Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
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This achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
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We are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
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Thank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
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1. Introduction
Orexin, also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, in which the sufferer experiences brief losses of muscle tone (cataplexy), is caused by a lack of orexin in the brain due to destruction of the cells that produce it. There are only 10,000–20,000 orexin-producing neurons in the human brain, located predominantly in the perifornical area and lateral hypothalamus. They project widely throughout the central nervous system, regulating wakefulness, feeding, and other behaviors. The orexin system was initially suggested to be primarily involved in the stimulation of food intake, based on the finding that central administration of orexin-A and orexin-B increased food intake. In addition, it stimulates wakefulness, regulates energy expenditure, and modulates visceral function [1, 2].
Two distinct types of orexin, orexin-A and orexin-B, were identified; they act on specific receptors called orexin receptor type 1 (OX1R) and orexin receptor type 2 (OX2R). Orexin-A activates both of these receptors equally, while orexin-B has a five times higher affinity to OX2R than OX1R. Upon activation, prepro-orexin will split to orexin-A and orexin-B, which act on their G protein-coupled receptors (Figure 1) [3].
Figure 1.
Schematic representation of orexin system.
Orexin receptors are distributed mainly in the lateral hypothalamus and adjacent areas, and their nerve fibers project to multiple brain regions. Orexinergic neurons in the lateral hypothalamus group are closely associated with reward-related functions. These neurons preferentially innervate the ventral tegmental area and the ventromedial prefrontal cortex. In contrast, the perifornical-dorsal group of orexinergic neurons is involved in functions related to arousal and autonomic response. These neurons project inter-hypothalamically, as well as to the brainstem, where the release of orexin modulates various autonomic processes. Indeed, accumulating evidence shows that the orexin/receptor system is ectopically expressed in several neurological disorders, suggesting that it plays an important role in the incidence and pathogenesis of these diseases [4].
It has been verified that hypothalamic orexigenic neurons are involved in reward functions, while prefrontal orexigenic neurons are linked in the regulation of autonomic and arousal functions. Moreover, orexin provokes and stimulates food intake via inhibition of autonomic digestive feedbacks. Orexigenic neurons are inhibited by leptin and food intake, while hypoglycemia and ghrelin activate orexigenic neurons. Amino acid and high-protein diets paradoxically provoke the hyperpolarization of orexigenic neurons and block glucose-induced orexigenic neuron activations [5]. Animal model studies have shown that orexin is a very important link between sleep and body metabolism since sleep deprivation leads to higher food intake and induction of catabolism [6].
Additionally, orexin stimulates different neurotransmitters which are linked to the activation of the central nervous system, including acetylcholine, histamine, noradrenaline, and dopamine. Therefore, mutations of orexin receptors lead to sleep disorders. Mice with orexin knockout are subjected to narcolepsy and excessive daytime sleepiness [7]. Alizamini et al. study showed that central administration of orexin leads to stimulation of locomotion, psychomotor performance, body temperature, and energy expenditure. Furthermore, mice with orexin deficiency are subjected to obesity due to reduction of basal metabolic and energy expenditure rates. Beside, orexin knockout out mice is characterized by a reduction in brown adipose tissue thermogenesis with poor differentiation of pre-adipocyte into adipocytes in the adipose tissue [8]. Central and peripheral effects of orexin are illustrated in Figure 2.
Figure 2.
Central and peripheral effects of orexin.
The aim of this study was to provide a narrative review of the neurobiological effect of orexin system and to examine the association between orexin neurotransmission and different psychoneurological disorders, including depression, schizophrenia, addiction, Parkinson’s disease, and dementia. Evidence from experimental, preclinical and clinical studies is evaluated for bidirectional relationships between orexin neurobiology and psychoneurological disorders. Given the nature of the subject area, it remains clear that this literature search cannot be regarded as a systemic review.
2. Method and search strategy
A diversity of search strategies was adopted and assumed which included electronic database searches of Medline and PubMed using MeSH terms, keywords, and title words. There is no limitation for publication year. The terms used for these searches were as follows: [orexin OR hypocretin] AND [cognitive function OR vigilance OR depression OR schizophrenia OR addiction OR Alzheimer dementia OR stroke OR sleep disorders]. [suvorexant OR orexin antagonists] AND [sleep disorders OR vigilance OR depression OR schizophrenia OR addiction]. Reference lists of identified and notorious articles were reviewed. Besides, only English articles were considered, and case reports were not involved in the review. The key features of recognized relevant search studies were considered, and the conclusions were summarized in a narrative review.
2.1 Orexin and cognitive function
Orexin regulates behavioral and neuroendocrine response during stressful conditions as these events lead to the impairment of cognitive flexibility and function. Also, patients with psychiatric disorders such as panic disorder are associated with significant reduction of hypothalamic orexin activations [9].
It has been shown that stress improves male cognitive flexibility, but it worsens female cognitive flexibility due to gender differences in stress-induced orexin neuropeptide activations. Women are twice as likely as men to suffer from stress-related psychiatric disorders, such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD); however, the biological basis of these sex differences is not fully understood. Interestingly, orexins are known to be dysregulated in these disorders. Both preclinical and clinical studies have reported higher orexin system expression in females, which contributes to exaggerated neuroendocrine and behavioral responses to stress. Therefore, orexins may be important in the etiology of stress-related psychiatric disorders that present differently in men and women [10]. Piantadosi et al. illustrated that stimulation of prefrontal cholinergic neurons leads to the release of orexin from hypothalamic neurons, which play an important role in cognitive activation since high orexin activates the arousal state and executive functions via activation of cortical cholinergic neurons [11]. Chieffi et al. study reported the beneficial effects of exercise in stimulation of orexin release due to enhancement of hippocampal activity as exercise attenuates hippocampal deterioration and depressive symptoms in elderly persons through regulation of orexin release [12].
Notably, cognitive impairment is the main feature of neurological and neuropsychiatric disorders as in dementia and narcolepsy, which are linked to orexin dysfunction. Therefore, intranasal orexin peptide may be an effective agent for cognitive dysfunction [13]. Astonishingly, orexin plays a crucial role in activation of learning and memory, as orexin-A provokes memory acquisition and consolidation through activation of monoaminergic system. Consequently, orexin antagonist leads to significant memory dysfunction in the experimental rats [14]. Kim et al. study revealed that orexin is an important key factor of hippocampal neurogenesis as orexin-A participates in the hippocampal neuronal proliferation and neuroprotection following stroke; thus orexin agonist participates in prevention of negative stroke outcomes [15]. On the other hand, Uslaner et al. exhibited that dual orexin receptor antagonists (DORA-22) is an effective sedative agent, with less cognitive disability than GABA allosteric modulators, which cause significant cognitive dysfunctions [16, 17]. Therefore, orexin improves cognitive functions as illustrated in different human and animal studies (Table 1).
Orexin is involved in the regulation of central and peripheral signals to regulate metabolic homeostasis. Alongside, orexin stimulates adrenocorticotrophin (ACTH) and corticosteroid secretions via activation of central corticotropin-releasing hormone (CRH) and vasopressin. Therefore, orexin through OX2R receptor controls the hypothalamic-pituitary-adrenal axis (HPA) [18]. Previously, Malendowicz et al. illustrated that chronic orexin administration led to dose-dependent increase in cortisol and aldosterone plasma levels independent of ACTH levels, indicating a direct stimulating effect of orexin on the adrenal cortex [19]. But in spite of these findings, Patel et al. study confirmed insignificant effect of orexin antagonists on ACTH and cortisol serum levels as well as on the markers of the sympathetic nervous system [20].
It has been reported that orexin administration leads to significant suppression of the hypothalamic prolactin release, which is not upturned by dopamine receptor antagonists like metoclopramide suggesting a novel pathway in controlling of prolactin secretion. The mechanism of prolactin inhibition may be through inhibition of prolactin-releasing factor or stimulation of prolactin-inhibiting factor. But previous study illustrated insignificant effect of orexin antagonist on prolactin plasma levels [21, 22].
Many studies showed that the blood glucose is regulated by central orexin through regulation of hepatic glucose production, skeletal glucose consumption and thermogenesis. High orexin or dysrhythmic in orexin secretion is linked with the development of obesity and insulin resistance [23, 24]. Thus, suvorexant and other orexin antagonists are effective in the management of obesity and insulin resistance via amelioration of body adiposity and augmentation of energy expenditure that improve glucose metabolism. Moreover, orexin-A has important roles in the regulation of pancreatic islet biology through activation of insulin secretion and prolongation of pancreatic islets life span [25].
