IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\n
By listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
All three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n
"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n
"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\n
In conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n
“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\n
We invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\n
Feel free to share this news on social media and help us mark this memorable moment!
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\n
By listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
All three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n
"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n
"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\n
In conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n
“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\n
We invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\n
Feel free to share this news on social media and help us mark this memorable moment!
\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:"6111",leadTitle:null,fullTitle:"Mobile Robots: towards New Applications",title:"Mobile Robots",subtitle:"towards New Applications",reviewType:"peer-reviewed",abstract:"The range of potential applications for mobile robots is enormous. 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1. Introduction
The history of nonsteroidal anti-inflammatory drugs (NSAIDs) dates as far back as thousands of years with Hippocrates and other physicians prescribing the willow bark for a wide range of conditions [1]. The tone for the modern era of NSAIDs was, however, set by identifying salicin as the willow plant’s active ingredient and the subsequent introduction of acetylsalicylic acid by the Bayer Company about two centuries later [2]. Today in addition to aspirin, nonselective NSAIDs, such as piroxicam, mefenamic acid, diclofenac, naproxen, and selective cyclooxygenase-2 (COX-2) inhibiting NSAIDs, such as celecoxib and rofecoxib, remain mainstays of pain and inflammatory disorder therapy.
NSAIDs remain one of the most consumed drugs either by prescription or over-the-counter [3]. Their fever relieving effect has been well documented since their discovery and they have proven effective over the years in controlling pain and inflammatory conditions. It is particularly effective in acute and chronic orthopedic pain (osteoarthritis, ankylosing spondylitis, and rheumatoid arthritis) and postsurgical pain [4]. While these represent the traditional uses of NSAIDs, studies have pointed to their potential in Alzheimer’s [5], cancer [6], and Parkinson’s disease [7]. Most of these studies exploit the benefits of controlling the underlying inflammatory mechanisms of these diseases.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of therapeutic agents with diverse structural and pharmacodynamics profiles but similar mode of action. Broadly, NSAIDs are grouped into aspirin and nonaspirin NSAIDs. Despite similarities in their mechanism of action and toxicity profiles, they differ slightly in the manner they each interact with the cyclooxygenase enzyme [8]. A more popular classification, however, is based on structural differences and similarities [9]. They are grouped as follows: salicylates (aspirin), aryl alkanoic acids (diclofenac, indomethacin, nabumetone, sulindac), 2-arylpropionic acids or profens (ibuprofen, flurbiprofen, ketoprofen, and naproxen), n-arylanthranilic acids or fenamic acids (mefenamic acids, meclofenamic acid, pyrazolidine derivatives, e.g., phenylbutazone), oxicams (piroxicam, meloxicam), and sulfonamides (nimesulide).
2. Mechanism(s) of NSAIDs action
2.1. COX and COX inhibition
There is overwhelming evidence pointing to the inhibition of cyclooxygenase enzyme as the main mechanism of NSAIDs’ analgesic, antipyretic, and anti-inflammatory properties. Since the characterization of this mechanism by Vane for aspirin [10], other drugs in this class have proven consistent this mechanism. This is surprising considering the differences in structures of the individual drugs as described above. Cyclooxygenase (COX) inhibition and the resulting inhibition of prostaglandin and other eicosanoid synthesis mitigate pain, fever, and inflammation. The cyclooxygenase (COX) enzyme also known as prostaglandin endoperoxide H synthase (PGHS) exists in two isoforms: PGHS-1 or COX-1 and PGHS-2 or COX-2. There is a significant structural distinction between the two, with only 60% homology [11]. Although encoded by different genes, both isoforms are membrane-bound glycoproteins that catalyze the formation of prostanoid from arachidonic acid [12].
COX-1 is expressed constitutively in most mammalian cells and tissues such as seminal vesicle, platelets, and endothelium. In quiescent conditions, it performs ongoing regulatory functions referred to as “housekeeping duties.” Prostaglandins produced by COX-1 activity perform functions such as gastro and renal protection, macrophage differentiation, platelet aggregation, and mucus production [3, 13]. In inflammatory conditions, molecular studies have demonstrated that COX-1 mRNA and protein expression do not change, confirming their limited role in the inflammatory process [14]. COX-1, however, remains both experimentally and clinically relevant due to the adverse effects triggered by the nonselective inhibition of cyclooxygenase enzymes by some NSAIDs.
COX-2 is an inducible enzyme called upon by tissue injury and other stimuli such as lipopolysaccharide (LPS), interleukin-1, and tumor necrosis factor alpha (TNFα) [15, 16]. It is active at injury sites and in a variety of tissues such as the vascular endothelium, and rheumatoid synovial endothelial cells mediating inflammatory, pain, fever, and carcinogenic responses [17, 18]. A manifold increase in COX-2 levels occurs in inflammatory processes triggering an increased synthesis of pro-inflammatory prostaglandins. Initially thought of as exclusively inducible in nature, studies have shown COX-2 has some constitutive or regulatory roles. Housekeeping duties in reproduction, renal physiology, bone resorption, and neurotransmission have been documented [19, 20].
Indeed studies have shown that both isotypes are constitutive and inducible depending on the physiological conditions [21, 22]. COX-3, a third isotype, has been identified [23]. Its function, distribution, and role in NSAIDs mechanisms are still uncertain and subject of debate [24].
2.2. Pain, fever, and inflammation
The arachidonic acid pathway is central to inflammatory responses and consequently the mechanism of action of NSAIDs. Prostanoids, the end product of this pathway, performs a wide range of physiological functions.
NSAIDs are largely thought of as inhibitors of peripheral pain though several works in literature point to a potential and significant central analgesic activity. At the periphery, a host of mediators occurs to trigger nociception in response to physical, chemical, or electrical stimuli. Prostaglandins act synergistically with other mediators to sensitize nociceptors [10, 25]. Some NSAIDs have exhibited central analgesic effects in several animal models of pain. This is attributed to disruption of synthesis of central prostaglandins and other modulators in the nociceptive pathway. Arguments in favor of central activity stem from studies showing the inhibitory effect of NSAIDs on N-methyl-D-aspartate (NMDA) receptor activation-induced prostaglandin expression in cerebrospinal fluid [26] and antinociceptive effect of spinally administered ibuprofen [27] among others. A classic study by Hunskaar [28] showed overlapping time-effect relationship for aspirin and morphine in the first phase of formalin-induced pain response; a feature highly indicative of central activity.
NSAIDs have proven effective in inflammatory conditions such as arthritis, acute trauma, and pain associated with inflammation. Inflammatory mediators at injury site mediate vasodilation extravasation of protein exudates and nociception. Here, prostaglandins that are key players in this process are inhibited. Though COX inhibition is maintained as the main mechanism for the anti-inflammatory activity of NSAIDs, other mechanisms loosely referred to as non-COX mechanisms have been reported in the literature. NSAIDs are documented to have the suppressive effect in nuclear factor (NF)-κB, a transcription factor for pro-inflammatory proteins such as chemokines, adhesion molecules, and cytokines. NSAIDs also exhibit some suppression of activator protein 1, membrane stabilizing, and inhibition of reactive oxygen species (ROS) production [29–31]. Although these are believed to contribute at a molecular level, it is unclear how they directly aid in the clinical benefits of NSAIDs.
NSAIDs relieve fever by inhibiting COX-mediated prostaglandin synthesis. Upon exposure to external pyrogens, mostly pathogen-associated molecular patterns (lipopolysaccharide, peptidoglycan, viral RNA, etc.), cells of the innate immune system respond by releasing endogenous pyrogens to induce pyrexia. Circulating interleukin-1, interleukin-6, and TNFα gets to the brain and induced the synthesis of prostaglandin via the cyclooxygenase in the preoptic hypothalamic region of the brain. Prostaglandin E2 (PGE2) binds to an EP-3 receptor of the endothelium of the hypothalamus to reset the body’s thermoregulation. An ensuing physiological process occurs to attain this set temperature. NSAIDs disrupt this process by COX inhibition and therefore have proven useful in curbing the harmful effects of high and persistent temperatures. It is important to note that they have no effect on normal body temperature or atypical rise in temperature such as malignant hyperthermia and heat stroke. Mechanisms in these cases are independent of the COX/prostaglandin inflammatory pathway.
2.3. Structure and mechanisms
Current studies have made it possible to understand the structural basis of both nonselective cyclooxygenase inhibition and COX-2 selective inhibition and the variations in individual NSAID’s interactions with COX. The catalytic site of COX-1 is long narrow hydrophobic channel spanning from the membrane-binding domain to the enzyme core. The threshold of the channel is made up of polar groups such as Arg120 and Glu524. NSAIDs bind at the upper portion of this channel specifically at a region near TYR385 and ARG120. Acidic NSAIDs, for instance, interact with ARG120 via hydrophobic and electrostatic forces [32].
While aspirin for instance irreversibly inhibits the COX enzyme by covalently modifying it active Ser529 [10], other NSAIDs such as ibuprofen and naproxen bind reversibly [33]. Studies by Kurumbail et al. [34] revealed a COX-2 3D structure closely resembling COX-1. An extra pocket in the COX-2 catalytic site, however, is created by the valine replacements at positions 523 and 434 (occupied by isoleucine in COX-1). This alteration in structure, among others, is exploited in the design of COX-2 selective drugs.
2.4. H2S-releasing derivatives of anti-inflammatory drugs
NSAIDs, including selective COX-2 inhibitors, are able to stimulate adherence of leukocytes to the vascular endothelium in the mesenteric circulations [35–38] and that has been strongly associated with NSAID-induced gastric damage [37–39]. With studies pointing to the ability of H2S donors to suppress leukocyte adherence, it would have been expected that an H2S-releasing NSAID would not induce leukocyte adherence and will be devoid of the gastric damaging property of NSAIDs. This is actually the case and was realized with studies conducted employing H2S-releasing derivative of diclofenac (ATB-337) on leukocyte adherence and gastric mucosal integrity in rat [40]. The diclofenac derivative did not stimulate leukocyte adherence and also not elevate lymphocyte function-associated antigen 1 (LFA-1) or intercellular adhesion molecule 1 (ICAM-1), as was observed in diclofenac; also, it did not cause gastric damage [41]. The H2S-releasing diclofenac, however, did not significantly inhibit gastric prostaglandin synthesis and systemic COX-1 activity [40]. Similar profile in activity was also observed in the H2S-releasing derivative of indomethacin (ATB-343).
