Secondary metabolites with antidepressant properties in preclinical study.
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These books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\\n\\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\\n\\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
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IntechOpen and Knowledge Unlatched formed a partnership to support researchers working in engineering sciences by enabling an easier approach to publishing Open Access content. Using the Knowledge Unlatched crowdfunding model to raise the publishing costs through libraries around the world, Open Access Publishing Fee (OAPF) was not required from the authors.
\n\nInitially, the partnership supported engineering research, but it soon grew to include physical and life sciences, attracting more researchers to the advantages of Open Access publishing.
\n\n\n\nThese books synthesize perspectives of renowned scientists from the world’s most prestigious institutions - from Fukushima Renewable Energy Institute in Japan to Stanford University in the United States, including Columbia University (US), University of Sidney (AU), University of Miami (USA), Cardiff University (UK), and many others.
\n\nThis collaboration embodied the true essence of Open Access by simplifying the approach to OA publishing for Academic editors and authors who contributed their research and allowed the new research to be made available free and open to anyone anywhere in the world.
\n\nTo celebrate the 50 books published, we have gathered them at one location - just one click away, so that you can easily browse the subjects of your interest, download the content directly, share it or read online.
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This book is divided in four parts: Hardware Development: Components and Systems, Biped Motion: Walking, Running and Self-orientation, Sensing the Environment: Acquisition, Data Processing and Control and Mind Organisation: Learning and Interaction.\r\nThe first part of the book deals with remarkable hardware developments, whereby complete humanoid robotic systems are as well described as partial solutions.\r\nIn the second part diverse results around the biped motion of humanoid robots are presented. The autonomous, efficient and adaptive two-legged walking is one of the main challenge in humanoid robotics. The two-legged walking will enable humanoid robots to enter our environment without rearrangement.\r\nDevelopments in the field of visual sensors, data acquisition, processing and control are to be observed in third part of the book.\r\nIn the fourth part some "mind building" and communication technologies are presented.',isbn:null,printIsbn:"978-3-902613-07-3",pdfIsbn:"978-953-51-5805-9",doi:"10.5772/37",price:159,priceEur:175,priceUsd:205,slug:"humanoid_robots_human_like_machines",numberOfPages:652,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"581c6d2ca6e91bebee1a1679c857a0c4",bookSignature:"Matthias Hackel",publishedDate:"June 1st 2007",coverURL:"https://cdn.intechopen.com/books/images_new/3372.jpg",numberOfDownloads:120807,numberOfWosCitations:112,numberOfCrossrefCitations:68,numberOfCrossrefCitationsByBook:6,numberOfDimensionsCitations:202,numberOfDimensionsCitationsByBook:6,hasAltmetrics:1,numberOfTotalCitations:382,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 26th 2012",dateEndSecondStepPublish:"May 17th 2012",dateEndThirdStepPublish:"August 21st 2012",dateEndFourthStepPublish:"November 19th 2012",dateEndFifthStepPublish:"December 19th 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"144263",title:"Dr.",name:"Matthias",middleName:null,surname:"Hackel",slug:"matthias-hackel",fullName:"Matthias Hackel",profilePictureURL:"https://mts.intechopen.com/storage/users/144263/images/system/144263.jpg",biography:"Matthias Hackel received his Master’s degree in physics in 1997 from RWTH Aachen, Germany. 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From 1998 to 2000, he presided over the implementation of the Graduate Program in Agronomy at Federal University of Uberlândia (master's and doctorate). He was director of the Institute of Agricultural Sciences at Federal University of Uberlândia from 2001 to 2004. He was president of the Brazilian Society of Phytopathology in the period from 2003 till 2004. Dr Juliatti is a member of the Brazilian Societies of Phytopathology, Plant Breeding and Brazilian Horticulture in addition to the Paulista Group of Phytopathology. He is technical consultant in the areas of corn and soybeans/ phytopathological problems in the Brazilian savannah. \nHe and the Plant Improvement team at Federal University of Uberlândia developed strains of soybean, tomato and beans with multiple resistance to phytopathogens. Together with this team, he launched 05 protected soybean cultivars for the Brazilian savannah with multiple resistance to important soybean pathosystems, including partial resistance to Soybean Asian rust. \nHe chaired the organizing committee of the Brazilian Congress on Agroenergy and the First International Symposium on Biofuel. He coordinated the Chamber of Agronomy of CREA-MG (in 2008 and 2009) and the National Coordination of Agronomy of the CREA / CONFEA system (in 2009). He is a coordinator of the Latin American Committee on studies on Sclerotinia (Sclerotinia International Working Group). Dr Juliatti is a Financial Director of SMEA (Minas Gerais Society´ of the Agronomy Engineers) and current member of the Fiscal Council of the same entity. He is also President of ABEAS (Brazilian Association of Higher Agricultural Education - Triennium 2011-2013 and 2013-2016). He is Winner of the 2011 Top Ethanol Award in the area of technological innovation in industrial energy offered by UNICA and Winner in 2008 and 2013 of the Top Science Award offered by the company Basf. S.A.\nDr Juliatti is a permanent professor in the Graduate Programs in Agronomy (UFU, Brazil - Master and Doctorate) and Biofuels (UFU-UFVJM - Master and Doctorate). He was the Technical Director for four terms at the Association of Agricultural Engineers of Triângulo Mineiro and Alto Paranaíba, Minas Gerais, Brazil. He was President of the Triângulo Mineiro and Alto Paranaíba Association (AGROTAP), from 2017 to 2018 . In 2017 he was President of 50 Brazilian Congress of Phytopathology (Golden Jubilee) and 16 International Workshop on Sclerotinia and II Brazilian Workshop on Soybean Rust. Currently he is coordinator of the UFU Agronomy Course at the Campus Uberlândia. 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In 2015, 4.4% (322 million people) of the world’s population suffered from depressive disorders, while 3.6% (264 million) were affected by anxiety [2]. In that year, the World Health Organization (WHO) estimated that by 2020 depression would be the second leading cause of disability; thus, its prediction has been confirmed. Depression is characterized by persistent sadness and a loss of interest in activities that an individual normally enjoys, accompanied by periods of at least 2 weeks marked by the inability to perform everyday activities [2]. Anxiety, in turn, is defined as an emotion expressed in response to stressful, dangerous, or unfamiliar situations, or some unidentified factor, that is, the feeling of unease, distress, or dread that one feels in the face of a significant event. A certain level of anxiety is necessary to keep us alert and aware, but for those who suffer from anxiety disorders, it can be totally debilitating [3]. Current pharmacological treatments for depressive disorders are mainly based on selective serotonin reuptake inhibitors (SSRIs), serotonin (5-HT) and noradrenaline (NE) reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs), all of which act by increasing short-term levels of neurotransmitters in the brain. One consequence of treatment is the desensitization of receptors, for example, 5-HT1A, with a downregulation of autoreceptors, but no changes in the postsynaptic receptors, which leads to the recovery of neuronal activity in the long term [4]. These changes are associated with the long latency to the onset of antidepressant effects. However, up to 70% of depressed patients have residual symptoms [5], and few options exist for transitioning treatment-resistant sufferers to alternative therapies that operate through distinct mechanisms [6]. It is important to note that conventional antidepressants produce significant side effects, such as nausea and vomiting, insomnia, agitation, fatigue, sedation, sexual dysfunction, headaches, and weight gain, which contribute to poor patient compliance and, in some cases, abandonment of treatment [7]. This occurs under such anxiolytic treatments as benzodiazepine (a GABAA receptor agonist) and SSRIs [8] and is the main cause of the increasing demand for alternative medicines, such as medicinal plants, to alleviate the symptoms of these psychiatric disorders. However, reports of adverse reactions to products of this kind have increased [9], leading WHO to publish the document, “The WHO’s traditional medicine strategy: 2014-2023”, which outlines a global approach to fomenting the appropriate integration, regulation, and supervision of natural substances. This paper will be useful in countries seeking to develop a proactive policy toward this important and expanding area of health care and will contribute to the use of herbal medicines of proven quality, safety, and efficacy, providing quality medical care to all people [10]. Recent decades have witnessed efforts to gather scientific evidence that validates the efficacy of plants commonly used for their antidepressant and anxiolytic properties [11], but research has been insufficient because of the wide range of plants available worldwide. We lack solid scientific data on the neurochemical pathways and mechanisms of action of medicinal plants or their active metabolites because few clinical studies have addressed these issues. Also, reports of adverse reactions to medicinal plants [9] may reflect the broad variety of active metabolites they contain, thus highlighting the need for preclinical and clinical studies that evaluate the possible biological activity of compounds isolated from plants or standardized crude extracts, their mechanisms of action, and possible toxicity.