Tsuneki et al. study illustrated that suvorexant improves glucose tolerance through inhibition of hepatic gluconeogenic factors, when administrated at resting time. However, administration of suvorexant at awaking time illustrates insignificant effect on glucose tolerance due to differential effects on the orexin sleep/wake operating system [26].
In addition, Flores et al. study illustrated an interaction between endocannabinoid and orexigenic neurons as there is a similarity between OX1R and CB1 receptors with diffuse overlapping in the anatomical distribution of these neurons. Therefore, the pharmacological effect of cannabinoid may be through orexigenic receptors [27]. The neuroendocrine effects of orexin are summarized in Table 2.
Among important etiological factors involved in the pathophysiology of depression, disturbances of monoamines and HPA are the main mechanistic pathways leading to functional disorders of neuroplasticity, which is regarded as a cardinal step in the onset of depression [28].
Diurnal variation in orexin serum levels revealed that high orexin levels are occurring at the middle of night. It has been reported that orexin level is significantly decreased in patients with depression in comparison with healthy subjects [29]. But paradoxical high orexin serum levels are seen in some depressed patients, which is normalized by selective serotonin reuptake inhibitors. Since, orexin-A CSF levels are negatively correlated with depressive symptoms [30].
Long-term antidepressant agents improve orexin serum levels regardless of the type of antidepressant medications [31]. Nevertheless, there are different findings concerning orexin levels in depression. Feng et al. reported that depression is linked to reduction of serotonergic neuronal activity which is responsible for modulation of orexinergic activity [32]. Thus reduction of serotonergic neuronal activity leads to activation of orexin neuroactivity leading to depression. However, orexin levels are significantly reduced in depression compared with healthy control [33].
The initial animal model study observed reduction in the orexinergic neurons by 18% with diminution in size of these neurons in comparison with normal rats. As well, prepro-orexin mRNA expression and orexin-A were reduced compared with control [34].
Previous preclinical study revealed a strong connection between low orexin and risk of depression which are inconsistent with previous studies that illustrated hypoactivity of orexinergic neurons in patients with depression since short-term antidepressant therapy improves sleep pattern through increasing and decreasing the expression of mRNA of orexin-A and orexin-B, respectively [35].
Ito et al. showed that administration of orexin-A leads to significant reduction of despair behavior in depression with important hippocampal neurogenesis via upregulation of neuropeptide Y (NPY). These changes are inhibited by co-administration of orexin-A antagonist [36].
Therefore, orexin levels are different according to the pathophysiology of depression. Low orexin in depressed patients is associated with hypersomnia, whereas high orexin in depressed patients is associated with insomnia and interrupted sleep [17]. Ji et al. illustrated that orexinergic neurons have direct connection to the ventral pallidum (VP) which is concerned with stress response and rewarding system. Orexin stimulates the VP and prevents depressive behavior. Therefore, high orexin in the VP is associated with elevated serum corticosterone serum levels during acute stress, which per se prevent a depressive reaction against stressful events through improvement of stress resilience [37].
2.3.2 Orexin and schizophrenia
The association between orexin and schizophrenia had not been previously explored precisely [38]. Clinical and preclinical findings proposed that orexin and orexin agonist are of great value and useful in treating cognitive deficit in schizophrenia [39]. There are widespread connection and interaction between orexin and dopaminergic neurons in midbrain, thalamocortical region, and amygdala suggesting the potential role of orexinergic neurons in schizophrenia [40].
Modafinil is an atypical dopamine reuptake inhibitor used in the treatment of narcolepsy and antipsychotic drug-induced sleep disorder (Figure 3) [41]. Modafinil has been revealed as a complement of drugs in therapy of schizophrenia, and it reduce negative symptoms with no effect on the positive symptoms. Modafinil improves locomotor and psychomotor performances through activation of orexinergic neurons [42].
Figure 3.
Chemical structure of modafinil.
Therefore, activations of orexinergic neurons by modafinil may be an imperative step for future antipsychotic medications. These findings document that dopaminergic agonists mainly at D1 and D2 receptors modify orexinergic neurotransmissions [43]. Also, dopamine antagonists that cause weight gain lead to activation of orexin pathway, but dopamine antagonists which do not cause weight gain do not activate orexin pathway [44]. Nevertheless, amphetamine which indirectly activates dopamine leads to activation of orexinergic neurotransmission despite induction of weight loss. Moreover, clozapine activates only orexinergic neurons in the prefrontal cortex [45]. Similarly, orexin antagonists abolish olanzapine and haloperidol effect on midbrain dopaminergic neurons, suggesting that orexin is an important neurotransmitter mediates the action of antipsychotic drugs [46]. As well, Chen et al. illustrated that orexin-A is stimulated and upregulated by non-obesegenic antipsychotic drugs [47]. Also, the high orexin level in patients with schizophrenia treated with antipsychotic drugs is regarded as a protective factor against the development and risk of drug-induced metabolic syndrome [48]. Furthermore, orexin agonist like modafinil ameliorates cognitive function, attention, and antipsychotic-induced sedation.
2.3.3 Orexin and addiction
The orexinergic system has broad projections and connections to different brain area which are concerned with drug-induced neuro-adaptation, including midbrain dopaminergic neurons, ventral tegmental area (VTA), nucleus accumbens (NA), amygdala, and medial prefrontal cortex (mPFC). Drug abuse leads to augmentation of dopaminergic activity in NA through activation of orexinergic neurons at mesocorticolimbic pathway [49]. Correspondingly, experimental studies illustrated that OX1R and OX2R are highly expressed in the NA leading to inhibitory effect instead of excitatory effects seen on the VTA, amygdala, and mPFC. Therefore, a differential effect of orexin is receptor type dependent [50].
Acute administration of addicting drugs such as methamphetamine, nicotine, and amphetamine leads to activation of orexinergic neurons at the lateral hypothalamus. However, acute administration of cocaine and morphine does not affect orexinergic neurons. Besides, chronic administration of addict drugs causes activation of orexinergic neurons mainly at OX2R receptors, but chronic increasing dose of addict drugs leads to downregulation of orexinergic receptors [51]. Carr and Kalivas reported that orexin is an important mediator which enables cocaine to induce addiction-like behavior in rats due to dopaminergic neuronal changes [52]. Also, James et al. verified that orexinergic neurons at the lateral hypothalamus play a vital role in expression of addiction-like phenotype [53]. Thus, the orexinergic system is regarded as an important novel target for drug therapies to treat addiction.
Orexin serum level in chronic smoker subjects is related to craving in the phase of abstinence since it increased during addiction phase and reduced during withdrawal phase. This reduction leads to increase in craving and risk of relapse [54]. Therefore, orexin serum level is regarded as a potential biomarker predicts time and risk of smoking relapse.
Furthermore, Tsai and Huang reported that the orexin serum level is increased in heroin addicts who shifted to methadone maintenance therapy compared with controls suggesting that methadone increases orexin serum levels [55]. Similarly, orexin serum level is increased in chronic alcoholism, which is positively correlated with the severity of alcohol withdrawal. Alleviation of alcohol withdrawal syndrome is linked with reduction of the orexin serum level, which monitors the status of alcoholic patients during the abstinence period [56].
2.3.4 Orexin and sleep disorders
Narcolepsy is a sleep disorder that causes excessive daytime sleepiness or an intractable urge to sleep in, in which duration of rapid eye movement sleep (REM) is reduced. Cataplexy is a sudden reduction in muscle tones with preserved consciousness. Narcolepsy is commonly associated with cataplexy, which is triggered by emotional stimuli [57]. Methylphenidate, modafinil, and other psychostimulants are effective in the management of these sleep disorders [58]. Dysregulation of NREM sleep leads to narcolepsy only, whereas dysregulation of REM sleep leads to combined narcolepsy with cataplexy [59]. It has been reported that orexin increases vigilance through increasing awaking time and decreasing REM and NREM sleep periods. Both OX1R and OX2R are involved in the maintenance of arousal state directly or indirectly through the activation of monoaminergic neurons (noradrenalin, dopamine, histamine, and serotonin). Also, orexin activates cholinergic neurons in the basal forebrain, which is also important for arousal statues [60]. Yamanaka et al. study illustrated that activation of OX2R by orexin leads to wakefulness which is mediated by a histamine neurotransmitter since antihistamine blocks the excitatory effect of orexin, while activation of OX1R by orexin leads to wakefulness, through noradrenalin neurotransmitter [61]. Reduction of orexin level in the cerebrospinal fluid was documented in patients with narcolepsy and nowadays is regarded as one of the diagnostic criteria in the diagnosis of narcolepsy. Likewise, human postmortem study found that orexin peptide and prepro-orexin mRNA are deficient in the pons and cerebral cortex [62]. Therefore, these findings unveil that orexin is an important neuropeptide in the regulation of sleep and consolidated wakefulness. Table 3 summarized the potential role of orexin in common psychiatric disorders.