H2S-releasing derivatives of NSAIDs have also been established to reduce infiltration of leukocytes in models of inflammation. A diclofenac derivative has been shown to reduce LPS-induced infiltration of neutrophils into the lung and liver [41]; also an H2S-releasing derivative of mesalamine profoundly reduced granulocyte infiltration in a mouse model of colitis [42] with effect significantly greater than that observed in the parent molecules in each case. H2S-releasing diclofenac was also realized to be more potent than diclofenac in reducing paw edema in the carrageenan-induced paw edema model in rat.
The upregulation in TNF-α and COX-2 expression in the rat stomach [43, 44] by NSAIDs is not observed in the H2S-releasing derivatives of NSAIDs despite their ability to cause marked suppression of gastric prostaglandin synthesis [40]. Moreover, these derivatives inhibit endotoxin-induced NF-κB activation and the associated increase in plasma TNF-α, nitrate, and nitrite [41].
2.5. Antitumor action of NSAIDs
NSAIDs have many effects that might contribute to chemoprevention of cancers such as colorectal cancer (CRC). This mode of prevention can be either COX-dependent or COX-independent which can be synergistic at different steps of this multistep process [45] with evidence for replacement of adenomatous polyposis coli (APC) function by NSAIDs. In this direction, sulindac and indomethacin have been shown to inhibit tumorigenesis through inhibition of peroxisome proliferator-activated receptor delta (PPARδ), a gene that is normally regulated by APC [46]. Currently, alterations of the COX-2-related pathways are in primary focus [47].
With NSAIDs being transcriptional inhibitors of COX-2 expression [48], these agents might selectively inhibit the induction of apoptosis in human intestinal stem cells with aberrant Wnt signaling [49]. The most compelling evidence of the possible chemopreventive action of some NSAIDs was the finding that aspirin reduces the risk of CRC in individuals with elevated COX-2 expression but not in those without [50] with associated reduced mortality [51], in an observational study. This was however experimentally confirmed when data affirmed the involvement of prostaglandins and nonprostaglandin COX-2 products were central to the development of CRC [52].
Measurable levels of NSAID-activated gene-1 (NAG-1) were detected in an NSAID-treated human CRC cell line. NAG-1 belongs to the transforming growth factor beta (TGFβ)-superfamily of growth factors and plays a significant role in apoptosis and tumorigenesis. In the CRC cells, NAG-1 expression positively correlates apoptosis and inversely correlates with COX-2 expression, with NAG-1 upregulation linked with NSAID administration in a Prostaglandin-independent manner [53]. Overexpression of NAG-1 in APC-mutated Min/+ mice results in reduced tumorigenesis. Interestingly, however, high COX-2 expression in colorectal tumors is associated with decreased expression of NAG-1, suggesting a reciprocal relationship [54]. It is henceforth being speculated that high levels of COX-2 in colorectal tumors suppress the expression of NAG-1; hence induction of NAG-1 by NSAIDs might contribute to the chemopreventive action of these agents [55].
Aspirin has a unique property of acetylating COX-2, which is not seen in other NSAIDs. This switches COX-2 from synthesizing prostaglandins (PGE2) (tumor promotion) to antitumorigenic 15-epi-lipoxin-A4 (LXA4), a 5-lipoxygenase catalyzed reaction. 15-epi-lipoxin-A4 is anti-inflammatory as well as anti-proliferative on carcinoma cells [56]. This effect of aspirin is seen at low antiplatelet doses with one study with 75 mg/day for 10 days not only reducing PGE2 formation and white cell accumulation in inflamed tissues but also significantly increasing local lipoxin production [57]. This establishes that the anticancer potential of aspirin may be due to lipoxin production.
Several studies also point to COX-2 independent actions may also play a role in apoptosis and such pathways have been realized to be sensitive to NSAIDs. Not all human CRCs express COX-2 and produce prostaglandins [58, 59]. However, the potency of NSAIDs to inhibit proliferation is similar to COX-2 producing CRC [60]. This is suggestive of the fact that the antitumor actions of NSAIDs are not necessarily via inhibition of COX-2 or prostaglandin formation [45, 59]. Sulindac reduces the number of aberrant crypt foci and adenomas in patients under conditions when etodolac, COX-2 inhibitor, was ineffective [61]. Moreover, sulindac was also found to significantly increase NAG-1 even in COX-2-deficient tumor cell lines [53].
The potential COX-2-independent mechanism of NSAIDs’ antineoplastic action includes downregulation of proto-oncogenes, such as c-myc, and transcriptional factors such as PPARδ, NF-κB, prostate apoptosis response-4 (PAR-4), and Bcl-2. The most recent therapeutic approach therefore entails combining NSAIDs and epidermal growth factor (EGF) receptor inhibitors in chemoprevention of CRC [62].
3. Conclusion
The therapeutic importance of NSAIDs in the management of acute and chronic pain and inflammation cannot be overemphasized. Also with the emergence of their therapeutic benefits in cancers, it is worth chronicling its pharmacological profile, specifically their established and expected mechanistic pathways of eliciting their activity. With promising outcomes in the experimental studies with improved gastrointestinal effects associated with modified NSAIDs and potential anticancer activity of NSAIDs, we strongly believe there is more to NSAIDs than we currently know. This chapter will henceforth give an insight into what is known and what could be possibly done in advancing the therapeutic potentials of NSAIDs beyond the management of pain and inflammation as we know.
\n',keywords:"nonsteroidal anti-inflammatory drugs, inflammation, cyclooxygenase, pain, fever",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/55279.pdf",chapterXML:"https://mts.intechopen.com/source/xml/55279.xml",downloadPdfUrl:"/chapter/pdf-download/55279",previewPdfUrl:"/chapter/pdf-preview/55279",totalDownloads:4834,totalViews:7460,totalCrossrefCites:9,totalDimensionsCites:20,totalAltmetricsMentions:0,impactScore:13,impactScorePercentile:99,impactScoreQuartile:4,hasAltmetrics:0,dateSubmitted:"October 19th 2016",dateReviewed:"February 23rd 2017",datePrePublished:null,datePublished:"August 23rd 2017",dateFinished:"May 10th 2017",readingETA:"0",abstract:"The use of nonsteroidal anti-inflammatory drugs (NSAIDs) dates back to thousands of years when man used natural sources of these agents in a lot of pain and inflammatory conditions. The tone for modern day discovery and use of NSAIDs was set with the discovery of aspirin. Today in addition to aspirin, a host of other NSAIDs of varying potency and efficacy is employed in the management of pain and inflammatory conditions. This chapter looks with key interest in the existing and evolving role of NSAIDs in therapeutics with emphasis on the current insights into their mechanism of action and side effect profiles associated with its use in pain and inflammation as well as its potential therapeutic benefits in cancer chemotherapy.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/55279",risUrl:"/chapter/ris/55279",book:{id:"5872",slug:"nonsteroidal-anti-inflammatory-drugs"},signatures:"Newman Osafo, Christian Agyare, David Darko Obiri and Aaron\nOpoku Antwi",authors:[{id:"182058",title:"Dr.",name:"Christian",middleName:null,surname:"Agyare",fullName:"Christian Agyare",slug:"christian-agyare",email:"cagyare.pharm@knust.edu.gh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Kwame Nkrumah University of Science and Technology",institutionURL:null,country:{name:"Ghana"}}},{id:"196452",title:"Dr.",name:"Newman",middleName:null,surname:"Osafo",fullName:"Newman Osafo",slug:"newman-osafo",email:"nosafo.pharm@knust.edu.gh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/196452/images/5741_n.jpg",institution:{name:"Kwame Nkrumah University of Science and Technology",institutionURL:null,country:{name:"Ghana"}}},{id:"197415",title:"Prof.",name:"David",middleName:null,surname:"Darko Obiri",fullName:"David Darko Obiri",slug:"david-darko-obiri",email:"ddobiri.pharm@knust.edu.gh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"197428",title:"Mr.",name:"Aaron",middleName:null,surname:"Antwi",fullName:"Aaron Antwi",slug:"aaron-antwi",email:"aaronantwi77@gmail.com",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. Mechanism(s) of NSAIDs action",level:"1"},{id:"sec_2_2",title:"2.1. COX and COX inhibition",level:"2"},{id:"sec_3_2",title:"2.2. Pain, fever, and inflammation",level:"2"},{id:"sec_4_2",title:"2.3. Structure and mechanisms",level:"2"},{id:"sec_5_2",title:"2.4. H2S-releasing derivatives of anti-inflammatory drugs",level:"2"},{id:"sec_6_2",title:"2.5. Antitumor action of NSAIDs",level:"2"},{id:"sec_8",title:"3. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Rao P, Knaus EE. Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): Cyclooxygenase (COX) inhibition and beyond. Journal of Pharmacy & Pharmaceutical Sciences. 2008;11(2):81-110'},{id:"B2",body:'Vane JR. The fight against rheumatism: From willow bark to COX-1 sparing drugs. Journal of Physiology and Pharmacology. 2000;51:573-586'},{id:"B3",body:'Bozimowski G. A review of nonsteroidal anti-inflammatory drugs. 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Nonsteroidal anti-inflammatory drugs and the induction of apoptosis in colon cells: Evidence for PHS-dependent and PHS-independent mechanisms. Apoptosis. 1999;4(5):373-381'},{id:"B46",body:'He TC, Chan TA, Vogelstein B, Kinzler KW. PPAR delta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell. 1999;99(3):335-345'},{id:"B47",body:'Wang D, Dubois RN. The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene. 2010;29(6):781-788'},{id:"B48",body:'Wu KK. Salicylates and their spectrum of activities. Anti-Inflammatory, Anti-Allergy Agents in Medicinal Chemistry. 2007;6:278-292'},{id:"B49",body:'Qiu W, Wang X, Leibowitz B, Liu H, Barker N, Okada H, et al. Chemoprevention by non-steroidal anti-inflammatory drugs eliminates oncogenic intestinal stem cells via SMAC-dependent apoptosis. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(46):20027-20032'},{id:"B50",body:'Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. The New England Journal of Medicine. 2007;356(21):2131-2142'},{id:"B51",body:'Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. Journal of the American Medical Association. 2009;302(6):649-658'},{id:"B52",body:'Fischer SM, Hawk E, Lubet RA. Non-steroidal anti-inflammatory drugs and coxibs in chemoprevention: A commentary based primarily on animal studies. Cancer Prevention Research. 2011;4(11):1728-1735'},{id:"B53",body:'Baek SJ, Kim KS, Nixon JB, Wilson LC, Eling TE. Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities. Molecular Pharmacology. 2001;59(4):901-908'},{id:"B54",body:'Iguchi G, Chrysovergis K, Lee SH, Baek SJ, Langenbach R, Eling TE. A reciprocal relationship exists between non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1) and cyclooxygenase-2. Cancer Letters. 2009;282(2):152-158'},{id:"B55",body:'Schrör K. Pharmacology and cellular/molecular mechanisms of action of aspirin and non-aspirin NSAIDs in colorectal cancer. Best Practice & Research Clinical Gastroenterology. 2011;25:473-484'},{id:"B56",body:'Claria J, Lee MH, Serhan CN. Aspirin-triggered lipoxins (15-epi-LX) are generated by the human lung adenocarcinoma cell line (A549)-neutrophil interactions and are potent inhibitors of cell proliferation. Molecular Medicine. 1996;2(5):583-596'},{id:"B57",body:'Morris T, Stables M, Hobbs A, de Souza P, Colville-Nash P, Warner T, et al. Effects of low-dose aspirin on acute inflammatory responses in humans. The Journal of Immunology. 2009;183(3):2089-2096'},{id:"B58",body:'Marnett LJ. Aspirin and the potential role of prostaglandins in colon cancer. Cancer Research. 1992;52(20):5575-5589'},{id:"B59",body:'Hanif R, Pittas A, Feng Y, Koutsos MI, Qiao L, Staiano-Coico L, Shiff SI, Rigas B. 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1. Introduction
Snakes produce venoms that finds its use in immobilizing and digesting the prey and acts as an effective defense system against threats. Thus, venom is a functional trait utilized by an organism to regulate homeostatic processes of another organism i.e., it mediates the outcome of interactions between two or more organisms [1]. These snake venoms are storehouse of fascinating and useful bioactive compounds. Although various studies have been carried out on venoms, only few of them are well understood and tapped for their potential use in medicine as pharmacological molecules and diagnostics, understanding the molecular mechanisms of bodily processes such as homeostasis, coagulation, thrombosis, angiogenesis, and metastasis. The enthusiasm to understand animal envenomation and associated medical treatments has driven the animal venom studies in a multifaceted manner [2]. This chapter deals with what is venom, need for venom, evolution of venom, the poison apparatus that aids in producing the venom, genetics and biochemistry of the venom, effects of venom, antivenom, and applications of venom as therapeutics, diagnostics, and as biochemical tool.