\nFajemiroye et al. [12] proposed a hypothetical model for identifying medicinal plant extracts and phytoconstituents with anxiolytic and/or antidepressant properties that is currently used by most researchers:
Plants used in traditional medicine contain compounds in their secondary metabolism [13] such as alkaloids, phenols, sterols, carbohydrates, tannins, terpenes, and phytoalexins, all of which have important biological activities [14]. The most widely studied metabolites are terpenes, flavonoids, alkaloids, and sterols, whose mechanisms of action stimulate the serotonergic, noradrenergic, dopaminergic, or GABAergic neurotransmission systems, acting on receptors or the synthetic pathways of neurotransmitters and their transporters. However, they may also stimulate other neurotransmission systems. For example, terpenes can stimulate at the same time serotonergic, dopaminergic, and noradrenergic neurotransmission systems [12] that can produce a similar effect on mood regulation, perhaps leading to an overstimulation that may generate undesirable collateral effects.
\nThis chapter reviews and discusses the findings from research on several metabolites of medicinal plants that have shown potential anxiolytic and antidepressant activities once screened for their biological mechanisms at various levels: receptor, transporter, synthesis, gene, protein, or metabolic. The studies analyzed were identified by a preliminary search in PubMed, Scopus and Ovid for articles on (i) the dose effects and possible mechanisms of action of metabolite(s) isolated from parts of plants with previously identified anxiolytic or antidepressant effects; and (ii) standard chemical tests performed with specific metabolites.
\nTerpenes are formed by the union of isoprene units (5 C atoms). Their classification depends on the number of units they contain: 10 C terpenes (two units) are called monoterpenes, while 15 C terpenes (three units) are called sesquiterpenes, and those with 20 C are diterpenes. Triterpenes have 30 C, tetraterpenes have 40 C, and polyterpenes are those with over 8 isoprene units. Studies have evaluated the effect of terpenes isolated from plants, including rosmanol from
Other terpenes with antidepressant properties include phenolic diterpene, carnosol, and pentacyclic triterpenoids like betulinic, oleanolic, and ursolic acids. Carnosol generated an antidepressant-like effect at doses of 0.01 and 0.1 mg/kg [16] on TST, and 10, 30, and 100 mg/kg, i.p., on TST and FST, as did the oleanolic and ursolic acids. Meanwhile, 100 mg/kg of ursolic acid showed an effect similar to that of imipramine at 60 mg/kg [17]. Betulinic acid at 10 mg/kg was evaluated in male mice on TST [16]. None of those metabolites had effects on locomotor activity. Ursolic acid at doses of 0.01 and 0.1 mg/kg produced an effect similar to that of fluoxetine (10 mg/kg), imipramine (1 mg/kg), and bupropion (10 mg/kg) on TST [18]. Only the 10-mg/kg dose had an antidepressant effect on FST, which was similar to that of bupropion at 10 mg/kg. Studies exploring the mechanism of action of ursolic acid found the involvement of D1 and D2 receptors and a pharmacological synergism with bupropion at 1 mg/kg, p.o. (dual dopamine/noradrenaline reuptake inhibitor, DDNRI) [18], 5 mg/kg of fluoxetine, or 2 mg/kg of reboxetine (SRNI) [19]. They also observed a related increase in noradrenaline and dopamine synthesis on TST [19]. These findings are noteworthy because they suggest the possibility that various mechanisms of action may be stimulated by the same metabolite.
\nA study of the essential oil of
Secondary metabolites with antidepressant properties in preclinical study.
NE = no explorated.
Secondary metabolites with anxiolytic properties in preclinical study.
NE = no explorated.
However, due to the terpene’s capacity to stimulate several neurotransmission systems—especially high doses of monoterpenes—possible collateral or undesirable effects as serotonergic syndrome need to be explored. The monoterpenic oxide, 1,4-cineole, for example, produced a prodespair effect at doses of 200 mg/kg, i.p., on FST and 400 mg/kg, i.p., and FST and TST, but did not induce any significant deficit in motor coordination on the rota-rod test (RRT). It did, however, have an anxiolytic effect at a dose of 400 mg/kg in male mice evaluated in EPM that was not associated with any sedative effect [23]. These findings require additional study in light of potential depressor effects on the CNS, and to elucidate the mechanisms of action involved.
\nAnxiolytic properties have also been attributed to terpenes. A combination of two monoterpenoids, p-cymene + thymol, both at doses of 3 mg/kg i.p., produced anxiolytic effects on the hole-board test (HBT) and EPM [24]. Studies have also demonstrated that (−)-myrtenol, a monoterpenoid alcohol, produced an anxiolytic effect on EPM at doses of 25, 50, and 75 mg/kg, i.p., though only the 25- and 50-mg/kg doses did so on LDB. On both tests, the anxiolytic effect of 25 mg/kg of (−)-myrtenol was mediated by GABAA receptors [25]. In another study, rosmanol produced an anxiolytic effect at doses of 10, 30, and 100 mg/kg in EPM and LDB, and the 10- and 30-mg/kg doses showed an effect similar to those of diazepam at 1 mg/kg [15]. This mechanism of action acts on GABAA receptors at a distinct site from the high-affinity benzodiazepine-binding region [15]. Triterpenes as ursolic acid, oleanolic acid, and carnosol produced anxiolytic effects at doses of 10, 30, and 100 mg/kg in EPM and LDB. The effect of the 30- and 100-mg/kg doses of these three metabolites was similar to that of diazepam at 1 mg/kg. No significant effect was seen on locomotor activity. We know that this effect was produced through GABAA receptors of the α1β2γ2L conformation because 2.5 mg/kg of flumazenil blocked the anxiolytic effects of 10 mg/kg of all three in EPM [17].
\nAlthough most terpenes have a GABAergic mechanism, their action may also occur through the serotonergic system, as evidenced in the study by Costa et al. [26]. In an experiment with male rats, those authors identified that acute administration of 5 mg/kg, p.o., or 14-day repeat doses (1 mg/kg/day), of the essential oil of ripe fruits of
Finally, songorine, a C20 diterpenoid alkaloid, produced an anxiolytic-like effect at 0.25 mg/kg v.o. for 5 days with greater efficacy than phenazepam on Vogel’s conflict test (VCT) [29]. For the terpenes described so far, we know that both the serotonergic and GABAergic systems are involved in their mechanisms of action, and these are the same systems that are activated by other groups of metabolites, such as flavonoids and sterols (see Tables 1 and 2 for summaries).
\nFlavonoids are the most widely studied active metabolites (for a broad review of research, see German-Ponciano et al. [30]). Genistein is an isoflavone that can cross the blood-brain barrier in mice [31] and rats [32]. Acute oral administration of 5, 15, and 45 mg/kg genistein in male mice did not reduce immobility time on FST or TST, but chronic, dose-dependent administration for 21 days produced antidepressant-like effects on both tests, without affecting locomotor activity [33]. This effect was associated with increased NA and 5-HT concentrations in the hippocampus and frontal cortex, and of 5-HT in the hypothalamus, though it decreased the 5-HTIAA/5-HT ratio in the hippocampus and frontal cortex. These results suggest an inhibition effect of genistein on MAO-A in the hippocampus, frontal cortex, and hypothalamus and on MAO-B in the hippocampus, three brain structures involved in the neurobiology of depression and anxiety. Their results [33] also demonstrate that central depletion of 5-HT reversed the antidepressant effect of genistein, suggesting a critical role of the serotonergic system, specifically through 5-HT1A receptors. It is important to note that these results on the serotonergic metabolic ratio (5-HIAA/5-HT) may be dependent on gonadal hormones. Ovariectomized rats (OVX, surgical removal of both ovaries) showed reduced immobility times on FST after administration of genistein (10 mg/kg, p.o. [34], or by i.m.) [35] for 14 days, but the downward tendency of the serotonergic metabolic ratio caused by FST was only evident in the hippocampus [34]. Sapronov and Kasakova [35] found antidepressant-like effects on FST at the same dose of genistein (10 mg/kg) but in non-ovariectomized rats. That effect was more marked in the metestrus and diestrus phases of the estral cycle, which are characterized by low plasmatic concentrations of ovarian hormones, than during the proestrus and estrus stages with their characteristically high hormone concentrations. This suggests that these hormones play a significant role in the antidepressant effect of genistein.