Orexinergic neurons are severely affected in Parkinson’s disease (PD); previously Fronczek et al. confirmed that orexinergic neuron density was reduced in the prefrontal cortex by 40% with significant reduction in CSF orexin levels in PD patients compared to the healthy control [63].
Furthermore, animal model study illustrated that 15% damage to the orexinergic neurons did not affect CSF orexin, while damage more than 70% leads to 50% decline in the CSF orexin [64]. These findings may explain the association of narcolepsy with PD since both dopamine and orexin interplay in the regulation of sleep pattern through activation of midbrain and thalamocortical pathway [65]. Feng et al. illustrated that in PD, there is a deficiency in hypoxia inducible factor 1 alpha (HIF1-α) due to mitochondrial dysfunction and the administration of orexin-A leads to significant neuroprotective effect on the dopaminergic neurons through the activation of HIF-α [66].
Moreover, orexin-A improves dopaminergic neurons in PD through the reduction of tyrosine hydroxylase (TH) and activation of brain-derived neurotrophic factor (BDNF) in the substantia nigra [43]. Therefore, orexin antagonist may increase risk of PD due to reduction of the neuroprotective and stimulating effects on the dopaminergic neurons at substantia nigra [67]. Sheng et al. found that orexin plays important roles in activation of the subthalamic nucleus which may give a new evidence for the participation of the subthalamic orexinergic system in PD. Importantly, orexin-A increased the protein level of brain-derived neurotrophic factor in dopaminergic neurons of the substantia nigra. The upregulation of BDNF is mainly via OX1R [68]. Long-term therapy with ropinirole in PD leads to significant reduction in the orexin activity which might explain the adverse effect of ropinirole-induced sleep disorder through inhibition of glutamatergic excitatory effect on the orexinergic neurons. Therefore, pharmacotherapy of PD should be re-evaluated in this context [69].
2.4.2 Alzheimer’s disease
Alzheimer’s disease (AD) is a neurodegenerative disease affecting different brain areas characterized by cognitive deficit and progressive memory loss [70]. AD also affects hypothalamic orexinergic neurons leading to excessive daytime sleepiness, which is correlated with low orexin CSF levels, as reduction 40% of the brain cell number is linked with a 14% reduction in orexin CSF levels [71]. Normally, orexin regulates cholinergic and monoaminergic neuron firing during sleep and wakefulness. In AD a reduction in the cholinergic pathway leads to disturbance in sleep patterns leading to daytime sleepiness and insomnia at night which are a hallmark of sleep rhythm in AD [72]. Besides, reduction of cholinergic activity causes overactivity of orexinergic neurons, which causes abnormal sleep and cognitive functions. These changes lead to an elevation of the orexin CSF level, which is linked with reduced REM sleep [73].
Dementia with Lewy bodies is characterized by an elevation in α-synuclein level, which is accumulated in orexin-containing neurons at the hypothalamus causing interference in orexin axonal transport. This effect leads to a reduction in the activity of the orexinergic system in dementia with Lewy bodies but not in AD [74]. Therefore, there are complexities in the orexinergic system according to the clinical presentation and sleep pattern in patients with AD.
2.4.3 Huntington’s disease
Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterized by personality changes, motor disturbances, cognitive decline, and weight loss [75]. HD is caused by a defect in the gene encoding huntingtin, a protein with unclear function, which is essential for cell survival during development and in adult life [76]. In HD there is neurodegeneration involving the neostriatum and cerebral cortex, with the manifestation of intraneuronal aggregates of misfolded huntingtin. Moreover, in patients with end-stage HD, there is about 90% of neuronal loss in the tuber nucleus of the lateral hypothalamus. Orexin-A and orexin-B are synthesized from the same precursor gene and are expressed in the same neurons with their cell bodies concentrated to the lateral hypothalamus [77]. Preclinical and clinical studies observed that orexin serum and CSF levels are decreased by 72% in HD. In healthy subjects, orexin CSF level is >200pg/ml, but in HD and narcolepsy, this level is decreased below 110 pg/ml, due to degeneration of orexinergic neurons in the lateral hypothalamus. Therefore, CSF orexin level is regarded as a biomarker to evaluate the disease progression and usefulness of therapeutic intervention in patients with HD [78, 79]. However, Meier et al. illustrated that CSF and serum orexin levels are of no diagnostic value in prediction and follow-up of HD [80].
Recently, Cabanas et al. observed that orexin in HD has aberrant effects leading to abnormal sleep pattern, and thus orexin antagonist suvorexant may be of great value in restoring normal sleep and behavioral disturbance in HD [81] in addition, these neurons remain functional and illustrate paradoxical effect, it become more modifiable and affect by serotonine and noradrenaline, and less sensitive to the effect of suprachiasmatic nucleus (the master clock of the brain) causing abnormal biological circadian rhythm [81, 82].
Therefore, orexin level in HD is reduced, but the remaining functional orexinergic neurons lead to abnormal circadian biological rhythm causing behavioral, motor, and sleep disturbances.
2.4.4 Multiple sclerosis
Multiple sclerosis (MS) is a demyelinating disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This damage disrupts the ability of parts of the nervous system to transmit signals, resulting in a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems. Specific symptoms can include double vision, blindness in one eye, muscle weakness, and trouble with sensation or coordination. MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms). Between attacks, symptoms may disappear completely; however, permanent neurological problems often remain, especially with the advancement of the disease [83, 84].
The three main characteristics of MS are the formation of lesions in the central nervous system, inflammation, and the destruction of myelin sheaths of neurons. These features interact in a complex and not yet fully understood manner to produce the breakdown of nerve tissue and in turn the signs and symptoms of the disease. Cholesterol crystals are believed to both impair myelin repair and aggravate inflammation. MS is believed to be an immune-mediated disorder that develops from an interaction of the individual’s genetics and as yet unidentified environmental causes. Damage is believed to be caused, at least in part, by attack on the nervous system by a person’s own immune system [85].
Considering the multiplicity of symptoms associated with multiple sclerosis (MS), there is possibility that hypocretin system function might be involved in the pathogenesis of the disease. Papuc et al. showed that high orexin CSF level in patients with MS as compared with healthy controls, but it positively correlated with fatigue level, suggesting a compensatory mechanism for the production of orexin in MS [86]. On the other hand, Nozaki et al. illustrated that orexin CSF level is reduced and correlated with symmetrical hypothalamic lesion and spinal cord damage in MS. Therefore, low orexin level was implicated in the pathogenesis of hypersomnia and cognitive deficit in patients with MS [87]. Recently, Pallais et al. confirmed that orexin has a neuroprotective effect in MS through inhibition of inflammatory and proinflammatory mediators mainly matrixmetaloproteinases (MMP-3, MMP-9) which are involved in damage of neuronal matrix proteins. Consequently, low CSF orexin level indicates underlying active disease [88].
Therefore, CSF orexin level is a valuable biomarker in the diagnosis and prediction of the severity of MS.
2.4.5 Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a disease that leads the death of neurons controlling voluntary muscles. The underlying mechanism involves damage to both upper and lower motor neurons. ALS is characterized by stiff muscles, muscle twitching, and muscle weakness is still unknown. The cause of ALS is not known in 90% of cases but is believed to involve both genetic and environmental factors. The remaining 10% of cases is inherited [89]. Previously, Van Rooij et al. illustrated that CSF orexin level was normal in patients with ALS and not correlated with age and gender. However, a disturbance in the orexinergic system is involved in the pathogenesis of ALS [90]. Moreover, the pathogenesis of ALS is associated with lateral hypothalamic lesions, a site of the orexinergic system leading to sleep disturbances and hypersomnia [91].
Despite different and large body of literature survey, little is known about CSF orexin levels, in clinical and preclinical studies in ALS.
