Chemical biology; Computational biology; Cytochemistry; Developmental biology; Disease mechanisms and therapeutics; DNA, and RNA metabolism; Gene functions, genetics, and genomics; Genetics; Immunology; Medical microbiology; Molecular biology; Molecular genetics; Molecular processes of cell and organelle dynamics; Neuroscience; Protein biosynthesis, degradation, and functions; Regulation of molecular interactions in a cell; Signalling networks and system biology; Structural biology; Virology and microbiology.",annualVolume:11410,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"79367",title:"Dr.",name:"Ana Isabel",middleName:null,surname:"Flores",fullName:"Ana Isabel Flores",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRpIOQA0/Profile_Picture_1632418099564",institutionString:null,institution:{name:"Hospital Universitario 12 De Octubre",institutionURL:null,country:{name:"Spain"}}},{id:"328234",title:"Ph.D.",name:"Christian",middleName:null,surname:"Palavecino",fullName:"Christian Palavecino",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000030DhEhQAK/Profile_Picture_1628835318625",institutionString:null,institution:{name:"Central University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",fullName:"Francisco Javier Martin-Romero",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",institutionString:null,institution:{name:"University of Extremadura",institutionURL:null,country:{name:"Spain"}}}]},{id:"15",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",annualVolume:11411,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null,editorialBoard:[{id:"241413",title:"Dr.",name:"Azhar",middleName:null,surname:"Rasul",fullName:"Azhar Rasul",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRT1oQAG/Profile_Picture_1635251978933",institutionString:null,institution:{name:"Government College University, Faisalabad",institutionURL:null,country:{name:"Pakistan"}}},{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",fullName:"Sergey Sedykh",profilePictureURL:"https://mts.intechopen.com/storage/users/178316/images/system/178316.jfif",institutionString:null,institution:{name:"Novosibirsk State University",institutionURL:null,country:{name:"Russia"}}}]},{id:"17",title:"Metabolism",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. Thus all studies on metabolism will be considered for publication.",annualVolume:11413,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",fullName:"Anca Pantea Stoian",profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"203824",title:"Dr.",name:"Attilio",middleName:null,surname:"Rigotti",fullName:"Attilio Rigotti",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"Pontifical Catholic University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"300470",title:"Dr.",name:"Yanfei (Jacob)",middleName:null,surname:"Qi",fullName:"Yanfei (Jacob) Qi",profilePictureURL:"https://mts.intechopen.com/storage/users/300470/images/system/300470.jpg",institutionString:null,institution:{name:"Centenary Institute of Cancer Medicine and Cell Biology",institutionURL:null,country:{name:"Australia"}}}]},{id:"18",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",annualVolume:11414,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,editorialBoard:[{id:"72288",title:"Dr.",name:"Arli Aditya",middleName:null,surname:"Parikesit",fullName:"Arli Aditya Parikesit",profilePictureURL:"https://mts.intechopen.com/storage/users/72288/images/system/72288.jpg",institutionString:null,institution:{name:"Indonesia International Institute for Life Sciences",institutionURL:null,country:{name:"Indonesia"}}},{id:"40928",title:"Dr.",name:"Cesar",middleName:null,surname:"Lopez-Camarillo",fullName:"Cesar Lopez-Camarillo",profilePictureURL:"https://mts.intechopen.com/storage/users/40928/images/3884_n.png",institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",institutionURL:null,country:{name:"Mexico"}}},{id:"81926",title:"Dr.",name:"Shymaa",middleName:null,surname:"Enany",fullName:"Shymaa Enany",profilePictureURL:"https://mts.intechopen.com/storage/users/81926/images/system/81926.png",institutionString:"Suez Canal University",institution:{name:"Suez Canal University",institutionURL:null,country:{name:"Egypt"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"chapter.detail",path:"/chapters/46432",hash:"",query:{},params:{id:"46432"},fullPath:"/chapters/46432",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()