2. Venom
Venom in layman’s terms is modified snake saliva. This concoction is a combination of zootoxins, enzymes, and pharmacologically active peptides [3, 4, 5]. Digestive enzymes and other proteins that act as a paralyzing and pre-digestive agent. Digestion is therefore initiated outside the predator’s alimentary canal while simultaneously immobilizing the prey. The snake then swallows the prey whole, liquefying most of the tissue and discarding what cannot be digested (feathers/hair/claws) along with the fecal matter. Although venomous snakes apply venom in the acquisition of the prey, they also fan out them in defensive bites against intimidating predators and aggressors.
2.1 The need for venom
Snakes are carnivores and actively hunt their prey. Most of them are ambush hunters and generalized feeders. Their geographic distribution and dietary preferences being varied, snakes had to evolve a method of incapacitating their prey quickly and their answer was venom. Geographic location and varied diet have led to the development of more and more complex venom. Being generalized feeders, many species of snake have a larger repertoire of proteins in their venom that affect individual prey animal species differently [6]. Honing the composition, mechanism of delivery, dosage and action of venom remains one of nature’s greater success stories to date. Venom production has aided the proliferation and diversification of snakes as a group.
2.2 Evolution of venom in snakes
The evolution of snakes remains a partially solved mystery to scientists. Though they have known that snakes are descended from lizards since the 1970’s there are many missing links due to a lack of proper fossil evidence. Debates of their descent from aquatic or terrestrial lizards persist as there is evidence to support both hypotheses. But the evolution of venom on the other hand has started to unravel. Initial research suggested that the venom and the venom delivery apparatus evolved together. But in 2002 a group of scientists in Australia led by Dr. B. Fry made amazing roads into the history of the evolution of venom. The major factor in the previous theory was that though many species had fangs they were in different locations in the jaw, size, and structure. The venom gland on the other hand remained the same.
Dr. Fry and his team examined the idea that the production of venom must predate the use of fangs. They looked at the extant lizard species which were said to contain toxins in their saliva. They discovered that the Komodo dragon and many of their related monitor lizards all had venom glands at the base of the lower jaw. This venom mixed with saliva caused damage to the prey previously thought to be caused by bacteria mixed in the saliva. The venom was like snake venom [7]. Most lizard species have been shown to have a gland like the venom gland of snakes, this led to the theory that snakes and lizards had a common venomous ancestor and that venom predated fangs.
Discoveries have shown around 1500 species of lizards had components like snake venom. Sea snakes are considered to have diverged from terrestrial snakes around 30 mya. Their venom is highly toxic. Studies have shown that they are evolving more complex toxin molecules to suit their ever-changing prey. This goes to show that venom is still evolving. The dietary preferences of the snake can magnify the change in venom. The snake can produce a potent mixture that can affect different prey animals uniquely [6]. There is no efficient antivenin generated against sea snakes.
There are so many species of snakes whose venom composition is yet to be studied in detail. These studies are crucial in understanding the evolution of venom and the effect of venom on prey species [8].
3. Poison apparatus
In reptiles, twice the venom glands have evolved; once in helodermatid lizards and secondly in advanced snakes belonging to colubroids, viperids, elapids and astractaspidids [9]. Venomous snakes belong to 4 genera. These snakes possess a poison apparatus or venom producing glands in their heads, which produces toxic substance that acts as either a poison or a venom. When the toxic substance is injected into the body of prey, it is venomous.
3.1 General plan
A poison apparatus of a snake consists of snakes consists of 4 major parts, namely, a pair of poison gland, poison ducts, fangs and muscles.
3.1.1 Poison glands
These glands situated on either side of the upper jaw, is possibly the superior labial glands or parotid glands. Each poison gland has a sac-like capsule and a narrow duct at the anterior end. The vascular fibrous septum of the capsule separates glandular substances into secretory pockets. The duct after passing along the sides of the upper jaw, opens at the base of the fang or at the base of the tunnel on the fang. The poison glands are held in position via anterior and posterior ligaments, which attaches anterior end of glands to maxilla and posterior end to the quadrate respectively. The fan shapes ligaments are situated between the side walls and squamosal-quadrate junction.
3.1.2 Ducts
The pair of ducts opens into a pocket of mucous sheath that covers the basal part of the fang. In spitting cobras (Naja nigricollis), the poison duct is modified into ‘L’ shaped bend prior to exiting the fang.
3.1.3 Fangs
The fangs evolved to inject venom into the prey is a grooved or tubular tooth. The paired pointed and hook-like teeth are modified form of maxillary teeth. They are long, curved, sharp and pointed. Based on the structure and position, fangs are of 3 types:
Proteroglyphous (Protero – first)
These are small, grooved, articulated at permanently erect at the anterior end of maxillae. They are found in Cobras, Kraits, Coral snakes and Sea snakes.
Opisthoglyphous (Opistho - behind)
They are small and grooved but remain associated with posterior end of maxillae.
Solenoglyphous (Solen – pipe; glyph - hollow)
This type of fangs is seen in vipers and rattle snakes. A large functional fang occurs on the front of each maxilla and are movable and turned inside to lie in the roof of mouth when it is closed. This fang contains a narrow hollow poison canal with enamel, which opens at anterior end of the fang.
3.1.4 Muscles
Positioning and functioning of the poisonous apparatus is enabled by the presence of 3 types of muscle bands, namely, Digastrics, Sphenopterygoid, and Anterior and posterior temporalis.
3.2 Venom glands of elapidae
Early description about the elapid venom gland dates to 1936 [10]. Elapidae venom gland is enclosed in a tough capsule of connective tissue and more compactly built than that of viperid snakes. It consists of a posterior main gland and an anterior secretory duct with an accessory mucous gland. Simple or compound multiple contiguous tubules that run in a posterior–anterior direction is seen in the main gland. The tubules converge toward the centre of the gland and open into a small lumen. The secretory epithelium is of a serous nature. Secretory cells of elapids at resting stage are loaded with granules that differ in structure and number than those found in viperid venom gland. The cells of the accessory glands are PAS-positive, and their secretions mainly consists of sialomucins [11].
3.3 Venom glands of viperidae
The venom glands belonging to two viperid subfamilies, namely Viperinae and Crotalinae exhibit similarity in shape and structure. Except for the mole vipers belonging to the genus Atractaspis, all other have a glandular structure. The mole vipers differ in not possessing a differentiated accessory glands unique to the “genuine” vipers. The glands consist of large numbers of radial tubules surrounding a central lumen. The tubules are unbranched, and the luminal end consists of a mucous epithelium [12]. The venom of Atractaspis engaddensis has a relatively high alkaline monophaosphatase activity and is devoid of arginine ester hydrolase activity that is seen in other vipers. The first person to give a detailed account of venom glands of a true viper, Vipera berus, is Wolter in 1924 [13].
The venom gland has four distinct regions: the main gland, the primary duct, the accessory glands, and the secondary duct that leads to the fang sheath. The accessory glands have two distinct regions. The anterior part is lined by mucous epithelium that contains goblet cells while the posterior part is lined with flat to cuboidal epithelium, correlating with the secretory function [14]. The main gland is made of repeatedly branched tubules arranged around a large central lumen, where a considerable amount of venom can be stored. The tubules are made of secretory cells.
3.4 Venom glands of colubroidea
A pair of homologous oral venom glands located behind the eye on either side of the upper jaw are connected to the ducts that transfers the secreted venom to the base if morphologically diverse teeth, fangs [15].
3.5 Venom glands of sea snakes
The venom glands and related muscles of sea snakes are like the general structure that we observe in the terrestrial elapids. The considerable reduction in venom gland as well as the accessory gland is attributed to the aquatic environment. An early divergence of sea snakes from an ancestral elapis stock has been proposed as the musculus compressor glandulae is well developed in the sea snakes. A possible phylogenetic relationship exists between Australian elapids and hydrophiine snakes which is evident from the similarities that exists between them [16].
3.6 Changes in venom gland following milking process
Morphological changes in the secretory epithelium of venom gland after the expulsion of venom was noticed by Velikii in Vipera ammodytes [17] which was later confirmed by further studies [18, 19].