Therefore, orexin CSF level and orexinergic activity in different neurodegenerative diseases are summarized in Table 4.
Regarding orexin antagonists, suvorexant is a dual orexin receptor antagonist was approved by the Food and Drug Administration (FDA) on 13 August 2014 [92]. Other orexin antagonists are almorexant, lemborexant, and filorexant are used in the management of insomnia and other sleep disorders. Also, these drugs may be of great value in the control of depressive disorders and peripheral diabetic neuropathy [93].
Suvorexant (Figure 2) is the first orexin antagonists approved in the United States for treatment of insomnia, which is effective in reduction of time to sleep onset and increase of total sleeping time [94]. Moreover, administration of SB-33867 which is an orexin antagonist leads to significant reduction of sympathetic tone causing a reduction in blood pressure, heart rate, and plasma noradrenalin. These findings suggest that orexin through OX1 receptor regulates sympathetic tone since intravenous administration of orexin leads to parallel increases in noradrenalin plasma levels [95].
Hatta et al. study confirmed the significant effect of suvorexant in the management of delirium in elderly patients in acute care units. The anti-delirium effect is due to the regulation of circadian biology [96]. Delirium is proposed to be related of suvorexant to disturbances and disorders in sleep pattern in critically ill patients in the intensive care unit. Also, attention disorders are caused by disturbances in the ascending reticular activating system (ARAS) which is responsible for maintenance of human arousal. Normally, the arousal state is regulated and stimulated by ARAS neurotransmitters and by hypothalamic orexin [97]. Therefore, orexin receptor antagonists may play important role in the regulation of hypothalamic and brain stem stress during acute injury. Moreover, a recent study by Kawada et al. illustrated that suvorexant add-on therapy to ramelteon in the management of sleep disorders in patients with acute stroke is more effective than when combined with benzodiazepines [98].
It has been verified that prolonged alcohol consumption is associated with sleep disturbance which is a powerful factor for relapse and setback to alcohol use. Suvorexant reduces the motivation properties of alcohol, so it plays a crucial role in the prevention of alcoholism [99].
Beside, Gentile et al. study revealed the possible role of suvorexant in reduction of motor impulsivity of cocaine-induced psychostimulant effects. Thus suvorexant may be effective in attenuation of cocaine withdrawal syndrome [100].
As well, suvorexant had placebo-like effect on EEG in comparison with zolpidem which has a significant reduction in the spectral density of rapid eye movement and non-rapid eye movement sleep (NREM) pattern [101].
In spite of the wide uses of suvorexant in the management of sleep disorders and controlling insomnia, it did not reduce the psychomotor performances as documented by Vermeeren et al. study [102].
Orexin-A is involved in regulation of feeding; it stimulates nocturnal feeding through OX1 receptor. Therefore, OX1 receptor antagonist regulates feeding and reduced nocturnal feeding; thus, orexin antagonist could be useful in the treatment of obesity [103]. Orexin-A is implicated in the pathogenesis of obesity; it promotes hyperphagia through central activation of cannabinoid receptors and inhibition of melanocyte-stimulating hormone [104]. Both orexin-A and endocannabinoid increases glucose response of neuronal excitability in the arcuate nucleus leading to induction of feeding and obesity [104].
In summary, more research is required to reinforce the extant information on the importance of the limited number of factors studied to date and provide data on additional potentially relevant effects. Similarly, rubric for such research should shift from preclinical and animal model studies to clinical studies to illustrate disease progression and treatment effects in relation to orexin neurobiology. This study suggests that orexin system is a future target in the management of different psychoneurological disorders after delineating the specific role of orexin receptor agonists and antagonists. Moreover, measurement of orexin serum level which is an easy method may be of great value in evaluation and assessment of different neurological disorders. Also, ratio of orexin serum level/CSF orexin level may reflect the activity of endogenous orexinergic system.
3. Conclusion
Orexin system is regarded as a potential novel target in the management of schizophrenia, depression, addiction, and sleep disorders. Orexin serum level might predict relapse and withdrawal of addict patients.
Conflict of interest
None.
Funding and support
None.
\n',keywords:"orexin, sleep disorders, psychiatric disorders, neurodegenerative disorders",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/71777.pdf",chapterXML:"https://mts.intechopen.com/source/xml/71777.xml",downloadPdfUrl:"/chapter/pdf-download/71777",previewPdfUrl:"/chapter/pdf-preview/71777",totalDownloads:663,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:33,impactScoreQuartile:2,hasAltmetrics:0,dateSubmitted:"December 12th 2019",dateReviewed:"February 21st 2020",datePrePublished:"April 13th 2020",datePublished:"September 9th 2020",dateFinished:"April 13th 2020",readingETA:"0",abstract:"Orexin is a neuropeptide secreted from the lateral hypothalamus and prefrontal cortex concerned in wakefulness and excitement. This study aimed to review the possible neurobiological effect of orexin. A diversity of search strategies was adopted and assumed which included electronic database searches of Medline and PubMed using MeSH terms, keywords, and title words. Orexin plays a vital role in activation of learning, memory acquisition, and consolidation through activation of the monoaminergic system, which affects cognitive flexibility and cognitive function. Orexin stimulates adrenocorticotrophin (ACTH) and corticosteroid secretions via activation of the central corticotropin-releasing hormone (CRH). Cerebrospinal (CSF) and serum orexin serum levels are reduced in depression, schizophrenia, and narcolepsy. However, high orexin serum levels are revealed in drug addictions. Regarding neurodegenerative brain diseases, CSF and serum orexin levels are reduced in Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Orexin antagonist leads to significant reduction of sympathetic overactivity during withdrawal syndrome. Also, orexin antagonist improves sleep pattern. The orexinergic system is involved in different psychiatric and neurological disorders; therefore targeting of this system could be a possible novel pathway in the management of these disorders. In addition measurement of CSF and serum orexin levels might predict the relapse and withdrawal of addict patients.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/71777",risUrl:"/chapter/ris/71777",book:{id:"8781",slug:"weight-management"},signatures:"Hayder M. Alkuraishy, Ali I. Al-Gareeb and Naseer A. Al-Harchan",authors:[{id:"306350",title:"Prof.",name:"Hayder M.",middleName:null,surname:"Al-kuraishy",fullName:"Hayder M. Al-kuraishy",slug:"hayder-m.-al-kuraishy",email:"hayderm36@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"320583",title:"Dr.",name:"Ali I.",middleName:null,surname:"Al-Gareeb",fullName:"Ali I. Al-Gareeb",slug:"ali-i.-al-gareeb",email:"dr.aliismalalgareeb@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"320584",title:"Dr.",name:"Naseer A.",middleName:null,surname:"Al-Harchan",fullName:"Naseer A. Al-Harchan",slug:"naseer-a.-al-harchan",email:"dr.nasswr@yahoo.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. Method and search strategy",level:"1"},{id:"sec_2_2",title:"2.1 Orexin and cognitive function",level:"2"},{id:"sec_3_2",title:"2.2 Orexin and neuroendocrinology",level:"2"},{id:"sec_4_2",title:"2.3 Orexin and psychiatric disorders",level:"2"},{id:"sec_4_3",title:"2.3.1 Orexin and depression",level:"3"},{id:"sec_5_3",title:"2.3.2 Orexin and schizophrenia",level:"3"},{id:"sec_6_3",title:"2.3.3 Orexin and addiction",level:"3"},{id:"sec_7_3",title:"Table 3.",level:"3"},{id:"sec_9_2",title:"2.4 Orexin in neurodegenerative diseases",level:"2"},{id:"sec_9_3",title:"2.4.1 Parkinson’s disease",level:"3"},{id:"sec_10_3",title:"2.4.2 Alzheimer’s disease",level:"3"},{id:"sec_11_3",title:"2.4.3 Huntington’s disease",level:"3"},{id:"sec_12_3",title:"2.4.4 Multiple sclerosis",level:"3"},{id:"sec_13_3",title:"Table 4.",level:"3"},{id:"sec_15_2",title:"2.5 Orexin antagonists and neurobiology",level:"2"},{id:"sec_17",title:"3. 