\nA similar effect on the serotonergic system and MAO-A activity was found with quercetin 4’-O-glucoside or quercetin administered at doses of 10 and 20 mg/kg, p.o., for 7 days in Swiss albino mice of both sexes. These substances produced antidepressant-like effects in mice on FST as well as those subjected to unpredictable, chronic mild stress (CUMS, a mouse model designed to induce depression) and subsequently evaluated on FST. In that study, a 20-mg/kg dose of quercetin 4’-O-glucoside showed a similar effect to that of fluoxetine at 20 mg/kg, p.o., on FST, with or without prior exposure to CUMS [36]. A consequence of CUMS on the sucrose preference test (SPT, a test used to study anhedonia rodents, the main symptom of depression in humans) is a decrease in the consumption of a sweetened solution. In these sense, both doses of quercetin 4’-O-glucoside reverted this effect, and interpreted as being antidepressant. Other consequences of CUMS are metabolic, for example, excessive production of reactive oxygen species that was evidenced by higher brain thiobarbituric acid reactive species (TBARS). Compromising endogenous anti-oxidants, like reduced glutathione (GSH), enhances MAO-A activity in the brain and, consequently, depletes monoamine levels there, especially serotonin 5-HT. The effects observed in that study were blocked by 21 days of treatment with 10 and 20 mg/kg of quercetin 4’-O-glucoside [36], suggesting a possible mechanism of action with an antioxidant effect that impedes ROS production. Another study [37] found that 10 mg/kg of quercetin administered for 14 days reduced immobility time on TST, but not FST, while doses of 25 and 50 mg/kg produced this effect in female mice on both tests. The mechanisms of action were explored on TST, where i.c.v. administration of N-methyl-D-aspartate (NMDA at 0.1 pmol/site) and L-arginine (at 750 mg/kg, i.p., a nitric oxide inhibitor) blocked the antidepressant effect of quercetin. Hence, the antidepressant-like effect of quercetin may involve inhibiting NMDA receptors to decrease intracellular calcium that, in turn, inhibits the protein calmodulin, which then inhibits neuronal nitric oxide synthase to decrease nitric oxide levels (NO). This hypothesis is supported by the finding that administering methylene blue (a NO synthase inhibitor) at 20 mg/kg, i.p., and soluble guanylate cyclase or 7-nitroindazole (another NO synthase inhibitor) at 50 mg/kg, i.p., improved quercetin’s antidepressant-like effect on TST. This indicates that the antidepressant effect may be dependent on limiting NO synthesis, either by inhibiting the enzyme or by reducing NO production, perhaps via decreased cyclic guanosine monophosphate (cGMP), since sildenafil (a phosphodiesterase 5 selective inhibitor that increases cGMP levels) also canceled this effect [37].
\nA model of depression induced by olfactory bulbectomy (OB, surgical removal of the olfactory bulbs) reduced the latency to immobility and increased immobility time on FST and TST. This was accompanied by an increase in the levels of the markers of oxidative stress, for example, 116% in the case of lipid hydroperoxide content (LOOH) in the hippocampus. This effect was reverted by 52.25% by administering 25 mg/kg of genistein in the content of LOOH, as observed on the immobility on FST and TST. In sham rats only (
Additional mechanisms of the antidepressant action of flavonoids have been explored. Administering chrysin for 14 days at a dose of 20 mg/kg, for example, increased grooming time in male OB C57B/6J mice evaluated on the splash test (ST), where 200 ml of a 10% sucrose solution is squirted on the mouse’s snout to initiate grooming behavior. Here, greater grooming time is considered an antidepressant effect. Doses of 5 and 20 mg/kg impeded an increase in immobility time by these OB mice on FST, but increased 5-HT and brain-derived neurotrophic factor concentrations in the hippocampus [39]. In another study, fisetin administered at 5 mg/kg v.o. increased activation of the tropomyosin kinase B receptor (TrkB) by signaling and increasing its phosphorylation in the hippocampus. This suggests that fisetin produced pro-neurogenesis [40] related to its antidepressant effect on FST and TST after 1 or 2 weeks of treatment with a relatively short therapeutic latency compared to clinically-effective antidepressants. Fisetin also reversed depression-like behaviors induced by spatial restraint stress in mice evaluated on FST and TST [40]. Other studies have found that the chemical standard dihydromyricetin activated the ERK1/2-CREB pathway and increased glycogen synthase kinase-3 beta (GSK-3β) phosphorylation at ser-9 with upregulation of BDNF expression in the hippocampus, while inhibiting neuroinflammation. These findings may be related to the antidepressant effect seen on TST and FST after once-daily administration of 10 and 20 mg/kg, v.o. for 3 days, but not after a single acute dose [41]. Interestingly, dihydromyricetin reverted the depressogenic effect caused by CUMS in mice subjected to SPT and FST, or TST, only after administration of once daily for 7 days, but not 3 days [41]. Another flavonoid analyzed is hesperidin, which increased BDNF levels in the hippocampus after administration of once daily for 21 days (0.3 and 1 mg/kg, i.p.). These doses produced an antidepressant effect on TST similar to fluoxetine (32 mg/kg i.p.) and imipramine (15 mg/kg, i.p.). Another research has also verified that when applied acutely (1 mg/kg after 30 min) or chronically (0.1, 0.3, and 1 mg/kg for 21 days) hesperidin significantly decreased nitrate/nitrite (NOX) levels in the hippocampus of mice, suggesting a possible inhibition of the L-arginine-NO-cGMP pathway [42].
\nAnother flavonoid that has shown effects on the CNS is baicalin, which may promote neuronal differentiation through neuronal maduration and ensure their survival via the associated Akt/FOXG1 pathway, which stimulates dendrite elongation. This is related to findings that indicated that, after 6 weeks of treatment, a 60-mg/kg dose of baicalin had an effect similar to that of fluoxetine (15 mg/kg, v.o.), because it reverted the decrease of sucrose intake on SPT and the increase in immobility on TST produced by CUMS [43]. Another flavonoid that associates antidepressant and antioxidant effects is naringin, which reduced immobility on FST at doses of 2.5, 5, and 10 mg/kg given for 7 days. The antidepressant effect of these doses correlated with enhanced cholinergic transmission due to a decrease in the activity of the enzyme acetylcholinesterase and of the antioxidant defense systems caused by higher GSH levels, as well as an increase in the activity of superoxide dismutase (SOD) and catalase (CAT) in mice brains.
\nStudies have demonstrated that naringin inhibits lipid peroxidation and nitrosative processes by reducing levels of ROS and nitrogen species [44]. Finally, the extract of
The varied mechanisms seen in flavonoids make them an important object of study, especially in the search for side effect-free treatments that can compromise their effectiveness or produce toxicity by interacting with other medications or food. This is another area of research that remains to be explored.
\nA particularly important fact concerning the potency of the biological activity of plants is that it depends on several factors, for instance, the part of the plant used, the region where it is gathered, the season, and harvesting time, among others [46]. For example, in male mice evaluated by HBT and EPM, a single dose of 100 mg/kg i.p. of the methanolic extract of inflorescences of
Another flavonoid known to have anxiolytic effects is formononetin, an active metabolite of traditional Chinese medicine red clover (
Other anxiolytic mechanisms of action seen in flavonoids are dopaminergic in nature. Theaflavins, for example, increased dopamine (DA) turnover to induce activation of the dopaminergic system in the frontal cortex in male mice in EPM and LDB [48], while chrysin at 2 and 4 mg/kg produced an anxiolytic effect in rats at 12 weeks postovariectomy on LDB by increasing the time spent in the light compartment. Those findings resembled the effect of diazepam. At doses of 1, 2, and 4 mg/kg, this flavonoid increased the frequency of entries into, and the time spent in, the open arms of EPM partially through action on GABAA receptors (pre-treatment with 1 mg/kg picrotoxin) [49]. On the other hand, neurosteroids and the serotonergic system have also been implicated in the anxiolytic effect of flavonoids, as in the case of puerarin, which increased 5-HT and allopregnanolone levels in the prefrontal cortex and hippocampus in male rats. These results have been associated with the finding that puerarin increased the time spent in the open arms and the percentage of entries into the open arms of EPM, whereas on the VCT test, it produced an increase in the number of shocks received. In both cases, the effect was similar to that of sertraline, which was used as a positive control drug to generate an anxiolytic effect on both tests [50].
\nIn an animal model of surgically-induced menopause, genistein at 0.09 and 0.12 mg/kg, s.c., for seven consecutive days, or the same treatment regimen but with 17β-estradiol, increased the time spent in, and the percentage and frequency of entries into, the open arms of EPM. These effects were caused by activation of the β-estrogenic receptor (ERβ) since pretreatment with tamoxifen (5 mg/kg, an ERβ antagonist) blocked the anxiolytic effect. Also, genistein and 17β-estradiol increased the frequency of rearing and grooming behaviors on the locomotor activity test (LAT), associated with an anxiety-reducing effect manifested in EPM [51]. Genistein tested at doses of 0.25, 0.5, and 1 mg/kg increased the time spent in, and the frequency of exploration of, the light compartment of LDB, while doses of 0.5 and 1 mg/kg increased rearing frequency, and 1 mg/kg increased grooming time. Those studies used rats at 12 weeks postovariectomy [52]. The authors suggest that “genistein is considered a phytoestrogen that acts in a dose-dependent manner with a broader margin of safety at anxiolytic doses. However, more studies are required to take advantage of its potential therapeutic anxiolytic effects” [51].
\nIn a distinct approach, a post-traumatic stress disorder (PTSD) model used a chamber with a grid floor connected to a system that delivered foot shocks, exposing rats to 5 shocks per day. There, an increase in the contextual freezing time on days 7, 14, and 21 indicated the induction of anxiety-like behaviors. The time spent in freezing behavior was calculated with the shock-administering system turned off. In that study, genistein at 4 and 8 mg/kg i.p. administered to male rats from day 7 reduced freezing time at 7, 14, and 21 days. Interestingly, only the 8-mg/kg dose returned freezing times to control levels on day 21 [53]. The stressed rats were also tested in EPM, where they spent less time in the open arms, indicating an anxiety-like effect that was reverted by administering 4 and 8 mg/kg of genistein. This reduced anxiety-like behavior in the stressed rats occurred in association with enhanced tryptophan hydroxylase (TPH) and 5-HT levels, but also promoted the 5-HT receptor-related CaMKII/CREB signaling pathway in the amygdala [53], likely reflecting the fact that the amygdala receives serotonergic projections from the raphe, two brain structures to which emotional valence and 5-HT synthesis, respectively, are attributed [54].