4. Genetics of snake venom
The bioactivity of the venom is determined by the complex and variable interactions between genes, their expression, their translation, and their post translational modification. Evidence that the loss of genes also has a strong influence on shaping venom phenotypes further reinforces the usage of animal venom systems to understand adaptation in the natural world is evident from the loss of genes that have a strong effect on forming the venom phenotype [20].
5. Biochemistry and physiology of snake venom
Venom was identified to be a proteinaceous concoction in the 1800s. 90 to 95% of the dry weight of venom is made of proteins. These proteins are also responsible for the biological effects of the venom. These proteins can be classified as enzymes and toxins [21]. The components of venom can vary from animal to animal within a species too. Research has shown that age [22], gender [23], geographic location [24], prey species/diet [25] and season [26] can all influence the composition of venom. All the proteins involved in venom are repurposed from regular physiological functions.
The proteins identified in venom have been studied individually, as protein complexes and as protein families. The proteins in the complex can be homodimers (made up of identical subunits) or heterodimers (made up of different subunits – sometimes these subunits are from different families). These complexes are held together by covalent bonds and the complexes are pharmacologically more potent than the individual enzymes or proteins. The complexes seem to expose critical residues that otherwise may have been buried in the individual enzymes [27].
5.1 Enzymes in snake venom
Typically, snake venom contains hundreds of components, all of which work in tandem to paralyze the prey and initiate digestion. Many enzymes are found and even some toxins have enzymatic functions. The most studied enzymes and their role are discussed below.
5.1.1 5’ Nucleotidase (5’-NT)
This is an enzyme made up of 548 amino acids and a molecular mass of 61 kDa found in almost all living cells. The enzyme hydrolyses nucleosides. It is found in all snake venom around the world. Isoforms have also been isolated, like the isoform from the venom of Vipera lebetina (Cypriot blunt-nosed viper) that is found to be a homodimeric monomer with a molecular mass of 60 kDa. This isomer inhibits ADP- or Collagen-induced platelet aggregation [28]. The isomer isolated from the Japanese pit viper (Gloydius blomhoffii blomhoffii) shows that the enzyme has 2 binding sites for Zn + and can exist as a trimer or a tetramer [29]. Venomous snakes belonging to the family Viperidae (Vipera russelli russelli- Russell’s viper, Echis carinatus- Indian saw-scaled viper, Eristocophis macmahonii - Asian sand viper) were studied in the country of Pakistan and were all found to have high 5’-NT activity venom wise [30]. Among the snakes in Brazil that were studied, Bothrops brazili (Brazil’s lancehead) had the highest 5’-NT activity. On the other hand, venom from Philodryas olferssi (South American green racer), a snake endemic to South America, showed little or no activity of 5’-NT. Among all the snakes studied there were differences in zymology and banding patterns among the enzymes thereby implying important physical structural differences [31]. The enzyme 5’-NT is found to act synergistically with other enzymes and have a pronounced anti-coagulant effect. It is said to liberate adenosine, and this helps immobilize the prey. In 2008, it was showed that the whole enzyme or a part of it is secreted in the venom. The soluble form of the enzyme is released by cleavage of the ectodomain in the venom gland or specialized tissues [29].
5.1.2 Acetylcholinesterase (AChE)
It is the primary enzyme that catalyzes the breakdown of Acetylcholine in the body among other related neurotransmitters. AChE is found in nerve and muscle tissue, especially abundant in synaptic junctions. This is perhaps one of the well-studied enzymes from snake venom, its structure has been elucidated in detail. AChE is abundant in the venom of all snakes and higher concentrations are observed in the Elapid snakes except the Mambas [32]. Although the enzyme is present in the venom of snakes belonging to Viperidae and Crotalidae the activity was not detected. The highest concentration of venom AChE (VAChE) is found in the venom of Bungarus sp. 8 mg/gm of dried weight [33]. VAChE is found to be optimally active at 45° C and pH 8.5 [34].
The protein structure of VAChE shows homology to mammalian and Torpedo AChE with a few major changes. These changes ensure that VAChE has a less complicated structure than membrane-bound AChE. Many isoenzymes exist and can be differentiated on charge alone [35]. Protein structure has been studied from the VAChE of Bungarus fasciatus (BfAChE) and Naja naja oxiana (NnAChE). BfAChE exists as a soluble hydrophobic monomer. The C terminal peptide has an alternative exon (‘S’). It is made up of 15 residues, the last 8 of these are removed in the mature protein. Compared to mammalian AChE, BfAChE has the following changes: Tyr70 is replaced by Met70, Acidic residue285 (glutamate/aspartate) is replaced by Lys285. The active site gorge is 20 A° deep and has two ligand-binding sites [36]. The crystallized structure shows evidence for a co-existing open/closed state in the back door channel and semi occuled gorge entrance. The presence of Met70 enlarges the entrance of the gorge, enabling better binding. It can form canonical dimers of subunits despite non-amphiphilic C terminus.
The NnAChE exists as a monomer at 0.2 mg/ml and a dimer at 2 mg/ml. It is a single polypeptide chain with a molecular weight of 67,000 ± 2000 Da and exists in several isoforms with different isoelectric points [37]. It differs from BfAChE by having a dimerization domain where His replaces Pro at position 514 [38]. VAChE has been associated with acute neuromuscular paralysis and neuromuscular weakness. This may be due to a defective transmission in the neuromuscular junction [5]. The function of AChE in elapid venoms could be to aid in the immediate hydrolysis of acetylcholine released from synaptic vesicles. This release could be under the influence of β-neurotoxin to avoid competitive protection by acetylcholine of postjunctional receptors against α-neurotoxin [39].
5.1.3 Phosphatases–acid phosphatase (ACP) and alkaline phosphatase (ALP)
These enzymes are found in lysosomes and during digestion they work on releasing the phosphoryl groups from molecules. They are found in all snake venoms. Both enzymes have a greater action in Elapids than Viperids. In a study that compared Cerastes cerastes (Saharan horned viper), Cerestes vipers (Saharan sand viper), Naja haje (Egyptian cobra) and N. nigricollis (Blacked neck spitting cobra) showed that N. nagiricollis showed higher ACP activity than ALP. But both enzymes needed Mg++ to activate them [40]. The enzymes play an important role in liberating the purines, mainly Adenosine, thereby aiding immobilization of the prey organism. The Purines act as multi-toxins inducing hypotension and paralysis [41] via purine receptors in the prey’s body [42].
5.1.4 Hyaluronidase (Hyl)
Hyaluronidases are a group of enzymes that are responsible for the degradation of Hyaluronic acid (HA), a glycosaminoglycan commonly found in abundance in nervous, epithelial, and connective tissues in all animals. Isolation and biological characterization of Hyl has been done from the venom of many snakes including N. naja – Indian Cobra [43], Agkistrodon contortrix contortrix – Eastern Copperhead [44], C. cerastes – Saharan Horned Viper [45], Crotalus durissus terrificus – South American Rattlesnake [46], Bothrops pauloensis- South American Pit viper and Bungarus caerulecs - Indian Krait. The snake Hyaluronidase (SHyl) from the venom of Bungarus caerulecs (Indian Krait) was found to have a molecular weight of 14 ± 2 kDa. The enzyme has an optimum temperature of 37°C and an optimum pH of 6 [47].
The cDNA of SHyl isolated B. pauloensis venom gland shows a protein with 194 amino acids synthesized from 1175 bps. The cDNA variants of SHyl isolated Echis pyramidum leakeyi (Kenyan Carpet Viper), Echis carinatus sochureki (Sochurek’s saw-scaled viper) and Bitis arietans (Puff Adder) all show the presence of a truncated protein: Hy-L- 1000 that encodes the consensus amino- and carboxyl-termini with a central deletion of 256 residues, Hy-L-750 that lacks the consensus amino-terminus and Hy-L-500 that lacks the amino-terminus and encodes a shorter carboxy-terminal segment [48]. The SHyl is referred to as a ‘Spreading factor’ as it destroys the extracellular matrix (ECM). By degrading Hyaluronic acid, the enzyme increases the permeability of the tissue paving the way for the other venom toxins to act [49]. Many Hyaluronidase-type proteins have been identified in snake venom. These variants are produced by alternative splicing pathways. The Hyaluronidase-type proteins have not been isolated or characterized as they are highly temperature and pH-sensitive.
5.1.5 Phospholipases
These are enzymes that generally hydrolyze phospholipids into fatty acids and lipophilic substances. There are four major classes named A, B, C and D which are differentiated by the type of reaction they catalyze. Phospholipase A2 (PLA2) is found to be present in the venom of snakes and bees [50]. The enzyme acts on intact lectin molecules and hydrolyses the fatty acids esterified to the second carbon atom [51]. The venom enzymes are like mammalian enzymes in structure and function. The Phospholipase A2 enzymes found in venom are further grouped as I, II and IIE. Group I are major components of Elapidae venom, Group II are major components Viperidae venom [52] and IIE have been identified in the venom of non-front fanged snakes [53]. This enzyme which has a high affinity to specific receptors and a separate pharmacological site can target a large spectrum of tissues and thereby induce pharmacological effects which are dependent or independent of the catalytic activity of the enzyme.
There exist many unique examples of modulation of PLA2 activity generated by molecular evolution. The enzyme can exist as a homodimer, a post synaptic complex called Vipoxin (South-Eastern European Viper, Vipera ammodytes meridionalis). It is composed of PLA2 along with an acidic/catalytic inactive PLA2 like component called the inhibitor (Inh). Both components have 62% sequence homology. It is thought that the Inh acts to stabilize the enzyme component. It could have evolved from the catalytic molecule to the inhibitor [54]. Further studies have shown that a single change in amino acid sequence alters the function of the molecule. Gln48 PL A2 (V. ammodytes meridionalis) acts as a chaperone molecule and directs a toxic His48 PLA2 onto an acceptor. Homodimer of Gln48 PLA2 or His48 PLA2 is less toxic when compared to the heterodimer containing both Gln48 PLA2 and His48 PLA2. In another example, neonates of the Mexican jumping viper, Metapilcoatlus sp., have been reported to lack PLA2s but in contrast the adults have large quantities of the enzyme. But the venom of both the neonates and the adults was found to be haemorrhagic [55].
5.1.6 L-amino acid oxidases
L-amino acid oxidases (LAAOs) are multifunctional enzymes. They produce hydrogen peroxide and ammonia as part of their catalytic activity. These are highly toxic and can destroy major components of the cell viz. nucleic acids, proteins and the plasma membrane [56]. Snake venom L-amino acid oxidases (SVLAAOs) were first detected in the venom of Vipera aspis. SVLAAOs are homodimers with cofactors FAD (Flavin Adenine Dinucleotide) or FMD (Flavin Mononucleotide) linked covalently. Abundance of Riboflavin, also a pigment, is a major contributor to the yellow color of snake venom [57].