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A patient with anti-aquaporin 4 antibody who presented with recurrent hypersomnia, reduced orexin (hypocretin) level, and symmetrical hypothalamic lesions. Sleep Medicine. 2009;10(2):253-255'},{id:"B88",body:'Pallais JP, Kotz CM, Stanojlovic M. Orexin/hypocretinin in multiple sclerosis and experimental autoimmune encephalomyelitis. Neural Regeneration Research. 2020;15(6):1039'},{id:"B89",body:'Takata M, Tanaka H, Kimura M, Nagahara Y, Tanaka K, Kawasaki K, et al. Fasudil, a rho kinase inhibitor, limits motor neuron loss in experimental models of amyotrophic lateral sclerosis. British Journal of Pharmacology. 2013;170(2):341-351'},{id:"B90",body:'Van Rooij FG, Schelhaas HJ, Lammers GJ, Verbeek MM, Overeem S. CSF hypocretin-1 levels are normal in patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis. 2009;10(5-6):487-489'},{id:"B91",body:'Panda S, Gourie-Devi M, Sharma A. Sleep disorders in amyotrophic lateral sclerosis: A questionnaire-based study from India. Neurology India. 2018;66(3):700'},{id:"B92",body:'Herring WJ, Roth T, Krystal AD, Michelson D. Orexin receptor antagonists for the treatment of insomnia and potential treatment of other neuropsychiatric indications. Journal of Sleep Research. 2018;18:e12782'},{id:"B93",body:'Perrey DA, Zhang Y. Therapeutics development for addiction: Orexin-1 receptor antagonists. Brain Research. 2018:24. pii: S0006-8993(18)30447-5'},{id:"B94",body:'Herring WJ, Connor KM, Ivgy-May N, et al. Suvorexant in patients with insomnia: Results from two 3-month randomized controlled clinical trials. Biological Psychiatry. 2016;79:136-148. DOI: 10.1016/j.biopsych.2014.10.003'},{id:"B95",body:'Li A, Hindmarch CC, Nattie EE, Paton JF. Antagonism of orexin receptors significantly lowers blood pressure in spontaneously hypertensive rats. Journal of Physiology. 2013;591:4237-4248. DOI: 10.1113/jphysiol 2013.256271'},{id:"B96",body:'Hatta K, Kishi Y, Wada K, Takeuchi T, Ito S, Kurata A, et al. Preventive effects of suvorexant on delirium: A randomized placebo-controlled trial. Journal of Clinical Psychiatry. 2017;78(8):e970-e979'},{id:"B97",body:'Al-Kuraishy HM. Central additive effect of Ginkgo biloba and Rhodiola rosea on psychomotor vigilance task and short-term working memory accuracy. Journal of Intercultural Ethnopharmacology. 2016;5(1):7-19'},{id:"B98",body:'Kawada K, Ohta T, Tanaka K, Miyamura M, Tanaka S. Addition of suvorexant to ramelteon therapy for improved sleep quality with reduced delirium risk in acute stroke patients. Journal of Stroke & Cerebrovascular Diseases. 2018:12. pii: S1052-3057(18)30527-5'},{id:"B99",body:'Campbell EJ, Marchant NJ, Lawrence AJ. A sleeping giant: Suvorexant for the treatment of alcohol use disorder? Brain Research. 2018:3. pii: S0006-8993(18)30419-0'},{id:"B100",body:'Gentile TA, Simmons SJ, Watson MN, Connelly KL, Brailoiu E, Zhang Y, et al. Effects of suvorexant, a dual orexin/hypocretin receptor antagonist, on impulsive behavior associated with cocaine. Neuropsychopharmacology. 2018;43(5):1001-1009'},{id:"B101",body:'Struyk A, Gargano C, Drexel M, Stoch SA, Svetnik V, Ma J, et al. Pharmacodynamic effects of suvorexant and zolpidem on EEG during sleep in healthy subjects. European Neuropsychopharmacology. 2016;26(10):1649-1656'},{id:"B102",body:'Vermeeren A, Vets E, Vuurman EF, Van Oers AC, Jongen S, Laethem T, et al. On-the-road driving performance the morning after bedtime use of suvorexant 15 and 30 mg in healthy elderly. Psychopharmacology. 2016;233(18):3341-3351'},{id:"B103",body:'Nixon JP, Mavanji V, Butterick TA, Billington CJ, Kotz CM, Teske JA. Sleep disorders, obesity, and aging: The role of orexin. Ageing Research Reviews. 2015;20:63-73'},{id:"B104",body:'Morello G, Imperatore R, Palomba L, Finelli C, Labruna G, Pasanisi F, et al. Orexin-A represses satiety-inducing POMC neurons and contributes to obesity via stimulation of endocannabinoid signaling. Proceedings of the National Academy of Sciences. 2016;113(17):4759-4764'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Hayder M. Alkuraishy",address:"hayderm36@yahoo.com",affiliation:'
Department of Clinical Pharmacology, Medicine and Therapeutic, Medical Faculty, College of Medicine, Al-Mustansiriya University, Baghdad, Iraq
'},{corresp:null,contributorFullName:"Ali I. Al-Gareeb",address:null,affiliation:'
Department of Clinical Pharmacology, Medicine and Therapeutic, Medical Faculty, College of Medicine, Al-Mustansiriya University, Baghdad, Iraq
'},{corresp:null,contributorFullName:"Naseer A. Al-Harchan",address:null,affiliation:'
Department of Clinical Pharmacology, Medicine and Therapeutic, Medical Faculty, College of Medicine, Al-Mustansiriya University, Baghdad, Iraq
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1. Introduction
Members of the class Actinobacteria produce an impressive range of bioactive metabolites that are of commercial importance and many more that have the potential for future exploitation. This includes biosurfactants which are synthesised by many actinobacterial species. Microbial biosurfactants are gaining increased attention in the biotechnology industries as they are multifunctional, enabling diverse applications. Biosurfactants can also claim strong green credentials as not only are they biorenewable with the possibility of production on various substrates including wastes, but they may also be applied to environmental remediation [1]. Further, biosurfactants are generally considered superior to their chemically synthesized counterparts. Amongst the most common biosurfactant producers are members of the mycolic acid-containing (mycolate) genus Rhodococcus which have received considerable attention. However, other related mycolate genera including Corynebacterium, Dietzia, Gordonia and Tsukamurella also possess biosurfactant-producing strains but have not been explored to the same extent. Additionally, there are several other mycolate genera that have received little or no investigation in this respect that may produce novel biosurfactant compounds.
Membership of the mycolic acid-containing actinobacterial (MACA) group has expanded considerably over the past 20 years with revisions to the classification of existing species and the publication of copious new mycolate species and genera [2]. This substantial and metabolically diverse group therefore warrants further attention in the search for valuable biosurfactants. This chapter provides an overview of the current knowledge on biosurfactants produced by members of this group and describes approaches to the recovery, screening and biosurfactant-producing strains from the environment and their growth requirements. Methodologies applied to screen for biosurfactant production and for extraction, purification, and structural elucidation of biosurfactant compounds are also described. Current and potential future applications of biosurfactants derived from MACA are examined with particular focus on potential biomedical and environmental possibilities.
1.1 Biosurfactant properties
Microbial biosurfactants are amphipathic compounds, with both hydrophilic (polar) and hydrophobic (non-polar) moieties. The hydrophobic portion has saturated, unsaturated, or hydroxylated long-chain fatty acids and the hydrophilic portion can contain amino acids, carbohydrate, carboxyl acid, peptides, phosphate, or alcohol [3]. Biosurfactants may be categorised according to molecular weight (low or high), ionic charge (anionic, cationic, neutral, or non-ionic) or according to chemical composition and structure. The main classes of biosurfactants include fatty acids, glycolipids, lipopeptides, lipoproteins, neutral lipids, phospholipids, and polymeric biosurfactants. Their amphipathic nature enables biosurfactants to partition at water-air, oil-air, or oil-water interfaces thereby reducing surface and/or interfacial tension. They exhibit many other useful properties including de-/emulsification, dispersion, foaming, lubrication, softening, stabilisation, viscosity reduction and wetting [4].
Biosurfactants may be located intracellularly, on the cell surface (cell-bound) or excreted extracellularly (free) [5] and are produced during growth on both hydrophilic and hydrophobic substrates, to reduce surface or interfacial properties of the microbial cell or the surrounding environment. Biosynthesis of these compounds is required for gliding, motility, swarming, and biofilm formation. Biosurfactants also mediate between cells and hydrophobic compounds, enabling enhanced solubilisation and uptake across the cell membrane for utilisation as a substrate for growth and energy (Figure 1).
Figure 1.
Emulsification of hydrocarbons by microbial biosurfactants to enhance bioavailability.