\nA study evaluated the pharmacokinetic profile of 6-methoxyflavanone and calculated the KP value (
Another flavonoid with anxiolytic effects is rutin at doses of 300 and 562 mg/kg, i.p., or 16 nmol/site, in the basolateral amygdala of male rats tested in EPM. This involves partial GABAergic neurotransmission that was not associated with BDZ binding in the GABAA receptors [57]. Finally, viscosine administered to male mice assessed in EPM and LDB was seen to exert its action through the α1β2γ2L and α2β2γ2L modulates of the GABAA receptors at a site distinct from the one classically associated with benzodiazepine [58].
\nAlkaloids purified from crude acid-base extracts have diverse chemical structures. They may contain one or more nitrogen atom(s) (in the heterocyclic ring) in the form of salt [59]. Pseudoalkaloids that possess nitrogen exist. They are not synthesized from amino acids, but by nitrogen transfer in the form of ammonia to a compound of terpenic origin, steroids, polyketides, monosaccharides, or fatty acids [59].
\nThe alkaloid berberine (50 mg/kg, i.p.) decreased immobility but increased climbing behavior on FST; results are considered to reflect an antidepressant-like effect in rats after abstinence from repeated morphine administration [59]. Chronic treatment with the extract of
In another work, the alkaloid derivatives of the β-carbolines (harmane 5, 10, and 15 mg/kg, norharmane 2.5, 10, and 15 mg/kg, and harmine 5, 10, and 15 mg/kg, all i.p.) showed antidepressant effects in mice that were dose-dependent, suggesting that the effect occurs through an inverse agonist mechanism of the benzodiazepine receptors due to flumazenil antagonism (5 mg/kg, i.p.) [61]. In addition, anhedonia was reversed in rats subjected to the CUMS model after harmine treatment at 15 mg/kg/day for 7 days. They showed increased adrenal gland weight, ACTH levels, and BNDF protein levels produced by the CUMS [62]. Treatment for 14 days with harmine (5, 10, and 15 mg/kg) and imipramine (10, 20, and 30 mg/kg) in rats subjected to FST produced antidepressant-like effects, while harmine (10 and 15 mg/kg), but not imipramine, increased BDNF protein levels in the hippocampus of rats [62]. These results indicate that the main mechanism involved in harmine’s antidepressant effect is an increase in hippocampal BDNF, though this may be dependent on treatment time and the precise region of the hippocampus.
\nAn infusion of harman (1-methyl-beta-carboline) into the hippocampus of rats, or through systemic administration, increased the concentration of 5-HT [63]. In addition, metabolite levels of 5-HT degradation decreased dose-dependently, probably due to inhibition of MAO-A [63]. Another study showed that harman bonds to type 5-HT2A serotonergic receptors but shows no affinity to dopaminergic or BZ receptors [64]. Injections of 2.5 and 10 mg/kg of harmane in rats under fear conditioning have been shown to increase plasma ACTH, corticosterone, 5-HT, and NA levels in limbic system structures. These results suggest that harman can modulate behavioral alterations, brain neurochemistry, and neuroendocrine functions through a mechanism that inhibits MAO-A [65].
\nSubchronic, oral administration for 21 days of the lyophilized extract of
Punarnavine administered at doses of 20 and 40 mg/kg, v.o., for 14 days decreased immobility on FST, MAO-A activity, and corticosterone levels in both stressed and unstressed mice [68], while treatment with evodiamine at 10 and 20 mg/kg in rats exposed to CUMS reversed the decrease in their preference for sugared water and immobility time on FST, but increased 5-HT and NA levels and the protein expression of BNDF in the hippocampus. However, it reduced corticosterone levels, suggesting that it likely modulates monoamines and BDNF-TrkB signaling in the hippocampus [69]. Chronic administration of piperine in rats at 5, 10, and 20 mg/kg has shown antidepressant-like effects on FST, probably due to a serotonergic mechanism [70]. At a dose of 30 mg/kg, protopine produced an antidepressant effect on TST in mice, perhaps by inhibiting the 5-HT and NA transporters, since
Because alkaloids have powerful antidepressant effects, many are used in clinical practice with effective therapeutic results. Preclinical studies have clearly demonstrated the antidepressant effects of alkaloids, but evidence of their mechanisms of action is still deficient or unclear. Alkaloids isolated from plants are an option for treating depression, but more studies are needed at the preclinical level to evaluate their potency, efficacy, and safety before they can be incorporated into clinical practice.
\nThe alkaloids gelsemine, koumine, and gelsevirine exerted anxiolytic effects in single doses of 2 and 10 mg/kg in mice in EPM and LDB [72]. Gelsemine in low doses (10−6 M and 10−14 M) administered to male rats for 7 days also showed anxiolytic effects in EPM [73]. Koumine has shown this effect on VCT in mice at doses of 0.167, 0.5, or 1.5 mg/kg [74]. Other reports indicate that the decoction of the African peach root (
The aqueous extract of
Turning to the species Magnolia (
Numerous reports attribute anxiolytic activity to a broad range of plants. However, isolating and identifying the alkaloids responsible for this activity have not advanced substantially. Preclinical reports point to a common mechanism of action that modulates the GABAergic and serotonergic systems. The data described here justifies the need to conduct preclinical and clinical studies using alkaloids as alternative treatments for some anxiety disorders.
\nPlants synthesize a class of sterols called phytosterols, whose chemical structure is similar to that of cholesterol. Phytosterols are found in nuts, vegetable oils, cereals, fruits, vegetables, and various plants [86]. Some 40 different types have been identified, including β-sitosterol, campesterol, fucosterol, and stigmasterol. Due to their lipidic nature and glycosylated forms, they are able to cross the blood-brain barrier and impact the CNS [87]. Trevisan et al. [88] suggest that α-spinasterol has the ability to cross the blood-brain barrier and exert an antagonistic effect on the transient potential receptor V1 (TRPV1). When these receptors are expressed in various areas of the brain—prefrontal cortex, amygdala, hypothalamus, and hippocampus—their activation augments the release of glutamate and, consequently, that of GABA, DA, or other catecholamines [89]. This fact involved TRPV1 receptors in the mechanism underlying the etiology of depression and anxiety. This was corroborated by Socała and Wlaź [90] by administering (1 and 2 mg/kg, i.p.) α-spinasterol to male mice and testing them on FST. Their results suggest an antidepressant effect. Also, intracerebroventricular (i.c.v.) coadministration of 50 μg of the TRPV1 receptor antagonist capsazepine/mouse with an ineffective dose of 0.5 mg/kg, i.p., of α-spinasterol, also reduced immobility time on FST, indicating the involvement of TRPV1 in the neurobiology of depression. However, α-spinasterol itself (0.5, 1, and 2 mg/kg) was unable to produce anxiolytic-like effects in EPM or LDB. In this sense, TRPV1-knockout mice manifested less anxiety behavior on the same tests [91]. Socała and Wlaź [90] proposed that α-spinasterol may be able to activate CB1 receptors with greater affinity because those neurons coexpress these receptors in various brain structures whose activation could activate TRPV1 receptors simultaneously to block their possible anxiolytic effects. In another work, administering fucosterol (10, 20, 30, or 40 mg/kg, v.o.) to male mice produced antidepressant effects on FST and TST, with the 20 and 30 mg/kg doses achieving an effect of comparable efficacy to 20 mg/kg of fluoxetine, a standard dose in humans [92]. Those doses also exerted an acute effect that increased BDNF levels in the hippocampus, a limbic structure involved in mood regulation. Fucosterol also blocked the decrease in 5-HT, 5-HTIIA, and NA levels in mice brains generated by the stress of FST. The effect of fucosterol on that test was similar to that of the positive control drug, but it was unable to prevent the reduction of DA, another factor caused by FST. These findings suggest that the antidepressant mechanism is mediated by increasing monoamines and reducing the rate of 5-HT metabolism. Fucosterol did not modify either motor or exploratory activity and showed no neurotoxic effects [92]. Similar results were found when administering β-sitosterol at 10, 20, and 30 mg/kg for 7 days. In that case, 30 mg/kg exerted effects similar to those of 20 mg/kg of fluoxetine on FST and TST. Finally, the effects on monoamine levels in mice brains confirm that sterols modify the serotonergic and noradrenergic systems but do not impact the dopaminergic system [93].
\nAnother case involved α- and β-amyrin (αβAMY) isolated from the resin of the stem of
This broad review constitutes a significant contribution to our understanding of the mechanisms of action that allow plants to produce antidepressant and anxiolytic effects (see Figure 1 for a summary). However, most of the studies reviewed were conducted with mice, due to the low yields achieved when isolating the metabolites of plant extracts [95], which limit the amount of testing that can be done. Another concern is that some infusions or extracts used as household remedies lose their antidepressant or anxiolytic effects when fractioned [96]. These findings indicate that in some cases it may be necessary to keep the metabolites together at the concentrations present in the original infusion or extract that has a proven therapeutic effect. As explained herein, some metabolites share pharmacological targets, which explains why they lose their effect when separated and emphasizes the importance of using standardized extracts with demonstrated therapeutic effects in animal and human studies [97, 98]. Unfortunately, very few clinical studies have evaluated the potential antidepressant or anxiolytic effects of isolated metabolites, so a great deal of work remains to be done.