SVLAAOs vary between snake species. The enzymes when injected into the prey cause the formation of oxygen reactive species extracellularly. These highly toxic oxygen reactive species, hydrogen peroxide and ammonia, alter the permeability of the plasma membrane and induce apoptosis, which in turn leads to cell death [58]. The SVLAAOs are dependent on ions for activation and inactivation. The LAAOs found in the venom of Crotalus adamanteus, Eastern Diamondback rattlesnake, require Mg2+ to be activated [59], whereas the enzymes in the venom of Lachesis muta, South American Bushmaster, and Bothrops brazli, Lancehead pit viper, are inhibited by the binding of Zn2+ [60].
Analysis of the sequences of SVLAAOs from around the globe showed ~60% similarity. The most dissimilar regions were the C and N terminals of the protein. Most SVLAAOs are rich in asparagine, glutamic acid and aspartic acid residues. The number of cysteine residues varies implying variation in the tertiary structure of these proteins [61].
5.1.7 Metalloproteinases
Metalloproteinases are typically enzymes that depend on a metal ion to aid their catalytic activity. Snake venom Metalloproteinases (SVMPs) are Zinc (Zn2+) dependent enzymes. Their size ranges from 20 to 110 kDa. They are broadly grouped into three (PI, PII, PIII) based on their structural domains. SVMPs in their varied isoforms are responsible for heaemorrhagic and coagulopathic nature of snake venoms. The SVMPs act on the different stages of the blood clotting pathway [62, 63].
5.2 Toxins in snake venom
The myriad of toxins found in snake venom are biologically costly to produce but potent and snakes have invested years of evolution to refine them. Many other toxins are species-specific and have been grouped by their pharmacological action to enable easy study. Though many toxins have been named, the neurotoxins and hemotoxins dominate them all. The identification, isolation characterization and evolution of snake venom toxins have been an area of prolific research since the 1970s.
5.2.1 Neurotoxins in snake venom: three-finger toxin (3FTx) super family
Many of the toxins predominant in snake venom belong to the three-finger toxin (3FTx) family. The group is named for the specific protein fold of three β strand loops connected to a central core with four disulphide bonds. This is a conserved feature. The proteins in this family are at an average of 60 to 74 amino acid residues in length [64]. These 3FTxs are peculiar to snakes although the superfamily of three-fold proteins is common to all eukaryotes [65]. Studies have shown that the 3FTxs of snakes have evolved from non-toxic three-finger proteins [3].
The number of 3FTxs varies from species to species. Elapsid and Colubrid venom are found to be abundant in 3FTxs [66]. 95% of the proteins in the venom of Micrurus tschudii, the desert coral snake [67], 70% of the proteins in the venom of Ophiophagus hannah, the King Cobra [68] and Dendroaspis angusticeps, the Eastern green mamba [69] are 3FTxs. These toxins bind post-synaptically and induce flaccid paralysis in the prey animal.
The structural differences between members of the family are broadly based on the length and number of disulphide bridges. - the longer 3FTxs with a chain length of 66–74 residues with 5 disulphide bridges (Examples: α-neurotoxins, γ-neurotoxins, hannalgesin, κ-neurotoxins) and the shorter chains with a chain length of 57–62 residues with 4 disulphide bridges (Examples: α-neurotoxins, β-cardiotoxins, cytotoxins, fasciculins and mambalgins). The 3FTxs can exist as covalent/non-covalent homo or heterodimers.
The mechanism of action of 3FTxs is varied despite them all having the same 3-finger fold. α-neurotoxins have been shown to inhibit acetylcholine receptors in muscle synapses [70]. κ-neurotoxins on the other hand inhibit acetylcholine receptors in neural synapses [71], fasciculins inhibit acetylcholinesterase [72], mambin interacts with platelet receptors [73], mambaligins inhibit ASIC channels [74] and calliotoxin activates voltage-gated sodium channel [75] to name just a few. It is to be noted that no 3FTxs are involved in inflammation and hyperalgesia typical of other snake toxins. The 3Ftxs target many ion channels and receptors in the prey animal. This is attributed to the unique capacity of the 3-finger fold and its ability to modulate diverse biological functions. Specific amino acid sequences in critical segments of 3FTxs have been identified, these sequences play an important role in binding to the target sites. The interactions of Acetylcholinesterase in the prey with the 3 loops in the fasciculin molecule show the first look of the fasciculin interaction with the outer enzyme but the second loop is inserted in the active site with hydrogen bonding (Lys 25, Arg24, Asn47, Pro31, Leu35 and Ala12) and hydrophobic interactions (Lys32, Cys59, Val34, Leu48, Ser26, Gly36, Thr15 and Asn20) [76]. The interactions of Muscarinic toxins from mamba venom [77], Neurotoxin II (NTII) from the venom of Naja oxiana, the Central Asian Cobra [78], Neurotoxin b (NTb) from the venom of O. hannah, King Cobra [79] have all been studied in detail and reports show the importance of the amino acid sequence in binding and modifying the action of the receptors. Any change in these sequences leads to loss of neurotoxicity of the molecule.
5.2.2 Cardiotoxins/cytotoxins
These toxins attack the cardiac muscle preventing muscle contraction. This leads to the irregularity of heartbeat and ultimately stopping of the heart. Experiments have shown that the toxins tend to bind to the surface of the muscle and cause depolarization. These toxins are ample in mamba venom and few species of cobra venom. Other cardiotoxins interact non-specifically with phospholipids [80] or induce insulin secretion [81]. Β – cardiotoxins inhibit β-adrenoreceptors [82].
Cardiotoxins are single chain, small molecular weight (~ 6.5 kDa) proteins that are highly basic (pI>10). They exhibit a broad spectrum of pharmacological action. The cardiotoxins share significant sequence homology to neurotoxins yet despite this homology they display remarkably different properties. As many as 52 cardiotoxins have been reported and they have a 90% homology of sequence among themselves [83]. Cardiotoxin III (CTx III, Cytotoxin 3) is a 60-residue long toxin peculiar to the Taiwan Cobra (Naja atra). It can induce apoptosis in cells via the release of cytochrome [84]. The structure of cardiotoxin VII4 isolated from Naja mossambica mossambica, the Mozambique spitting cobra, was crystalized proving it was a dimer and have a molecular mass of 6715 Da. Studies have shown the cardiotoxin blocked nicotinic acetylcholine receptors [85].
A set of proteins called Cardiotoxin-like basic proteins (CLBP) are found to have homology with cardiotoxins but where cardiotoxins have the triple peptide signature (-I-D-V-) between 39 and 41, CLBPs lack this. Other differences include CLBPs having a Gln at 17 which is absent in cardiotoxins. CLBPs also lack the Met residue needed for activity [86]. These molecules are now being assessed for therapeutic ability.
6. Effects of snake bite and snake venom
Snake bite is a neglected public health issue in many tropical and subtropical countries. According to WHO (2021), an annual record of about 5.4 million snake bites and 1.8 to 2.7 million cases of envenomings has been reported. They have also reported that about 140,000 deaths occur. Bites by venomous snakes can cause acute medical emergencies involving severe paralysis that may prevent breathing, cause bleeding disorders that can lead to fatal hemorrhage, cause irreversible kidney failure and severe local tissue destruction that can cause permanent disability and limb amputation. The more severe effects experienced by the children is because of their smaller body mass [87].
The response of neurotoxicity to snake antivenom is dependent on the type of neurotoxins that the snake possess. Cobra venom contains post-synaptic nerutoxins that produce curare-like effect and hence can be reversed by snake antivenom after clinical effects have developed. While krait venom which contains many pre-synaptic neurotoxins, causes paralysis that is irreversible once developed and hence their response to antivenom is very poor [88, 89].
7. Antivenom
One of the major public health issues in the rural tropics is snake bites. Currently, the only specific treatment available to ameliorate the effect of snake bite is antivenom [90]. Snake antivenom was produced by raising hyperimmune serum in animals, such as horses. The hyerimmune serum was further purified to produce whole immunoglobulin G (IgG) antivenoms and then fractionated to F(ab) and F(ab′)2 antivenoms to reduce adverse reactions and increase efficacy.
A significant challenge in manufacturing of antivenoms is the preparation of the correct immunogens (snake venoms). At present very few countries have capacity to produce snake venoms of adequate quality for antivenom manufacture, and many manufacturers rely on common commercial sources [87]. Poor data on the number and type of snake bites have led to difficulty in estimating needs, and deficient distribution policies have further contributed to manufacturers reducing or stopping production or increasing the prices of antivenoms. Weak regulation and the marketing of inappropriate or poor quality antivenoms has also resulted in a loss of confidence in some of the available antivenoms by clinicians, health managers, and patients, which has further eroded demand.
8. Applications of snake venoms
8.1 Therapeutic implications
Snake venom consists of pharmacologically active proteins and peptides. The snake venoms show a distinct complexity from other animal venoms in that they possess a diverse array of proteins and peptides with wide range of pharmacological and toxicological effects.
8.1.1 Snake venom-based drugs
Based on the pharmacological effects produced, snake venom has been classified into haemotoxic, neurotoxic and cytotoxic venom. Although snake venoms are considered as mini drug libraries, only about 0.01% venom has been characterized. Snake venom is considered a valuable source of new principal compounds in drug discovery. Components of snake venom such as PLA2, serine proteases, metalloproteinase, lectins, l-amino acid oxidases, bradykinin potentiating factors, natriuretic factors, integrin antagonists possess pharmacological properties and exhibit neurotoxicity, myotoxicity, cytotoxicity, hemotoxicity, antimicrobial activity, which in turn exerts its action and disrupts the central and peripheral nervous systems, the blood coagulation cascade, the cardiovascular and neuromuscular systems and the general homeostasis state [5].
Importance of snake venom in medicine dates to thousands of years in Ayurveda, homeopathy and traditional or folk medicines. Cobra venom is used in the ayurvedic treatment of joint pain, inflammation, and arthritis [91] and other body fluids such as blood and bile duct in Chinese medicine [92] and lots of the snake venom-based drugs are available in the market and in clinical trials [93].