Many microbially derived biosurfactants are already used in diverse industries including agriculture, bioremediation, cosmetics, food, healthcare and medicine, and the petrochemical industry (Figure 2). In addition to being multifunctional, biosurfactants have several advantages over chemically synthesised surfactants. They are less/non-toxic and biodegradable, have higher surface activity and lower critical micelle concentrations (CMC), greater biocompatibility and selectivity, they function over wide pH, salinity, and temperature ranges, and can be produced using renewable and waste substrates [6]. These unique eco-friendly features make biosurfactants particularly attractive options as industries focus on longer-term sustainability and working towards a circular economy.
Figure 2.
Various sectors of application for microbial biosurfactants.
1.2 Mycolic acid-containing actinobacteria
The MACA form a phylogenetically coherent group that resides in the order Corynebacteriales based on 16S rRNA gene sequence analysis. The members are Gram-positive with high guanine-plus-cytosine (G + C) content in their genomic DNA. They currently comprise more than 400 species classified in 15 genera, namely Corynebacterium, Dietzia, Gordonia, Hoyosella, Lawsonella, Millisia, Mycobacterium, Nocardia, Rhodococcus, Segniliparus, Skermania, Smarigdococcus, Tomitella, Tsukamurella and Williamsia [2]. The almost universal production of mycolic acids by members of this group is a synapomorphic trait that is unique to this phylogenetic lineage [7]. However, several members of this order appear to have lost the ability to produce mycolic acids over the course of evolution, including several species of the genus Corynebacterium and Hoyosella. It was recently proposed that the single species belonging to the genus Turicella, also characterised by the absence of mycolic acids, be reclassified in the genus Corynebacterium [8].
Mycolic acids, which are high molecular weight 3-hydroxy fatty acids with a long alkyl branch in the 2-position, represent the major lipid constituents of the cell envelope of these organisms. They show structural variations from relatively simple mixtures of saturated and unsaturated compounds in corynebacteria to highly complex mixtures in mycobacteria. Mycolic acids also vary in the number of carbons on the 2-alkyl-branch from C22–C38 in corynebacteria to C60–C90 in mycobacteria [9]. Mycolic acids play an essential role in the architecture and functions of the cell envelope, where attached to the cell wall arabinogalactan they help to form a barrier that contributes to impermeability and resilience and conveys hydrophobicity to the cell surface. Trehalose mycolates, also termed cord factors, play an important role in pathogenicity in mycobacterial species that cause infection [9]. The presence and carbon chain length of mycolic acids can be used as taxonomic markers for the identification and classification of actinobacteria to the order Corynebacteriales [2].
Members of order Corynebacteriales can usually be distinguished from one another and from corresponding taxa in the phylum Actinobacteria based on 16S rRNA phylogeny supported by phenotypic (cell wall chemistry and morphology) features. Cell morphology amongst the MACA varies from simple rods and cocci to branched filaments that fragment to pleomorphic forms (Table 1). Members of the species Skermania piniformis are micromorphologically unique in this group as they form pine tree-like acute-angle branched filaments [10]. Colonies growing on agar plates are normally visible within several days of inoculation (Figure 3) although slow-growing mycobacteria take considerably longer. Species vary widely in colony appearance and are often colourful however it is usually not possible to unambiguously assign strains to a genus based on this feature alone.
Genus
Micro-morphology
Acid-fastness
Aerial hyphae
Visible colonies (days)
Strictly aerobic
Corynebacterium
Pleomorphic rods, often club-shaped in palisade or angular arrangements
Some weakly acid-fast
Absent
1–2
No
Dietzia
Short rods and cocci
No
Absent
1–3
Yes
Gordonia
Rods, cocci and/or moderately branching hyphae
Partially acid-alcohol fast
Absent
1–3
Yes
Hoyosella
Cocci occur singly, in pairs, tetrads or in groups
Slightly acid–alcohol-fast
Absent
2
Yes
Lawsonella
Pleomorphic bacilli and cocci
Partially acid-fast
Absent
5–7
No
Millisia
Short rods
Acid-alcohol fast
Absent
1–3
Yes
Mycobacterium
Rods, occasionally branched filaments that fragment to rods and cocci
Strongly acid-fast
Rare
2–40
Yes
Nocardia
Mycelia that fragment into rods and cocci
Partially acid-fast
Present
1–5
Yes
Rhodococcus
Rods to extensive substrate mycelia that fragment to irregular rods and cocci
Partially acid-fast
Absent
1–3
Yes
Segniliparus
Rods
Acid-alcohol fast
Absent
3–4
Yes
Skermania
Acute angled branched mycelia
No
Only visible under the microscope
10–21
No
Smaragdicoccus
Coccoid
ND
Absent
7–14
Yes
Tomitella
Irregular rods
ND
Absent
ND
Yes
Tsukamurella
Single rods or in pairs or masses, sometimes rudimentary filaments and coccobacillary forms
Partially alcohol-acid fast
Absent
1–3
Yes
Williamsia
Thin rods or cocci in pairs or clusters
ND
Present
1–4
Yes
Table 1.
General phenotypic features of mycolate genera classified in the order Corynebacteriales.
The appearance of (a) Gordonia amarae, (b) Rhodococcus erythropolis and (c) Tsukamurella spumae on glucose yeast-extract agar after 7 days incubation at 30°C.
Chemotaxonomy is the study of the distribution of various cell wall components to classify and identify strains and is particularly useful to differentiate between the various mycolic acid-containing genera. Cell wall markers typically used to differentiate between MACA genera are summarised in Table 2. Some of the methods used to analyse these chemotaxonomic markers provide quantitative or semi-quantitative data, as in the case of fatty acids, whereas other techniques provide only qualitative data as in the case of muramic acid type and phospholipid pattern.
Reliable identification of MACA strains to species level depends upon phylogenetic analysis of the gene encoding 16S rRNA and DNA:DNA homology determination provides definitive delineation of species with 70% homology and above signifying membership of same species [11]. Increasingly, whole-genome sequencing (WGS) is becoming a standard technique and comparative genomic analysis is providing useful insights to the relatedness and divergence of MACA species [11]. Protein sequences from Corynebacteriales genomes have revealed many conserved signature indels (CSIs) conserved signature proteins (CSPs) that are specific for members of this order [12].
2. Biosurfactants produced by MACA
In addition to Rhodococcus, diverse members of the order Corynebacteriales have been reported to synthesise extra-cellular and cell-bound biosurfactants, including members of the genera Corynebacterium, Dietzia, Gordonia, Mycobacterium, Nocardia, and Tsukamurella. Species belonging to the genus Rhodococcus have been most extensively investigated and are known to produce different chemical types, including a variety of glycolipids. However, an interesting array of biosurfactant structures are synthesized by MACA including lipopeptides, oligosaccharide lipids, polymeric glycolipids, terpenoid glycosides, trehalose corynemycolates, trehalose mycolates and dimycolates, and trehalose lipid (THL) esters [13]. Example structures of the different types of biosurfactants produced by MACA are shown in Figure 4. The chemical structure of trehalose-containing glycolipids have perhaps been studied in most detail. Several structural types have been reported including mono-, di- and tri-corynemycolates which have been characterised for species such as Rhodococcus erythropolis, Rhodococcus ruber and Rhodococcus wratislaviensis [14] and trehalose di-nocardiomycolates which have been characterised for Rhodococcus opacus [13]. The mycobacterial trehalose mycolates or di-mycolates (cord factors) are also thoroughly investigated given their role as modulators of mycobacterial pathogenesis and host immune response.
Figure 4.
Types and key structural features of various biosurfactants produced by MACA. (Adapted from [13]).
3. Habitats, recovery, and growth requirements of MACA
MACA are widely distributed in the environment including natural habitats such as mangroves, soil, freshwater, and deep ocean sediments as well as man-made sites such as activated sludge foams, biofilters, industrial wastewater and indoor building materials. Although predominantly saprophytic, many species are opportunistic pathogens forming parasitic associations with plants and animals, including humans, notably immunocompromised individuals. Several members of the genus Mycobacterium cause a plethora of diseases most notably tuberculosis caused by Mycobacterium bovis and Mycobacterium tuberculosis.