\nPrincipal mechanisms of action of flavonoids, terpenes, sterols, and alkaloids with antidepressant and anxiolytic properties. DAG: diacylglycerol; IP3: inositol triphosphate; AMPC: adenosine monophosphate 3; PKA: protein kinase A; PLC: phospholipase C; AC: adenylyl cyclase; ATP: adenosine triphosphate; GDP: guanosin trifosfato; VDC: canal dependiente de voltaje; BNDF: factor neurotrófico derivado del cerebro; TrkB: tropomyosin receptor kinase B; Ca2+: calcium ion; Cl−: chloride ion; R-5HT1A: 5HT1A receptor; α2AR: alpha 2-adrenergic receptor; D1-R: dopamine receptor D1; D2-R: dopamine receptor D2; DAT: dopamine transporter; NAT: noradrenaline transporter; SERT: serotonin transporter; MAO-A: monoamine oxidase A; MAO-B: monoamine oxidase B; AD: antidepressant; AX: anxiolytic.
Several observations suggest that active metabolites share the mechanism of action of antidepressant and anxiolytic drugs like SSRIs, SNRIs, MAOIs, DDNRI, and BZDs, but we should emphasize that some metabolites—at least in preclinical studies—produced better effects than conventional drugs, even at lower doses, while others presented a pharmacological synergism between both types at suboptimal doses that improved the effects exerted separately at higher doses. A second shared characteristic is that they contain active stereoisomers and probably, some metabolites, once metabolized, could become more active. This encourages us to consider a significant number of substances with anxiolytic and/or antidepressant pharmacological profiles and invites us to take on the challenge of evaluating their pharmacokinetics, pharmacodynamics, and safety.
\nIn conclusion, terpenes, flavonoids, alkaloids, and sterols share mechanisms of action that include activation of the critical enzyme for catecholamine synthesis (e.g., tyrosine hydroxylase) or the inhibition of their limiting enzymes, MAO-A and MAO-B, and transporters, thus stimulating the vesicular storage monoamine and the release of neurotransmitters toward the synaptic cleft. Finally, they can prevent the production of ROS and inhibit NO synthesis and, further downstream, interact with the 5-HT1A, 5-HT2A, D1, D2, GABAA receptors, and α1, α2, β-adrenoceptors that contribute to stimulating PKA. One consequence is that CREB increases BDNF levels, which foster the appearance of dendritic contacts that improve cerebral neurotransmission and modulate the emotions.
\nThis chapter discusses the efficacy of some plant metabolites in treating anxiety and depression disorders, as demonstrated in preclinical studies. In the future, this option for treating such disorders will allow us to reduce treatment costs and moderate the side effects produced by drugs currently in use. However, our review also points out that few clinical studies have focused on the pharmacokinetic and pharmacodynamic processes involving metabolites that would permit the safe use of these extracts. Despite this, research has shown that traditional medicine, especially forms that use medicinal plants that have been passed down through several generations, constitutes an important alternative for health care.
\nThe third author received (Ramos-Molina Ana Raquel) fellowships from Consejo Nacional de Ciencia y Tecnología (CONACyT) for postgraduate studies in Science and Technology (Reg. 631048).
\nFollowing the survey carried out in Germany in 2017, the number of cases with temporomandibular joint dislocation as hypermobility movement accounts for 3% of all documented dislocation, which means at least 25 cases per 100,000 inhabitants each year [1]. Following European Commission rules, it could be classified as a rare disease – affecting fewer than 5 people in 10,000 are considered to be so. It is also reported to represent 3% of all dislocated joints cases in the human body. On the other hand, dislocation of temporomandibular joint occurs in up to 7% of people during their lifetime [2]. Shorey and Campbell [3] referred to Sir Astley Cooper’s research from the year 1832, who proposed principles for diagnosis and treatment of lower jaw dislocations and introduced nomenclature of joints hypermobility: ‘complete dislocation’ as luxation and ‘imperfect dislocation’ as subluxation. The incidences of subluxation are estimated to occur in about 70% of the population based on clinical and radiographic analysis [4]. In new classification proposed by Akinbami [5], three types of dislocation based on clinic-radiological evaluation were presented: type I – the head of condyle directly below the tip of the eminence; type II – the head of condyle in the front of the tip of the eminence; type III – the head of condyle located high up in the front of base of the eminence. Two types of dislocation with a possibility to self-reduce the hypermobility can be distinguished - subluxation – with, or luxation – without self-reducing.
From The Glossary of Prosthodontic Terms [6], the definition of temporomandibular joint condylar subluxation is: ‘self-reducing incomplete or partial dislocation of the condyle’, and of incomplete dislocation is: ‘a border position of the disk-condyle complex out of the physiological end of movement position in relation to articular eminence’. Partial dislocation is explained in the glossary [6] as a ‘displacement of the articular disk resulting in a seriously impaired disk-condyle complex function’. Condylar dislocation [6] is defined as ‘a non-self-reducing displacement of the mandibular condyle usually forward of the articular eminence’.
For the condylar displacement, the definition stands as follow – it is when the condyle stands out of the articular eminence in maximal jaw opening position. However, definitions confuse subluxation, luxation and disk displacement. From the clinical point of view, subluxation occurs when the opening of patient’s mandibular ends with disk-condyle complex position forward to the articular eminence, which is self-reducing [3]. It means that the patient can close the mandible without any assistance, only by repositioning the mandibular into the disk-condyle complex. It usually concerns joint on one side. With both sides affected it could be more difficult to close the mouth, but patients can usually manage with that on their own. This concerns especially patients with general joints hypermobility, like the Ehlers-Danlos syndrome [7]. They may be frightened or disoriented when it happens for the first time i.e. during yawning. If there is a problem with self-healing and the patient is looking for medical help it could be named as joint dislocation, complete dislocation or luxation. When the dislocation concerns both joints, it looks very dramatic, because patient is unable to speak, swallow and of course, close the mouth. Such cases require medical help, whereas in recurring cases surgical treatment should be considered. It is compatible with Cooper and other authors who followed him, that suggest calling it habitual or recurrent dislocation in cases with more frequent incidents of dislocation and when it is going progressively wrong [3, 8, 9].
As with the other temporomandibular disorders, joint dislocation is often reported by females, especially in recurrent cases. Tendency to dislocation is associated with the shape of anatomical elements like the condyle, glenoid fossa and articular eminence. The pathogenesis is multifactorial, however, for almost 60% of cases, a preceding trauma has been indicated. The mechanism of dislocation also contributes: age, dentition and neurological or neuromuscular diseases. The older the patient, the more he/she is exposed. Lack of posterior teeth support, correlated with advanced tooth loss or edentulous arches without the denture is regarded as favorable to develop joint dislocation. As a recurrent problem for older people with multimorbidity, it significantly reduces their quality of life.
The ‘displacement of the articular disk’ which is ‘non-self-reducing’ is usually understood as a pathological position of the disk in relation to the condyle. That pathology is explained as a forward movement of the disk in relation to the condyle (non-reducing), which results in limitations of condylar head movements, and it is often called ‘disk lock’ or ‘disk displacement without reduction’. The main symptoms of that pathology are sudden disappearance of joints sounds, limitation in jaw opening, and lateral jaw displacement during movement, and usually acute pain from the joint region. The above symptoms are opposite to suspected joint subluxation.
From the anatomy of the temporomandibular joints’ point of view, it is well known that these joints are extremely complex synovial articulations. In the distal part of the joints — which is in the backside of the disk — exists a bilaminar zone, named also retro-articular structure or hydrodynamic retral pad or retrodiscal tissue [10, 11]. It is a mass of loose, highly vascularized and innervated, connective tissue attached to the posterior edge of the articular disk which extends and fills the loose folds of the posterior capsule of the temporomandibular joint [6]. It changes its position simultaneously with all the disk moves and protects the joints against posteriorly oriented trauma [12]. Although the research of Schmolke [13] carried out on human cadavers has concluded, that it was not possible to distinguish the distal disk as a part of a separated structure, Merida-Velasco et al. [10] reported that after examination of 20 cadavers they have identified two separated laminae and retroarticular region filled with venous plexus. The authors confirmed the presence of discomalleolar ligaments in that region and agreed with suggestion about limitation of the range of opening function by those ligaments [14]. Apparently, that part of the joint capsule is still not fully explored.
During the jaw function, both left and right joints move and they are in mutual interdependence. Going again to the anatomy, joints are divided by the disk into two compartments — the upper and the lower. In that two compartments, different movements take place. The movement in the upper one is mostly translational. In the lower compartment movements are mostly rotational. One of the joint’s functions is to connect the mandibular condyle movements in relation to the articular fossa of the temporal bone with the temporomandibular disk interposed. The disk itself is connected with the joint capsule. The capsule is constructed from fibrous ligaments that enclose the joint and limit its motion [15]. It is lined with the synovial membrane.