Various drugs based on snake venom in the market are Captopril® (Enalapril), Integrilin® (Eptifibatide) and Aggrastat® (Tirofiban) and many more are in the pipeline at pre-clinical or clinical trial stage [94]. Captopril®, approved by FDA in 1981, was the first successful drug derived from snake venom [95]. This drug is a biomimetic of bradykinin-potentiating peptide, isolated from the venom of Brazilian arrowhead viper Bothrops jararaca, was discovered by the Nobel prize winner Sir John Vane and its commercial production was taken care of by the pharmaceutical giant Squibb. It finds its use in treating hypertension and cardiovascular disease, where it acts by inhibiting the angiotensin converting enzyme that converts angiotensin I to angiotensin II [96].
Two drugs based on snake venom disintegrins, Aggrastat® (Tirofiban) marketed by Medicure Pharma in the US and Correvio International outside US, and Integrilin® (Eptifibatide) developed by Millennium Pharmaceuticals and co-promoted by Schering-Plow (which are both now part of Merck and Takeda Pharmaceuticals) are used as antiplatelet agents [97]. Aggrastat, belonging to the platelet glycoprotein (GP) IIb/IIIa inhibitors and developed based on the RGD sequence (Arg-Gly-Asp) motif from snake venom disintegrins isolated from the venom of E. carinatus is administered to treat heart attack patients [98]. Integrilin, which is used for treating acute coronary syndrome, is a peptide drug which mimics a small portion of the glycoprotein (GP) IIb/IIIa inhibitor barbourin found in the venom of the Southeastern pygmy rattlesnake (Sistrurus miliarus barbouri) based on the KGD sequence (Lys-Gly-Asp) [99]. Both Aggrastat® and Integrilin® was approved for medical use by FDA in 1998.
Defibrase®/Reptilase® (Batroxobin), a drug based on the thrombin-like serine protease enzyme isolated from the snake venom of two subspecies Bothrops atrox and Bothrops moojeni [100] is an approved drug mainly used in China to treat a range of disorders, including stroke, pulmonary embolism, deep vein thrombosis, myocardial infarction and perioperative bleeding. Another drug derived from the venom of B. atrox, Hemocoagulase® has been widely used in plastic surgery, abdominal surgery, and human vitrectomy [101]. Exanta® (Ximelagatran) derived from cobra venom, a thrombin inhibitor anticoagulant, is used as blood thinner and thrombin inhibitor [102].
Botrocetin® is a drug that is developed based on the platelet aggregating protein from the venom of B. jararaca and it is found to enhance the affinity of the von Willebrand factor A1 domain for the platelet receptor glycoprotein Ibalpha (GPIbalpha) [103]. The thrombin like serine proteinase RVV-V from Vipera russelli venom, an activator of factor V of the blood coagulation cascade, is tried for destabilizing and selectively inactivating factor V in plasma [104]. Ecarin, a metalloprotease isolated from the venom of the saw-scaled viper (E. carinatus) is used as prothrombin activator [105].
8.1.2 Putative therapeutic substances
Taipoxin, a powerful presynaptic neurotoxin from Oxyuranus scutellatus (Australian taipan) snake venom, consists of three polypeptides, referred as alpha, beta, and gamma subunits. Trypsin degradation of the β-subunit yields Oxynor which has pharmacological properties against wounds [106]. Oxynor was subjected to clinical development by Ophidia Products, Inc., but no further progress has reported in literature.
Vicrostatin (VCN) is a chimeric disintegrin, made by the fusion of echistatin and contortrostatin, seen in crotalids snake venom. When VCN, packaged in liposome (LVCN), was intravenously administered in vivo to breast cancer models, a delayed tumor growth and prolong animal survival was observed [107]. The drug was in pre-clinical studies by Applied Integrin Sciences Inc., but no further progress has reported in literature.
In vitro studies of Salmosin, a disintegrin of 7.8 kDa (73 residues), isolated from Agkistrodon halys brevicaudus (Korean mamushi) venom, demonstrated its capacity to inhibit the proliferation of bovine capillary endothelial cells, induced by bFGF (basic fibroblast growth factor) by competing with ECM for binding with αvβ3, detaches cells, and inactivates FAK-dependent signaling pathways, thereby leading to apoptosis [108]. Hence, Salmosin could be used as an anti-cancer agent in future.
Hannalgesin, an α-neurotoxin of approximately 7.9 kDa (72 residues) isolated from O. hannah (King cobra) venom, exhibits analgestic effect through nitric oxide or opioid systems. Its analgesic effect is higher than morphine [109].
8.2 Diagnostics
The feature of not being not affected by therapeutic or physiological coagulation inhibitors [Marsh, 2002], it has been applied for the analysis of hemostatic parameters, such as fibrinogen (dysfibrinogenemia, its breakdown products), antithrombin III, prothrombin (dysprothrombinaemias), von Willebrand factor (vWF), blood clot- ting factors (V, VII, X), protein C (PC), activated protein C (APC), and lupus anticoagulants (LA) [110]. Protac® and Proc Global assay, reptilase® and reptilase time, Anti-nAChR antibodies assay, textarin time, botrocetin®, RVV-V, RVV-X, and dRVVT (dilute Russell’s viper venom time), etc. are the tests available [111].
8.3 Biochemical tool
The structures, functions and molecular mechanisms of receptors/ ion-channels that exhibit high potency, selectivity, and efficacy can be studied using snake venom peptides as molecular probes [112]. α- neurotoxins such as erabutoxin, α-cobratoxin, and α- bungarotoxin have high affinity for nicotinic acetylcholine receptors (nAChR). This feature is applied in isolating the α-bungarotoxin, from Bungarus sp. [113]. The muscarinic neurotoxins (MTs) or mamba toxin produced by D. angusticeps (green mamba) and related species is composed of 64–66 amino acids, homologous to α-neurotoxins and are highly selective for muscarinic receptor subtypes (mAChRs) [114]. This study gains importance in studying the role of mAChRs in Alzheimer’s disease using mamba toxin and used as therapeutic agent in treating Alzheimer’s and Parkinson’s disease as it selectively blocks the receptor sub-types [115]. Dendrotoxins and related proteins, from Dendroaspis species (mamba snakes), belonging to sub-family of voltage-dependent potassium channels, are homologous to Kunitz-type serine protease inhibitors, composed of 57–60 amino acids polypeptide chain that is stabilized by the presence of three disulphide bridges. Therefore, these toxins could serve as biochemical tools to study various sub-type of L-type calcium channels.
9. Conclusions
Snake venoms are complex mixtures of toxins that exhibit interspecies and intraspecies variation due to the rapidly evolving and diverging venom genes in relation to the geographical area, environmental niches etc. The efficacy of snake venom is influenced by these variations. Future implications on the venom study are in the direction for search of effective pharmacological and diagnostic products.
Conflict of interest
“The authors declare no conflict of interest.”
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The modified parotid gland, encapsulated in a muscular sheath, present on each side of the head, below and behind the eye, have large alveoli which temporarily stores the secreted venom and later conveyed by a duct to tubular fangs through which venom is injected. Venoms are complex mixtures of more than 20 different compounds, mostly proteins and polypeptides, including proteins, enzymes and substances with lethal toxicity which are either neurotoxic or haemotoxic in action and exert effects on nervous/muscular impulses and blood components. Lots of research are directed to use venoms as important pharmacological molecules for treating various diseases like Alzheimer’s disease, Parkinson’s disease etc.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/79936",risUrl:"/chapter/ris/79936",signatures:"Asirwatham Pushpa Arokia Rani and Marie Serena McConnell",book:{id:"10885",type:"book",title:"Snake Venom and Ecology",subtitle:null,fullTitle:"Snake Venom and Ecology",slug:null,publishedDate:null,bookSignature:"Dr. Mohammad Manjur Shah, Dr. Umar Sharif, Dr. Tijjani Rufai Buhari and Dr. Tijjani Sabiu Imam",coverURL:"https://cdn.intechopen.com/books/images_new/10885.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-064-0",printIsbn:"978-1-80355-063-3",pdfIsbn:"978-1-80355-065-7",isAvailableForWebshopOrdering:!0,editors:[{id:"94128",title:"Dr.",name:"Mohammad Manjur",middleName:null,surname:"Shah",slug:"mohammad-manjur-shah",fullName:"Mohammad Manjur Shah"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Venom",level:"1"},{id:"sec_2_2",title:"2.1 The need for venom",level:"2"},{id:"sec_3_2",title:"2.2 Evolution of venom in snakes",level:"2"},{id:"sec_5",title:"3. Poison apparatus",level:"1"},{id:"sec_5_2",title:"3.1 General plan",level:"2"},{id:"sec_5_3",title:"3.1.1 Poison glands",level:"3"},{id:"sec_6_3",title:"3.1.2 Ducts",level:"3"},{id:"sec_7_3",title:"3.1.3 Fangs",level:"3"},{id:"sec_8_3",title:"3.1.4 Muscles",level:"3"},{id:"sec_10_2",title:"3.2 Venom glands of elapidae",level:"2"},{id:"sec_11_2",title:"3.3 Venom glands of viperidae",level:"2"},{id:"sec_12_2",title:"3.4 Venom glands of colubroidea",level:"2"},{id:"sec_13_2",title:"3.5 Venom glands of sea snakes",level:"2"},{id:"sec_14_2",title:"3.6 Changes in venom gland following milking process",level:"2"},{id:"sec_16",title:"4. Genetics of snake venom",level:"1"},{id:"sec_17",title:"5. Biochemistry and physiology of snake venom",level:"1"},{id:"sec_17_2",title:"5.1 Enzymes in snake venom",level:"2"},{id:"sec_17_3",title:"5.1.1 5’ Nucleotidase (5’-NT)",level:"3"},{id:"sec_18_3",title:"5.1.2 Acetylcholinesterase (AChE)",level:"3"},{id:"sec_19_3",title:"5.1.3 Phosphatases–acid phosphatase (ACP) and alkaline phosphatase (ALP)",level:"3"},{id:"sec_20_3",title:"5.1.4 Hyaluronidase (Hyl)",level:"3"},{id:"sec_21_3",title:"5.1.5 Phospholipases",level:"3"},{id:"sec_22_3",title:"5.1.6 L-amino acid oxidases",level:"3"},{id:"sec_23_3",title:"5.1.7 Metalloproteinases",level:"3"},{id:"sec_25_2",title:"5.2 Toxins in snake venom",level:"2"},{id:"sec_25_3",title:"5.2.1 Neurotoxins in snake venom: three-finger toxin (3FTx) super family",level:"3"},{id:"sec_26_3",title:"5.2.2 Cardiotoxins/cytotoxins",level:"3"},{id:"sec_29",title:"6. Effects of snake bite and snake venom",level:"1"},{id:"sec_30",title:"7. Antivenom",level:"1"},{id:"sec_31",title:"8. Applications of snake venoms",level:"1"},{id:"sec_31_2",title:"8.1 Therapeutic implications",level:"2"},{id:"sec_31_3",title:"8.1.1 Snake venom-based drugs",level:"3"},{id:"sec_32_3",title:"8.1.2 Putative therapeutic substances",level:"3"},{id:"sec_34_2",title:"8.2 Diagnostics",level:"2"},{id:"sec_35_2",title:"8.3 Biochemical tool",level:"2"},{id:"sec_37",title:"9. Conclusions",level:"1"},{id:"sec_41",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Jackson TNW, Jouanne H, Vidal N. Snake venom in context: Neglected clades and concepts. Frontiers in Ecology and Evolution. 2019;7:332. DOI: 10.3389/fevo.2019.00332'},{id:"B2",body:'Zhang Y. Why do we study animal toxins? Dongwuxue Yanjiu. 2015;36(4):183-222. DOI: 10.13918/j.issn.2095-8137.2015.4.183'},{id:"B3",body:'Casewell NR, Wüster W, Vonk FJ, Harrison RA, Fry BG. Complex cocktails: The evolutionary novelty of venoms. Trends in Ecology & Evolution. 2013;28(4):219-229. 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DOI: 10.1016/s0041-0101(02)00278-7'},{id:"B115",body:'Mulugeta E, Karlsson E, Islam A, Kalaria R, Mangat H, Winblad B, et al. Loss of muscarinic M 4 recep- tors in hippocampus of Alzheimer patients. Brain Research. 2003;960(1):259-262'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Asirwatham Pushpa Arokia Rani",address:"aparani@ldc.edu.in",affiliation:'