MACA capable of producing various biosurfactants have been isolated from environments (Table 3) including oil-contaminated soils [24, 25], water from oil wells [26], wastewater from the rubber industry [21], activated sludge, and effluent and sediment from pesticide manufacturing facilities [23]. The ability of MACA to produce biosurfactants in these habitats appears to be driven by the environmental conditions to which they are exposed whereby the biosurfactants act as mediators for the biodegradation of hydrophobic carbon substrates. Genes involved in biosynthesis of rhamnolipids by Dietzia maris for example have been shown to be upregulated in the presence of hydrophobic substrates including n-hexadecane, n-tetradecane and pristane [15]. However, the true distribution of biosurfactant-producing MACA in the environment may not solely depend on the presence of hydrophobic substrates.
Various environmental sources of biosurfactant-producing MACA.
Isolation of biosurfactant producers largely relies on selective isolation strategies, utilising hydrophobic compounds as sole carbon sources for energy and growth. Typically, strains are isolated and cultivated using mineral salt medium containing essential trace elements supplemented with a hydrocarbon substrate such as crude oil, diesel, n-alkanes, n-hexadecane, paraffin, polyaromatic hydrocarbons (PAHs), or vegetable oils such as olive oil and rapeseed oil, as the sole carbon source. These may be incorporated into the liquid or solid medium, spread across the agar surface or soaked onto a filter in the lid of petri dishes. Besides the selectivity of the culture medium, pre-enrichment techniques utilising hydrophobic compounds as the sole carbon source, can be used [27]. The principle of enrichment is to provide growth conditions that are favourable for the organisms of interest but not for competing organisms. This selective advantage allows target populations to expand through a series of passages, maximising the chances of successful recovery at the isolation stage. Incorporating antibiotics into the isolation media may provide a useful additional selective pressure to eliminate or reduce unwanted fungi and bacteria.
The ability of an organism to grow on hydrophobic compounds is a good indicator of biosurfactant production but is not a guarantee. It is therefore important that isolates of interest are tested in pure culture for biosurfactant production using further screening assays. It is also possible that biosurfactant-producing organisms may be present in an environment but not enriched by in the conditions provided or indeed producers may be recovered from the environment but not synthesize biosurfactants under the culture conditions imposed. Mining genomes for cryptic biosurfactant biosynthesis pathways, and metagenomic screening of DNA from environmental samples promise an alternative approach to biosurfactant discovery that may circumvent some of the issues associated with culture-dependent strategies [28].
4. Detection and characterisation of biosurfactants
4.1 Biosurfactant screening methods
A variety of methods, both qualitative and quantitative, have been applied to screen microbial cultures and cell-free media for total (intracellular, surface-bound, and freely released) and freely released biosurfactants, respectively. As biosurfactants are structurally diverse, complex molecules, most of these methods are indirect, reliant on physico-chemical properties such as emulsification, surface activity or hydrophobicity. Commonly reported screening methods used to detect biosurfactant production amongst MACA strains are listed in Table 4. Besides the bacterial adhesion to hydrocarbons (BATH) assay [37] other tests based on cell surface hydrophobicity include salt aggregation [38] and hydrocarbon overlay [39] assays. The atomized oil assay [40] may be used to directly screen colonies growing on primary isolation plates and is therefore useful as an initial screen for novel-producing strains recovered from the environment. The microplate assay [41] which relies on the wetting properties of biosurfactants and the penetration assay [42], which relies on the reduction of interfacial tension are also considered useful for screening large numbers of strains. Recently, a rapid, high throughput assay that utilises Victoria pure blue BO dye, and is based on surface-active properties, has been developed for quantitative screening, but has not yet been applied to MACA [43].
Examples of screening methods used to detect biosurfactant production by MACA.
These assays are simpler and more rapid than chemical analytical procedures, and most enable larger-scale screening for biosurfactant production. However, perhaps owing to the general and indirect nature of these assays and various limitations associated with some, test results between assays are not always congruent and no one assay is considered definitive for biosurfactant production. It is thus advisable to use several methods in combination, adopting simple methods to undertake preliminary screening of large strains collections prior to further investigation of those found to be most promising. The development of high-throughput screening, metabolic profiling technologies, and whole-genome analysis promise a more thorough investigation of potential biosurfactant producing strain in the future [28].
4.2 Extraction and structural analysis of biosurfactants
Crude biosurfactant extracts may be obtained from cell cultures (cell-associated and free surfactants) or cell-free broth (free surfactant only) by acidification and solidification followed by solvent extraction of the precipitate. In the case of MACA commonly used solvents include MTBE, dichloromethane, or varying ratios of chloroform–methanol or MTBE–chloroform [44]. Various analytical techniques are used in combination to detect, quantify, and characterise biosurfactants. Thin layer chromatography (TLC) is a straightforward method to separate biosurfactant fractions present in crude extracts. Samples are spotted at the base of a silica plate before development in a solvent system, then air-dried and sprayed with a particular reagent to detect certain chemical groups based on spot colour and/or Rf values. Orcinol, for example, allows detection and differentiation of glycolipids and can distinguish mono-rhamnolipid (MRL) and DRL congeners [45]. However, TLC provides little further detail on congener structure, and it is not generally considered suitable for quantitative analysis although densiometry has been used for this purpose [46]. Biosurfactants may be further separated by silica gel column chromatography.
High-performance liquid chromatography-mass spectrometry (HPLC-MS) allows more precise and accurate characterisation and quantitation of biosurfactant compounds. Isocratic HPLC-UV has been reported for structural and yield determination of THLs produced by R. erythropolis strain MTCC 2794 from semi-purified extractions of whole-cell broth [47]. Nuclear magnetic resonance spectroscopy (NMR) is considered the gold standard method to characterise the chemical structure of novel biosurfactants. This has been used in combination with matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-ToF/MS) to elucidate the structure of two novel extracellular THLs TL A and TL B from Tsukamurella spp. [18].
A combination of Fourier transform infrared spectroscopy (FTIR), NMR, and liquid chromatography-mass spectrometry (LC-MS) enabled structural characterisation of a novel cyclic lipopeptide, Coryxin, produced by Corynebacterium xerosis NS5 [48]. Multiple-Stage Linear Ion-Trap Mass Spectrometry with Electrospray Ionization has been used to determine the structure of trehalose monomycolate (TMM) and trehalose dimycolate (TDM) in the cell wall of Rhodococcus equi and R. opacus [49]. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) has been utilised successfully for the purification and characterisation of sophorolipids and rhamnolipids in Pseudomonas aeruginosa [50] and could be applied to similar compounds produced by mycolate species. Gas chromatography-mass spectrometry (GC-MS) is used to characterisation of the fatty acid and mycolic acid components and for the carbohydrate portion of THLs.
5. Potential applications of biosurfactants from MACA
Biosurfactants produced by rhodococci and related MACA have been investigated primarily for their potential application in oil remediation but are otherwise under-studied and under-exploited. However, research studies reveal various potential applications for these molecules, including in environmental and medical fields as summarised in Figure 5.
Figure 5.
Promising medical and environmental applications for biosurfactants produced by MACA.
5.1 Biomedical applications
Biosurfactants produced by microorganisms are reported to have various potential biomedical and pharmaceutical applications which have been reviewed widely [1, 51, 52]. This stems from an array of biological properties including anti-adhesion and antibiofilm, anti-inflammatory, antimicrobial (anti-bacterial, anti-fungal and anti-viral), antioxidant, anti-tumour, and wound healing activities. Other potential applications include adjuvants for antigens in vaccines, pulmonary surfactants, drug delivery systems, enhanced vehicles for gene therapy and in dermatological care. Biosurfactants also have several applications in therapeutic dentistry [53]. Daptomycin, a cyclic lipopeptide produced by the actinobacterium Streptomyces filamentosus, is used as an antibiotic to treat serious blood and skin infections caused by Gram-positive pathogens [54] and there are other examples of actinobacteria that produce surfactants with potential biomedical applications, such as Nocardiopsis strains [55]. Only limited investigation has focused on the biomedical potential of biosurfactants from MACA, except for TDM or cord factors synthesised by intracellular pathogens of the genera Mycobacterium. Nevertheless, as shown in Table 5, studies over the past two decades reveal that various biosurfactants produced by members of the genera Corynebacterium, Nocardia, Rhodococcus, and Tsukamurella demonstrate a range of promising properties.