In order for the movement to be smooth and free of any sound, each surface of the joints, the disks and condylar heads as well as the articular fossae should be sleek and moistened. The articular surfaces are covered by synovial membrane and moistened by synovial fluid. That fluid is produced by specialized endothelial cells capable of producing synovial fluid. It fills all joints’ cavities surrounded by the membrane. For proper joints movements, the capsules need to be flexible enough and tight to keep joints parts together during all joints positions [11].
The joints’ shifting results in opening, closing, forward, backward and lateral movements of the mandible. During the first four movements, both joints work simultaneously, in mirror reflection. Yet, in the lateral movements, the movement made by the side joint is smaller than the one made by the opposite joint. When one moves, it always results in the movement of the other. That relationship — where one bone (the mandible) moves between two joints, which are mutually dependent on each other — is specific in human skeleton and occurs only in that very specific joints.
Movements are related to joints disks position, capsules and ligaments tension and muscle function. Muscles that are involved in the temporomandibular joint functions are mainly the temporal, masseter, digastricus, medial and lateral pterygoid. From contemporary anatomy, we know that some fibers of temporal, masseter and upper head of lateral pterygoid muscle penetrate to the joint capsule and even to the joint disk [11, 16]. This can result in disk movements, but in the case of muscle hyperactivity could cause disk displacement.
The physiological joints opening movement starts with condyles located in the higher position in relation to the glenoid fossa with the disk between them in the uppermost position. Then, the condyle’s head makes a rotation movement in relation to the disk in the lower joint compartment, and the disk translates down and forward in relation to the glenoid fossa and the articular eminence, as a movement in the upper jaw compartment. At the end of the movement, the condyle head is covered by the disk and located on the top of the articular eminence in its lowest possible position. This movement is limited by the joint capsule tension and the ligaments. The bilaminar zone tissues are maximally stretched. In the physiological movement of the joints, the relation between the condyles and the eminences is expected to be the same during the entire action of the opening and closing of the lower jaw. That condyle head position in relation to the fossa and the eminence can be visualized by pantomographic x-ray examination [17].
The diagnostic methods of temporomandibular joint hypermobility are various and there is a possibility to use non-invasive methods such as clinical examination, auscultation, ultrasonography (USG) or magnetic resonance imaging (MRI). It can be also diagnosed by some invasive methods such as X-ray or computed tomography (CT). Clinical examination, X-rays and auscultation are more convenient for the patients and they give enough medical data for proper diagnoses, so there is no need to buy advanced equipment.
Firstly, the clinical examination should be carried out in a repetitive way at every patient [18]. To realize the assumptions a way of examination was thoroughly described in the validated international protocol Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) [19]. It helps to make the examination in a repeatable way and find a proper diagnosis. The stethoscopes are the main instruments for joint auscultation, their advantage is their vast accessibility [20, 21]. The researchers used various modifications of stethoscopes for joints auscultation [22]. The use of a stethoscope, especially an electronic one for examination allows sending the signal via Bluetooth to the computer for further analysis. That tool was used in the research by Wiedmann et al. [23]. Such a method could also help an inexperienced dentist to consult the cases with a specialist. USG of joints region, especially made by an experienced person allows detecting the position of the disk-condyle complex in a dynamic, real way during the test [24]. It informs about the muscle tension, shape of joints compartments and the amount of synovial fluid. This method is non-invasive, repetitive and gives a satisfying amount of information. MRI, belonging also to the non-invasive examination methods, requires dedicated tools and an experienced person for proper interpretation of the results. It can help to detect disc position, the amount of joint fluid and present the bones structures, yet this technique is the most expensive of the non-invasive methods [25].
Computed tomography (CT) belongs to the invasive examination methods and the radiation dose is the biggest. The advantage of this examination is the very precise detection of the properties of the osseous components of the temporomandibular joints [26]. A much lower radiation dose and sufficient amount of clinical data are obtained from an x-ray examination from pantomographs. Currently, they are the very basic equipment of almost all dental offices so diagnostic technic seems to be very easy and common. As the result of that examination, we receive four pictures, two of each side of the face. Two of them present the mandible in the state of closing and the other two in the maximal opening position. The analysis of both sides is possible and easy. Not too many anatomical structures disturb the image. The example of that x-ray is presented in Figure 1.
Right (two left pictures) and left temporomandibular joints in opening (outer images) and closing position with physiological relation of joints elements.
That examination informs us about condyle bone structure, shape and relation to the fossae in maximal intercuspal position and at the end of opening movement. The result of such an x-ray should be compared with patient’s clinical status. It is important to analyze the opening and closing jaw movements in relation to upper and lower incisor midline positions during all the movements. The range of openings should be measured between the incisal edges. Then palpation in temporomandibular joints region during mandibular movements and auscultation of that region would be crucial [27].
Signs and symptoms of acute or chronic dislocation as hypermobility are the same and include temporary inability to close the mouth, preauricular depression of the skin, excessive salivation, tense, spastic muscle of mastication and pain of temporomandibular joint. At the time of a wide opening, specific sounds may appear. It would happen during excessive mouth opening such as yawning, eating, singing or vomiting. The people who are most vulnerable are the ones who suffer from generalized joint hypermobility as Ehlers-Danlos syndrome or Marfan syndrome as well as neurodegenerative/neurodysfunctional diseases or muscle dystrophies [28, 29]. In the described groups of patients, that symptom could be physiological and often that joint hypermobility is painless. Very characteristic in that cases of hypermobility movement are self-reducing, but sometimes the patients are afraid about complications. The problem could also appear after intubation in general anesthesia too. Repeated episodes of subluxation may result in the lengthening of the capsule ligaments or cause damage to the joint capsule. To make the proper diagnosis clinical examination with joint auscultation and x-ray examination are required.
The clinical examination includes the measurement of jaw abduction, lateral movements and protrusion. The symmetry of movements and their straight direction inform us about their proper function. Then the palpation of jaw movement muscle is required. During the examination, muscles should be in the relaxed position. Before palpation, the stretch of the muscle should be investigated. We are expecting symmetrical contraction in the muscles on both sides during the opening and closing of the mandible. Similarly during forward and backward movement. At that moment the tendons and muscle bodies are palpated, especially temporalis, masseter and digastricus. Those muscles are suitable for direct palpation. Lateral pterygoid muscle can be examined using indirect movements. In such a case the examiner’s hands should block patient’s forward and lateral jaw movements and the doctor should ask the patients about the pain in the region of the joints. The appearance of pain informs about muscle dysfunction, hyperfunction or overactivity [30].
During physiological jaw movements, neither sound nor noises from joints region are expected. If they appear, some disturbances occur i.e. in relation between disk and condylar head or between disk-condyle complex and fossa to articular eminence. The joint dysfunction might be differentiated by sound and it requires auscultating them. Typical sound associated with joints dislocation correlated with hypermobile movement appears at the end of the movement, usually when the mouth is being opened. Subluxation sounds are very specific. Using two electronic stethoscopes the examination takes place during opening and closing movements. That examination is safe for the patient and is easy even for inexperienced doctors. The measured signals from electronic stethoscopes are sent to the computer and the signals are analyzed [31].
In our examination the patients with temporomandibular disorders were included based on our national version of The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) as well as a group of patients without diagnoses but with symptoms and sounds from the joints region [32, 33]. After clinical examination, the auscultation procedure takes place. Patients with diagnoses based on RDC/TMD with sounds from temporomandibular joints and that those with joints sounds who did not receive the diagnoses were taken to the analyzes. All patients with other diagnoses without joints sounds were excluded from the study. After sound differentiation, the group suspected hypermobile joints were selected and an x-ray as confirmation was recommended.
Two electronic stethoscopes (Littmann Model 3200 Manufacturer 3 M Health Care, St. Paul, MN, USA) were used for the examination. Patients were asked to open and close the mouth 5 to 8 times. The auscultation of the temporomandibular joints region was carried out on both sides simultaneously. Electronic stethoscopes convert analogue signals to digital domains and make it possible to analyze about 15 s sounds. Stethoscopes provide a 4000 Hz sampling rate that ensures possibilities to reproduce sound components up to 2000 Hz. The measured sounds were sent to the computer to analyses the recorded signals. The representation of the signal in the frequency domain was computed with the use of the Numpy library and the fast Fourier transform algorithm. In order to achieve local spectral representation, we split the signal into atomic sections with the Blackman window of 512 samples length and 256 samples overlapping. The frequencies below 80 Hz were removed from spectrograms to emphasize higher harmonics that were responsible for the effect of clicking [31]. Usage of two independent stethoscopes is beneficial in terms of capability of identification which joint generates sounds but on the other hand, makes difficulties in interpretation. Vibrations are conducted by bone and tissues therefore to differentiate where the origin of sound is located signals recorded by stethoscopes have to be synchronized. This feature is based on an external synchronization system. Small actuators placed on stethoscopes generate synchro beep sound and are triggered by physician during auscultation using a footswitch [34]. Promising results were achieved by signal analysis in time-frequency domain. This representation provides both information, when acoustic event occurred and which frequency components are present. Artificial intelligence-based approach seems to be the most appropriate in terms of mentioned signal analysis. Dedicated algorithms are still being developed. One of the main challenges is signal identification and segmentation [35]. Only when the auscultation signals will be split into parts corresponding to each jaw movement there will be possible to provide comprehensive automatic signals recognition algorithms.