PG and Research Department of Zoology, Lady Doak College, Affiliated to Madurai Kamaraj University, Madurai, Tamil Nadu, India
PG and Research Department of Zoology, Lady Doak College, Affiliated to Madurai Kamaraj University, Madurai, Tamil Nadu, India
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It has low toxicity to human health and the environment. It is a good solvent for resins and polymers, replacing solvents derived from petroleum, and can be used as an additive of (bio) fuels. This work aimed to study acidy zeolites (H-BEA, H-MOR, H-MFI, and H-FER) as new heterogeneous catalysts of solketal production, through the ketalization reaction of glycerol with acetone. The catalytic activity showed H-BEA > H-MOR = H-MFI > H-FER after 180 min, in kinetics study. The major conversion was 85% for H-BEA. It was also verified that all the catalysts can be reused four times without washing or pretreatment among reactions in batch reactor. The solketal produced in this work was characterized by comparing it with its commercial standard, obtaining very similar characteristics.",signatures:"Vinicius Rossa, Gisel Chenard Díaz, Germildo Juvenal Muchave, Donato Alexandre Gomes Aranda and Sibele Berenice Castellã Pergher",authors:[{id:"197429",title:"Dr.",name:"Sibele",surname:"Pergher",fullName:"Sibele Pergher",slug:"sibele-pergher",email:"sibelepergher@gmail.com"},{id:"285323",title:"Dr.",name:"Vinicius",surname:"Rossa",fullName:"Vinicius Rossa",slug:"vinicius-rossa",email:"vinnyrossa@gmail.com"},{id:"293254",title:"Ph.D. Student",name:"Germildo",surname:"Muchave",fullName:"Germildo Muchave",slug:"germildo-muchave",email:"germildomuchave@gmail.com"},{id:"293257",title:"Dr.",name:"Gisel Chenard",surname:"Díaz",fullName:"Gisel Chenard Díaz",slug:"gisel-chenard-diaz",email:"gisemarina@yahoo.es"},{id:"293258",title:"Dr.",name:"Donato Alexandre",surname:"Gomes Aranda",fullName:"Donato Alexandre Gomes Aranda",slug:"donato-alexandre-gomes-aranda",email:"donato.aranda@gmail.com"}],book:{id:"8448",title:"Glycerine Production and Transformation",slug:"glycerine-production-and-transformation-an-innovative-platform-for-sustainable-biorefinery-and-energy",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"94936",title:"Dr.",name:"José Luis",surname:"Contreras",slug:"jose-luis-contreras",fullName:"José Luis Contreras",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidad Autónoma Metropolitana",institutionURL:null,country:{name:"Mexico"}}},{id:"153619",title:"Emeritus Prof.",name:"Masahide",surname:"Yasuda",slug:"masahide-yasuda",fullName:"Masahide Yasuda",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/153619/images/2377_n.jpg",biography:null,institutionString:null,institution:{name:"University of Miyazaki",institutionURL:null,country:{name:"Japan"}}},{id:"269599",title:"Dr.",name:"Tomoko",surname:"Matsumoto",slug:"tomoko-matsumoto",fullName:"Tomoko Matsumoto",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"284261",title:"Ph.D.",name:"Israel",surname:"Pala-Rosas",slug:"israel-pala-rosas",fullName:"Israel Pala-Rosas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/284261/images/system/284261.jpg",biography:"Israel Pala-Rosas is a biochemical engineer at the Instituto Tecnológico de Tehuacán (Tehuacán, México), with a Master\\'s degree in chemical engineering from the Benemérita Universidad Autónoma de Puebla (Puebla, México) and a Ph.D. in chemical engineering from the School of Chemical Engineering and Extractive Industries of the Instituto Politécnico Nacional (México).\nDr. Pala-Rosas has experience in the areas of production and quality in the canned food and beverage industry, and also in the processing of triglycerides for the production of soap and biodiesel. In addition, he has served as a professor at higher level institutions where he has been co-director of thesis and synodal at the undergraduate and graduate levels in works on catalysis, reactor modeling, and separation processes.\nHis interest lays in the research and development of catalytic and biotechnological processes for the transformation of biomass-derived molecules to compounds of technological and industrial interest. He focuses his work on the synthesis, characterization, and testing of catalysts, as well as the design and analysis of chemical and biochemical reactors. Areas related to the catalytic processes, such as chemical thermodynamics, unit operations, and economics, are also under his scope.",institutionString:"Instituto Politécnico Nacional",institution:{name:"Instituto Politécnico Nacional",institutionURL:null,country:{name:"Mexico"}}},{id:"284262",title:"Dr.",name:"Jose",surname:"Salmones",slug:"jose-salmones",fullName:"Jose Salmones",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRe9pQAC/Profile_Picture_2022-04-22T09:36:13.jpg",biography:"José Salmones graduated with a Ph.D. from the Universidad Autónoma Metropolitana-Iztapalapa (Mexico), an M.A. in Chemical Engineering from the Universidad Autónoma Metropolitana-Iztapalapa (Mexico) and is a chemical engineer from the Universidad Veracruzana (Veracruz, Mexico). \r\nDr. Salmones has taught numerous courses in the Postgraduate Studies and Research Section of the Higher School of Chemical Engineering and Extractive Industries of the Instituto Politécnico Nacional (Mexico), his place of assignment since 2004. Previously, he has held various positions at the Instituto Mexicano del Petróleo and at the Universidad Autónoma Metropolitana. He is the author of 65 international indexed articles, co-author of a published book, author of two book chapters, and has 27 registered patents, out of which 20 have been granted by the Instituto Mexicano del Petróleo and 2 by the Instituto Politécnico Nacional. He has participated in national and international forums with 217 papers. He has supervised 18 bachelor's thesis, 10 master's, and 2 doctorates. He is a member of the National System of Researchers in Mexico since 1986 and currently has level II.\r\nThe current research of Dr. Salmones deals with the synthesis and application of catalysts and nanostructured materials for the synthesis and storage of hydrogen and carbon dioxide.",institutionString:"ESIQIE-Instituto Politecnico Nacional",institution:null},{id:"284263",title:"Dr.",name:"Beatriz",surname:"Zeifert",slug:"beatriz-zeifert",fullName:"Beatriz Zeifert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"284730",title:"Dr.",name:"Priya",surname:"Samudrala",slug:"priya-samudrala",fullName:"Priya Samudrala",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Monash University",institutionURL:null,country:{name:"Australia"}}},{id:"285216",title:"Prof.",name:"Toshiaki",surname:"Yamashita",slug:"toshiaki-yamashita",fullName:"Toshiaki Yamashita",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"286183",title:"Prof.",name:"Jun",surname:"Wang",slug:"jun-wang",fullName:"Jun Wang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"295779",title:"Prof.",name:"Jose Luis",surname:"Contreras",slug:"jose-luis-contreras",fullName:"Jose Luis Contreras",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"copyright-policy",title:"Copyright Policy",intro:"
As this section deals with legal issues pertaining to the rights of individual Authors and IntechOpen, for the avoidance of doubt, each category of publication is dealt with separately. Consequently, much of the information, for example definition of terms used, is repeated to ensure that there can be no misunderstanding of the policies that apply to each category.
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Copyright is the term used to describe the rights related to the publication and distribution of original Works. Most importantly from a publisher's perspective, copyright governs how Authors, publishers and the general public can use, publish, and distribute publications.
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IntechOpen only publishes manuscripts for which it has publishing rights. This is governed by a publication agreement between the Author and IntechOpen. This agreement is accepted by the Author when the manuscript is submitted and deals with both the rights of the publisher and Author, as well as any obligations concerning a particular manuscript. However, in accepting this agreement, Authors continue to retain significant rights to use and share their publications.
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Originally published in {full citation}. Available from: {DOI}
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Copyright is the term used to describe the rights related to the publication and distribution of original Works. Most importantly from a publisher's perspective, copyright governs how Authors, publishers and the general public can use, publish, and distribute publications.
\n\n
IntechOpen only publishes manuscripts for which it has publishing rights. This is governed by a publication agreement between the Author and IntechOpen. This agreement is accepted by the Author when the manuscript is submitted and deals with both the rights of the publisher and Author, as well as any obligations concerning a particular manuscript. However, in accepting this agreement, Authors continue to retain significant rights to use and share their publications.
\n\n
HOW COPYRIGHT WORKS WITH OPEN ACCESS LICENSES?
\n\n\n\t
By accepting the agreement terms Authors retain their copyright on their Work but grant broad publishing and distribution rights to the publisher.
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Depending on the type of publication (Chapter or Long Form Monograph/Compacts; see definitions below), IntechOpen applies a Creative Commons license to the publication, allowing readers to use and share it freely.
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IntechOpen makes the publication available online under an appropriate license.