Totally 120 patients participated in the study. For sounds analyses were qualified 40 persons, in that group 32 were women. Hypermobile sounds were recognized in 4 patients (2 men and 2 women) based on lack of RDC/TMD diagnoses, sound analyses and x-ray confirmation.
From our research, we have very characteristic results for hypermobile joints in relation to the healthy one and with disk displacement with reduction, which is presented in Figures 2–4.
The signal traces recorded on both sides in time domain in healthy joints.
The signal traces recorded on both sides in time domain from patients with disk displacement with reduction in both joints.
The signal traces recorded on both sides in time domain from patients with hypermobile joints as subluxation.
The sound record from a healthy temporomandibular joint presented in Figure 2 concerns the time representation. The record representation is obtained from the serving program from electronic stethoscope Littmann 3200. It is worth mentioning that both joints do not present pathological sounds. Graphs represent a sound that indicates the correct movement of the structures of the temporomandibular joints during opening and closing.
In Figure 3, there is the signal representation from software Littmann 3200 from patient with disk displacement with reduction in both joints.
The signal time representation in Figure 4 is characteristic for a person with subluxation in both joints.
Another helpful auscultation result is presented as time-frequency domain in the form of spectrograms (Figures 5–7).
The signal traces recorded on the short-time Fourier transform (STFT) representation of healthy joints.
The signal traces are recorded on the STFT representation of a disk displacement with reduction in both joints.
Signal traces were recorded on the STFT representation of a hypermobile joints as subluxation.
As a complementary examination x-ray of the joints was required. The results are very characteristic in hypermobile jaw movements patients with a subluxation in one or both joints. For example, in Figure 8 the position of the condyles in the front of the articular eminence was visible.
An example of both sides subluxation x-ray. From left to right: Right side joint in wide jaw open position (the condyle head in the front of articular eminence), right side joint in maximal intercuspation position (the condyle head in glenoid fossa), left side joint in maximal intercuspation position (the condyle head in glenoid fossa) and left side joint in wide jaw open position (the condyle head in the front of articular eminence).
The presented method of examination in the group of patients with temporomandibular joints region sounds is easy, inexpensive and gives possibility for future development. It takes the way for telemedicine as remote consultation. It allows enlargement of patients’ medical data for monitoring present status and progress of treatment. Hypermobile jaw sounds are rare problem in a group of patients with temporomandibular disorders. In our group, it was 3.3% of examined patients which was correlated with the literature [2]. Although the problem affects a relatively small group of patients, it should not be underestimated. It is worth searching for simple solutions for diagnosis. It is possible that the lack of diagnosis is associated with the difficulty and no additional equipment. There is an alternative tool- BioJVA (BioResearch Associates, Inc. Milwaukee WI USA) that can be used to diagnose patients with temporomandibular disorders and for joints sounds analysis [36, 37, 38]. It is non-invasive diagnostic equipment, supplementing the basic clinical examination that can help to observe the present status and the effectiveness of the therapy. The use of this device is not common, it usually occurs in research medical centres due to very high prices and lack of knowledge of how to interpret diagnostic results. The use of a stethoscope could be a common examining method performed by every practising dentist.
As the summary about hypermobile temporomandibular jaw movements, it is important to know, that in all cases with subluxation the appearing sounds are frightening, and sometimes the doctors are more surprised than the accustomed patient. The associated unexpected jaw movements which are correlated with the thud sound in relation to inexperienced dentists would lead to a patient becoming sick. On the other hand, subluxation in some cases would lead to luxation and the patients may require surgery which is at risk of multiple complications. So the necessary recommendations for patients with hypermobile joints with the subluxation are to avoid wide mouth opening during yawning, eating or singing. The most difficult is to control jaw opening during yawning. Our recommendation is to bend your head to the chest and protect jaw opening by neck spine. Another possibility is to suction the tongue to the palate during yawning and protect wide opening by tongue frenulum. In addition, physiotherapeutic procedures are required, to strengthen the muscle for joints protection.
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Due to its small size and amphiphilic nature, it increases the efficacy of mitochondrial electron transport chain and reduces electron leakage. Melatonin prevents degenerative changes in the central nervous system in models of Alzheimer’s and Parkinson’s disease and reduces free radical damage to DNA which may lead to cancer and many other situations. Consequently, melatonin has beneficial effects including stimulation of antioxidant enzymes, inhibition of lipid peroxidation, and so it contributes to protection from oxidative damages.",book:{id:"7328",slug:"melatonin-molecular-biology-clinical-and-pharmaceutical-approaches",title:"Melatonin",fullTitle:"Melatonin - Molecular Biology, Clinical and Pharmaceutical Approaches"},signatures:"Aysun Hacışevki and Burcu Baba",authors:[{id:"248612",title:"Associate Prof.",name:"Aysun",middleName:null,surname:"Hacışevki",slug:"aysun-hacisevki",fullName:"Aysun Hacışevki"},{id:"248614",title:"Ph.D.",name:"Burcu",middleName:null,surname:"Baba",slug:"burcu-baba",fullName:"Burcu Baba"}]},{id:"42117",doi:"10.5772/51819",title:"The Role of Copper as a Modifier of Lipid Metabolism",slug:"the-role-of-copper-as-a-modifier-of-lipid-metabolism",totalDownloads:4478,totalCrossrefCites:9,totalDimensionsCites:38,abstract:null,book:{id:"2552",slug:"lipid-metabolism",title:"Lipid Metabolism",fullTitle:"Lipid Metabolism"},signatures:"Jason L. Burkhead and Svetlana Lutsenko",authors:[{id:"139755",title:"Dr",name:null,middleName:null,surname:"Lutsenko",slug:"lutsenko",fullName:"Lutsenko"}]},{id:"45956",doi:"10.5772/57282",title:"Oxidative Stress and Diabetic Complications: The Role of Antioxidant Vitamins and Flavonoids",slug:"oxidative-stress-and-diabetic-complications-the-role-of-antioxidant-vitamins-and-flavonoids",totalDownloads:4061,totalCrossrefCites:13,totalDimensionsCites:37,abstract:null,book:{id:"3829",slug:"antioxidant-antidiabetic-agents-and-human-health",title:"Antioxidant-Antidiabetic Agents and Human Health",fullTitle:"Antioxidant-Antidiabetic Agents and Human Health"},signatures:"Omolola R. Ayepola, Nicole L. Brooks and Oluwafemi O. 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Due to its small size and amphiphilic nature, it increases the efficacy of mitochondrial electron transport chain and reduces electron leakage. Melatonin prevents degenerative changes in the central nervous system in models of Alzheimer’s and Parkinson’s disease and reduces free radical damage to DNA which may lead to cancer and many other situations. Consequently, melatonin has beneficial effects including stimulation of antioxidant enzymes, inhibition of lipid peroxidation, and so it contributes to protection from oxidative damages.",book:{id:"7328",slug:"melatonin-molecular-biology-clinical-and-pharmaceutical-approaches",title:"Melatonin",fullTitle:"Melatonin - Molecular Biology, Clinical and Pharmaceutical Approaches"},signatures:"Aysun Hacışevki and Burcu Baba",authors:[{id:"248612",title:"Associate Prof.",name:"Aysun",middleName:null,surname:"Hacışevki",slug:"aysun-hacisevki",fullName:"Aysun Hacışevki"},{id:"248614",title:"Ph.D.",name:"Burcu",middleName:null,surname:"Baba",slug:"burcu-baba",fullName:"Burcu Baba"}]},{id:"75377",title:"Pathophysiologic Approach to Type 2 Diabetes Management: One Centre Experience 1980–2020",slug:"pathophysiologic-approach-to-type-2-diabetes-management-one-centre-experience-1980-2020",totalDownloads:805,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This overview summarizes the evolution of pathophysiologic treatment of diabetes type 2 (T2D) in the period of the last 40 years. Randomized Controlled Trials (RCT) and Real World Evidence (RWE) studies resulted in recent Statements of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) in the year 2020. Case reports and studies of a single-centre in Czech Republic are reported. The authors demonstrate the impact of (1) multiple doses of rapid insulin, (2) multiple doses of rapid or ultrarapid insulin analogs (3) continuous subcutaneous insulin infusion (CSII) (4) incretin receptor agonists, (5) fixed combination of insulin degludec with liraglutide (IDegLira) and (6) SGLT2 inhibitor dapagliflozin, on plasma glucose concentration, HbA1c, body mass and patient satisfaction. The importance of therapeutic patients’ education and technology (personal glucometers, continuous/flash glucose monitors, insulin