\n\n\n
Agreement samples are listed here for the convenience of prospective Authors:
The following definitions apply in this Copyright Policy:
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Author - in order to be identified as an Author, three criteria must be met: (i) Substantial contribution to the conception or design of the Work, or the acquisition, analysis, or interpretation of data for the Work; (ii) Participation in drafting or revising the Work; (iii) Approval of the final version of the Work to be published.
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Work - a Chapter, including Conference Papers, a Scientific Article and any and all text, graphics, images and/or other materials forming part of or accompanying the Chapter/Conference Paper.
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Monograph/Compacts - a full manuscript usually written by a single Author, including any and all text, graphics, images and/or other materials.
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Compilation - a collection of Works distributed in a Book that IntechOpen has selected, and for which the coordination of the preparation, arrangement and publication has been the responsibility of IntechOpen. Any Work included is accepted in its entirety in unmodified form and is published with one or more other contributions, each constituting a separate and independent Work, but which together are assembled into a collective whole.
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Scientific Journal – Periodical publication intended to further the progress of science.
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IntechOpen - Registered publisher with office at 5 Princes Gate Court, London, SW7 2QJ - UNITED KINGDOM
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IntechOpen platform - IntechOpen website www.intechopen.com whose main purpose is to host Monographs in the format of Book Chapters, Long Form Monographs, Compacts, Conference Proceedings, Scientific Journals and Videos.
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Video Lecture – an audiovisual recording of a lecture or a speech given by a Lecturer, recorded, edited, owned and published by IntechOpen.
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All Works published on the IntechOpen platform and in print are licensed under a Creative Commons Attribution 3.0 Unported and Creative Commons 4.0 International License, a license which allows for the broadest possible reuse of published material.
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Copyright on the individual Works belongs to the specific Author, subject to an agreement with IntechOpen. The Creative Common license is granted to all others to:
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Share — copy and redistribute the material in any medium or format
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Adapt — remix, transform, and build upon the material
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An Attribution, giving appropriate credit and providing a link to the license, with an indication as to whether changes to the original were made
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A commitment not to add additional restrictions. In effect, this prohibits the application of legal conditions or technological measures that legally restrict others from doing anything that the license permits.
\n
\n\n
All Works are published under the CC BY 3.0 and CC BY 4.0 license. However, please note that book Chapters may fall under a different CC license, depending on their publication date as indicated in the table below:
Creative Commons Attribution 3.0 Unported (CC BY 3.0)
\n\t\t\t
\n\t\t\t
5 October 2011 (2011-10-05)
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Currently
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Creative Commons 4.0 International (CC BY 4.0) – for Journal Articles
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15 March 2022
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The CC BY 3.0 and CC BY 4.0 license permits Works to be freely shared in any medium or format, as well as the reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as the source Work is cited and its Authors are acknowledged in the following manner:
Originally published in {full citation}. Available from: {DOI}
\n\n
Republishing – More about Attribution Policy can be found here.
\n\n
The same principles apply to Works published under the CC BY-NC-SA 3.0 license, with the caveats that (1) the content may not be used for commercial purposes, and (2) derivative works building on this content must be distributed under the same license. The restrictions contained in these license terms may, however, be waived by the copyright holder(s). Users wishing to circumvent any of the license terms are required to obtain explicit permission to do so from the copyright holder(s).
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DISCLAIMER: Neither the CC BY 3.0 license, CC BY 4.0, nor any other license IntechOpen currently uses or has used before, applies to figures and tables reproduced from other works, as they may be subject to different terms of reuse. In such cases, if the copyright holder is not noted in the source of a figure or table, it is the responsibility of the User to investigate and determine the exact copyright status of any information utilised. Users requiring assistance in that regard are welcome to send an inquiry to permissions@intechopen.com.
\n\n
All rights to Books and Journals and all other compilations published on the IntechOpen platform and in print are reserved by IntechOpen.
\n\n
The copyright to Books, Journals and other compilations is subject to separate copyright from those that exist in the included Works.
Copyright to the individual Works (Chapters) belongs to their specific Authors, subject to an agreement with IntechOpen and the Creative Common license granted to all others to:
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Share — copy and redistribute the material in any medium or format
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\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
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\r\n\t
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\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
\r\n
\r\n\t
\r\n
\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
\r\n
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
\r\n
\r\n\t
\r\n
\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
\r\n
\r\n\t
\r\n
\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
\r\n
\r\n\t
\r\n
\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
\r\n
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\r\n
\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
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She is now a lecturer at the University of Witwatersrand, South Africa, and a principal researcher at the Health Economics and Epidemiology Research Office (HE2RO), South Africa. Dr. Moolla holds a Ph.D. in Psychology with her research being focused on mental health and resilience. In her professional work capacity, her research has further expanded into the fields of early childhood development, mental health, the HIV and TB care cascades, as well as COVID. 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He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. In addition, he is also a Collaborating Professor in several Postgraduate programs at different universities all over the world.",institutionString:null,institution:{name:"Universidad Católica San Antonio de Murcia",country:{name:"Spain"}}},{id:"342152",title:"Dr.",name:"Santo",middleName:null,surname:"Grace Umesh",slug:"santo-grace-umesh",fullName:"Santo Grace Umesh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/342152/images/16311_n.jpg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"333647",title:"Dr.",name:"Shreya",middleName:null,surname:"Kishore",slug:"shreya-kishore",fullName:"Shreya Kishore",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/333647/images/14701_n.jpg",biography:"Dr. Shreya Kishore completed her Bachelor in Dental Surgery in Chettinad Dental College and Research Institute, Chennai, and her Master of Dental Surgery (Orthodontics) in Saveetha Dental College, Chennai. She is also Invisalign certified. She’s working as a Senior Lecturer in the Department of Orthodontics, SRM Dental College since November 2019. She is actively involved in teaching orthodontics to the undergraduates and the postgraduates. Her clinical research topics include new orthodontic brackets, fixed appliances and TADs. She’s published 4 articles in well renowned indexed journals and has a published patency of her own. Her private practice is currently limited to orthodontics and works as a consultant in various clinics.",institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"323731",title:"Prof.",name:"Deepak M.",middleName:"Macchindra",surname:"Vikhe",slug:"deepak-m.-vikhe",fullName:"Deepak M. Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. His research interests include root canal morphology, functionally graded concept, dental biomaterials, epidemiology and dental education, biomimetic restoration, finite element analysis and endodontic regeneration. Dr. Madfa has numerous international publications, full articles, two patents, a book and a book chapter. Furthermore, he won 14 international scientific awards. Furthermore, he is involved in many academic activities ranging from editorial board member, reviewer for many international journals and postgraduate students' supervisor. Besides, I deliver many courses and training workshops at various scientific events. Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Univeristy of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:null},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:null},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"355660",title:"Dr.",name:"Anitha",middleName:null,surname:"Mani",slug:"anitha-mani",fullName:"Anitha Mani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"355612",title:"Dr.",name:"Janani",middleName:null,surname:"Karthikeyan",slug:"janani-karthikeyan",fullName:"Janani Karthikeyan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}},{id:"334400",title:"Dr.",name:"Suvetha",middleName:null,surname:"Siva",slug:"suvetha-siva",fullName:"Suvetha Siva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"SRM Dental College",country:{name:"India"}}}]}},subseries:{item:{id:"2",type:"subseries",title:"Prosthodontics and Implant Dentistry",keywords:"Osseointegration, Hard tissue, Peri-implant soft tissue, Restorative materials, Prosthesis design, Prosthesis, Patient satisfaction, Rehabilitation",scope:"
\r\n\tThe success of dental implant treatment is not solely dependent on the osseointegration around the implant. Aside from the criteria used to describe the hard tissue response at the implant level, the success criteria in implant dentistry include three additional aspects: peri-implant soft tissue, prosthesis, and patient’s satisfaction.
\r\n
\r\n\tThe Prosthodontics and Implant Dentistry topic will provide readers with up-to-date resources on the prosthodontics factors such as aesthetics, restorative materials, the design of prosthesis, case selection, occlusion, oral rehabilitation, among others, all of which play an important role in determining the success of a well osseointegrated implant. With the help of digital dental technology, these can now be accomplished more predictably.
\r\n
\r\n\tThe end goal of prosthesis is always considered when planning successful implant placement. The readers in this field will be able to learn more about taking a holistic approach when treating their dental implant cases.
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She was awarded an Excellent Exchange Award by the University of Sheffield which gave her the opportunity to work at the famous Faculty of Dentistry of the University of Gothenburg, Sweden, under the tutelage of Prof. Peter Thomsen. In 2016, she was appointed as a visiting scholar at UCLA, USA, with attachment in Hospital Dentistry, and involvement in research work related to zirconia implant. In 2016, her contribution to dentistry was recognized by the Royal College of Surgeon of Edinburgh with her being awarded a Fellowship in Dental Surgery. She has authored numerous papers published both in local and international journals. She was the Editor of the Malaysian Dental Journal for several years. Her main research interests are implant-soft tissue interface, zirconia implant, photofunctionalization, 3D-oral mucosal model and pulpal regeneration.",institutionString:null,institution:{name:"University of Malaya",institutionURL:null,country:{name:"Malaysia"}}},editorTwo:{id:"479686",title:"Dr.",name:"Ghee Seong",middleName:null,surname:"Lim",slug:"ghee-seong-lim",fullName:"Ghee Seong Lim",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003ScjLZQAZ/Profile_Picture_2022-06-08T14:17:06.png",biography:"Assoc. Prof Dr. Lim Ghee Seong graduated with a Bachelor of Dental Surgery from University of Malaya, Kuala Lumpur in 2008. He then pursued his Master in Clinical Dentistry, specializing in Restorative Dentistry at Newcastle University, Newcastle, UK, where he graduated with distinction. He has also been awarded the International Training Fellowship (Restorative Dentistry) from the Royal College of Surgeons. His passion for teaching then led him to join the faculty of dentistry at University Malaya and he has since became a valuable lecturer and clinical specialist in the Department of Restorative Dentistry. He is currently the removable prosthodontic undergraduate year 3 coordinator, head of the undergraduate module on occlusion and a member of the multidisciplinary team for the TMD clinic. He has previous membership in the British Society for Restorative Dentistry, the Malaysian Association of Aesthetic Dentistry and he is currently a lifetime member of the Malaysian Association for Prosthodontics. Currently, he is also the examiner for the Restorative Specialty Membership Examinations, Royal College of Surgeons, England. He has authored and co-authored handful of both local and international journal articles. 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