pens/pumps) is emphasized. Most of the observations were already published. Hence, individually adopted education, lifstyle, technical equipment, incretin receptor agonists and/or metformin and/or gliflozins and/or insulin analogs appear to be the core of an effective pathophysiologic approach. Scientific conclusions from RCTs, RWE trials and own clinical case reports may prevail over clinical inertia and induce early implementation of effective methods into routine T2D treatment.",book:{id:"9517",slug:"type-2-diabetes-from-pathophysiology-to-cyber-systems",title:"Type 2 Diabetes",fullTitle:"Type 2 Diabetes - From Pathophysiology to Cyber Systems"},signatures:"Rudolf Chlup, Richard Kaňa, Lada Hanáčková, Hana Zálešáková and Blanka Doubravová",authors:[{id:"278357",title:"Prof.",name:"Rudolf",middleName:null,surname:"Chlup",slug:"rudolf-chlup",fullName:"Rudolf Chlup"},{id:"346119",title:"Dr.",name:"Richard",middleName:null,surname:"Kaňa",slug:"richard-kana",fullName:"Richard Kaňa"},{id:"346120",title:"BSc.",name:"Lada",middleName:null,surname:"Hanáčková",slug:"lada-hanackova",fullName:"Lada Hanáčková"},{id:"346121",title:"BSc.",name:"Hana",middleName:null,surname:"Zálešáková",slug:"hana-zalesakova",fullName:"Hana Zálešáková"},{id:"346122",title:"Dr.",name:"Blanka",middleName:null,surname:"Doubravová",slug:"blanka-doubravova",fullName:"Blanka Doubravová"}]},{id:"61064",title:"Secretions of Human Salivary Gland",slug:"secretions-of-human-salivary-gland",totalDownloads:2805,totalCrossrefCites:4,totalDimensionsCites:6,abstract:"The salivary glands play an important role in our body by the virtue of its ability to secrete saliva. Saliva has a role to play in maintaining the health of the oral cavity and for carrying out physiological functions like mastication, taste perception, speech etc. It also acts as a mirror to the systemic status of an individual owing to its ability to act as a diagnostic fluid for detecting a number of conditions and diseases. Saliva is a potential noninvasive diagnostic fluid for detection of a number of biomarkers of disease and health. Advancement in diagnostic methods has helped in identifying biomarkers of disease in saliva. In order to understand and diagnose pathological changes, a thorough understanding of the salivary gland anatomy, physiology and regulation of its secretion is warranted. This chapter aims to provide the basic understanding of the secretions of saliva.",book:{id:"6246",slug:"salivary-glands-new-approaches-in-diagnostics-and-treatment",title:"Salivary Glands",fullTitle:"Salivary Glands - New Approaches in Diagnostics and Treatment"},signatures:"Anahita Punj",authors:[{id:"226076",title:"Dr.",name:"Anahita",middleName:null,surname:"Punj",slug:"anahita-punj",fullName:"Anahita Punj"}]},{id:"63301",title:"Role of PI3K/AKT Pathway in Insulin-Mediated Glucose Uptake",slug:"role-of-pi3k-akt-pathway-in-insulin-mediated-glucose-uptake",totalDownloads:3601,totalCrossrefCites:12,totalDimensionsCites:29,abstract:"Glucose uptake is regulated by several mechanisms, where insulin plays the most prominent role. This powerful anabolic hormone regulates the transport of glucose into the cell through translocation of glucose transporter from an intracellular pool to the plasma membrane mainly in metabolically active tissues like skeletal muscles, adipose tissue, or liver (GLUT4). This translocation occurs through multiple steps of PI3K/AKT signaling pathway. In this chapter, we will focus on molecular events leading to GLUT4 translocation, starting with activation of insulin receptors through signaling cascade involving phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB) and finally, the action of their effectors. We will present regulatory mechanisms and modulators of insulin-mediated glucose uptake.",book:{id:"7061",slug:"blood-glucose-levels",title:"Blood Glucose Levels",fullTitle:"Blood Glucose Levels"},signatures:"Ewa Świderska, Justyna Strycharz, Adam Wróblewski, Janusz Szemraj, Józef Drzewoski and Agnieszka Śliwińska",authors:null},{id:"70711",title:"Fetal Growth Restriction",slug:"fetal-growth-restriction",totalDownloads:3143,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Fetal growth defect is classified into intrauterine growth restriction (IUGR) and small-for-gestational-age (SGA) fetus based on the estimated fetal weight percentile and Doppler hemodynamic parameters. IUGR pathophysiology and etiology are complex and diverse, highlighting placental insufficiency as a paradigm, which explains its association with other entities of great clinical importance such as preeclampsia. The poor long- and short-term perinatal and postnatal results associated with this context make it necessary to establish an early diagnosis and a therapeutic strategy, which can be challenging due to the compromise between the threat of intrauterine permanence and the prematurity problem. Consequently, a systematic and protocolized diagnostic-therapeutic management, based on scientific evidence, is necessary to determine whether obstetric intervention through a preterm delivery is advisable to improve the perinatal outcomes of these patients.",book:{id:"8224",slug:"growth-disorders-and-acromegaly",title:"Growth Disorders and Acromegaly",fullTitle:"Growth Disorders and Acromegaly"},signatures:"Edurne Mazarico Gallego, Ariadna Torrecillas Pujol, Alex Joan Cahuana Bartra and Maria Dolores Gómez Roig",authors:[{id:"202446",title:"Ph.D.",name:"Maria Dolores",middleName:null,surname:"Gómez Roig",slug:"maria-dolores-gomez-roig",fullName:"Maria Dolores Gómez Roig"},{id:"311835",title:"Dr.",name:"Edurne",middleName:null,surname:"Mazarico",slug:"edurne-mazarico",fullName:"Edurne Mazarico"}]}],onlineFirstChaptersFilter:{topicId:"178",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:32,numberOfPublishedChapters:318,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:15,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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",coverUrl:"https://cdn.intechopen.com/series/covers/3.jpg",latestPublicationDate:"May 13th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:8,editor:{id:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000038WgMKQA0/Profile_Picture_2022-06-02T11:44:20.jpg",biography:"Dr. Sergio Alexandre Gehrke is a doctorate holder in two fields. The first is a Ph.D. in Cellular and Molecular Biology from the Pontificia Catholic University, Porto Alegre, Brazil, in 2010 and the other is an International Ph.D. in Bioengineering from the Universidad Miguel Hernandez, Elche/Alicante, Spain, obtained in 2020. In 2018, he completed a postdoctoral fellowship in Materials Engineering in the NUCLEMAT of the Pontificia Catholic University, Porto Alegre, Brazil. 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",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:2,paginationItems:[{id:"1",title:"Oral Health",coverUrl:"https://cdn.intechopen.com/series_topics/covers/1.jpg",isOpenForSubmission:!0,annualVolume:11397,editor:{id:"173955",title:"Prof.",name:"Sandra",middleName:null,surname:"Marinho",slug:"sandra-marinho",fullName:"Sandra Marinho",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRGYMQA4/Profile_Picture_2022-06-01T13:22:41.png",biography:"Dr. Sandra A. Marinho is an Associate Professor and Brazilian researcher at the State University of Paraíba (Universidade Estadual da Paraíba- UEPB), Campus VIII, located in Araruna, state of Paraíba since 2011. She holds a degree in Dentistry from the Federal University of Alfenas (UNIFAL), while her specialization and professional improvement in Stomatology took place at Hospital Heliopolis (São Paulo, SP). Her qualifications are: a specialist in Dental Imaging and Radiology, Master in Dentistry (Periodontics) from the University of São Paulo (FORP-USP, Ribeirão Preto, SP), and Doctor (Ph.D.) in Dentistry (Stomatology Clinic) from Hospital São Lucas of the Pontifical Catholic University of Rio Grande do Sul (HSL-PUCRS, Porto Alegre, RS). She held a postdoctoral internship at the Federal University from Jequitinhonha and Mucuri Valleys (UFVJM, Diamantina, MG). She is currently a member of the Brazilian Society for Dental Research (SBPqO) and the Brazilian Society of Stomatology and Pathology (SOBEP). Dr. Marinho's experience in Dentistry mainly covers the following subjects: oral diagnosis, oral radiology; oral medicine; lesions and oral infections; oral pathology, laser therapy and epidemiological studies.",institutionString:null,institution:{name:"State University of Paraíba",institutionURL:null,country:{name:"Brazil"}}},editorTwo:null,editorThree:null},{id:"2",title:"Prosthodontics and Implant Dentistry",coverUrl:"https://cdn.intechopen.com/series_topics/covers/2.jpg",isOpenForSubmission:!0,annualVolume:11398,editor:{id:"179568",title:"Associate Prof.",name:"Wen Lin",middleName:null,surname:"Chai",slug:"wen-lin-chai",fullName:"Wen Lin Chai",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRHGAQA4/Profile_Picture_2022-05-23T14:31:12.png",biography:"Professor Dr. Chai Wen Lin is currently a lecturer at the Department of Restorative Dentistry, Faculty of Dentistry of the University of Malaya. She obtained a Master of Dental Science in 2006 and a Ph.D. in 2011. Her Ph.D. research work on the soft tissue-implant interface at the University of Sheffield has yielded several important publications in the key implant journals. 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. 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