Strain (origin)
Biosurfactant
Biomedical properties
Reference
C. xerosis NS5 (human axilla)
Purified Coryxin (lipopeptide)
Antibacterial activity, biofilm inhibition and disruption of pre-formed biofilms of Gram-positive S. aureus and Streptococcus mutans and Gram-negative E. coli and P. aeruginosa strains
Anti-tumour activity: cytotoxic effects on human tumour cell lines BV-173 and SKW-3, and to a lesser extent, HL-60. Mediated cell death by the induction of partial apoptotic DNA laddering
N. vaccinii IMB B7405 (K-8) (oil-contaminated soil)
Complex of amino lipids; neutral lipids (mycolic and n-alkanic acids); trehalose di-acelates and di-mycolates (surfactant solution and supernatant)
Anti-adhesive activity against Gram-negative bacteria E. coli, Proteus vulgaris, P. aeruginosa and Enterobacter cloaceae and the yeast Candida albicans on silicon urogenital catheters. Anti-adhesive activity against fungus C. albicans and bacterium E. coli on treated acrylic dental material and against Gram-positive Bacillus subtilis and micromycete Aspergillis niger when coated on various abiotic substrates
In vitro induction of human promyelocytic leukaemia (HL60) cell line differentiation into monocytes and inhibition of protein kinase C
R. erythropolis IMВ Ac-5017 (EK-1) (oil-contaminated soil)
Complex of trehalose mono- and di-mycolates; neutral lipids (cetyl alcohol, palmitic acid, methyl ether of n-pentadecanoic acid, mycolic acids); phospholipids (phosphatidylglycerol, phosphatidylethanol-amine) (surfactant solution and supernatant)
Antibacterial activity against Gram-positive bacteria B. subtilis and S. aureus and Gram-negative E. coli and Pseudomonas sp., and anti-fungal activity against C. albicans, C. utilis and C. tropicalis
Anti-adhesive activity against Gram-negative bacteria and fungus C. albicans on silicon urogenital catheters. Anti-adhesive activity against B. subtilis on various abiotic substrates, against C. albicans and E. coli on acrylic dental material and S. aureus and P. aeruginosa on plastic and steel
R. fascians BD8 (Arctic soil polluted with hydrocarbons
THL
Antibacterial activity against Vibrio harveyi and P. vulgaris, and partial inhibition of other Gram-positive and negative bacteria and fungus C. albicans. Anti-adhesion properties on polystyrene against various Gram-positive and negative strains and fungal strains of C. albicans. Biofilm inhibition on glass, polystyrene, and silicone urethral catheters against Gram-positive Enterococcus hirae and E. faecalis, Gram-negative E. coli, and fungus C. albicans
R. ruber IEGM 231 (spring water, oil-extracting enterprise)
Crude trehalolipids
Anti-adhesive activity against exponentially growing Gram-positive bacteria Arthrobacter simplex, B. subtilis, Brevibacterium linens, Corynebacterium glutamicum, and Micrococcus luteus and against Gram-negative bacteria E. coli and P. fluorescens on polystyrene.
In vitro induction of Th1-polarizing factors IL-12 and IL-18 by human mononuclear cells and monocytes and reactive oxygen species (ROS) by peripheral blood leukocytes
In vivo suppression of bactericidal activity and proinflammatory cytokine IL-1β of mouse peritoneal macrophages, antibody production by splenocytes and stimulates the production of IL-10
Biomedical research on biosurfactants produced by MACA.
The amphipathic nature of biosurfactants makes them suitable for anti-adhesion and anti-biofilm applications such as the development of anti-adhesive coatings for intra-urinary devices that are prone to the formation of intractable biofilms, to prevent or delay the onset of biofilm growth by pathogens such as Escherichia coli and Proteus mirabilis. C. xerosis strain NS5, Nocardia vaccinii K-8 and various Rhodococcus strains demonstrate anti-adhesion, biofilm inhibition and/or biofilm disruption effects against various clinically significant pathogens (Table 5). Some also exhibit antimicrobial properties although in the case of R. ruber strain IEGM 231 the trehalolipids had no effect on cell viability despite preventing adhesion of various bacteria to polystyrene [63]. Oligosaccharides produced by Tsukamurella tyrosinosolvens (DSM 44370) showed some activity against Gram-positive bacteria, although the pathogenic strain Staphylococcus aureus was not affected. Rhodococcus strain I2R shows anti-viral activity against herpes simplex virus 1 (HSV-1) and human coronavirus HcoV-OC43 [62].
Nocardia farcinica BN26 produces a THL with anti-cancer effects, showing cytotoxicity against human tumour and promyelocytic leukaemia (HL60) cell lines [57]. Rhodococcus erythropolis SD-74 and Rhodococcus sp. TB-43 also cause the induction of HL60 cells [59, 60]. R. ruber has been studied in some detailed and reported to show immunomodulatory effects, including both in vitro induction of Th1-polarizing factors IL-12 and IL-18 by human mononuclear cells and monocytes and in vivo induction of IL-1β by mouse peritoneal macrophages [64, 65, 68, 69]. Two succinoyl trehalose lipids, STL-1 and STL-3, produced by R. erythropolis SD-74 inhibit growth and induce cell differentiation into monocytes instead of cell proliferation when tested on the HL60 cell line.
Glycolipid bearing mycolic acids, such as trehalose dimycolate (TDM) have attracted extensive investigation as they play a central role in pathogenesis during infection by intracellular pathogens such as M. tuberculosis and R. equi. TDM’s have been researched as a possible tuberculosis vaccine and as an adjuvant. In addition, modification of mycobacterial TDM has been shown to reduce virulence and suppress the host immune response [9]. Interestingly, TDM also possesses biological activities that point towards medical and pharmaceutical applications, such as antitumor activity and immunomodulating functions. Despite this, the potential for TDM is perhaps limited by relatively high toxicity and the pathogenic nature of the species that produce them.
Although biologics including surfactants are generally regarded as less toxic than synthesized pharmaceuticals not much work has focussed on this with respect to MACA surfactants. However, a THL from R. erythropolis strain 51T7 has been reported to be suitable for use in cosmetic preparations as it was less irritating than SDS when tested on mouse fibroblast and human keratinocyte lines [70]. Further investigation into the potential biomedical and pharmaceutical applications of biosurfactants produced by members of the MACA, including toxicity testing, is certainly warranted. The high costs and technical challenges associated with production and downstream extraction of biosurfactants may not be a barrier to their commercial application in biomedical fields given that smaller-scale productions would likely be required.
5.2 Environmental applications
Biosurfactants have a range of promising, and increasingly important, applications in the environmental, industrial, and agricultural sectors (Table 6). These include bioremediation of both organic pollutants (especially hydrocarbons) and metals, microbial enhanced oil recovery (MEOR), cleaning and maintenance of tanks and pipelines in the petroleum industry, wastewater treatment, and agricultural applications such as promotion of plant growth/health and inhibition of phytopathogenic fungi [1, 78]. MACA-derived surfactants have been investigated in some of these contexts, although the focus is on well-known species such as R. ruber and R. erythropolis. Members of Gordonia, Corynebacterium, Nocardia and Dietzia have also been investigated but there is likely to be much unexplored potential within the group [79]. This is supported by the promising results obtained with rhamnolipids produced by other bacteria, most notably P. aeruginosa, and their commercialisation [80]. It is not unreasonable to expect that rhamnolipids produced by MACA may also exhibit such properties. Indeed, the search for non-pathogenic producers is important for further development of biosurfactant production at industrial scale [81].
Application
Examples of MACAs
Reference/s
Bioremediation: enhanced hydrocarbon solubility and degradation
D. maris As-13-3 D. maris WR3 G. amicalis HS-11 Gordonia cholesterolivorans AMP 10 N. otitidiscaviarum R. erythropolis 3C-9 R. pyridinivorans NT2
Various potential environmental applications of biosurfactants produced by MACA.
Pollution of soils with organic and inorganic chemical compounds is a major environmental issue. Biosurfactants are used to improve the solubility of hydrocarbon organic compounds, either to make them available for subsequent biodegradation or to facilitate removal by soil washing. A remediation agent called JE1058BS containing biosurfactant from Gordonia sp. strain JE-1058 was evaluated as an oil spill dispersant using the baffled flask test recommended by the US Environmental Protection Agency and performed better than commercially available dispersants. It also enhanced the bioremediation of crude oil by indigenous marine bacteria and significantly improved removal of crude oil from contaminated sea sand by washing compared with the use of seawater alone [73]. Various Dietzia, Gordonia and Rhodococcus strains have been shown to degrade hydrocarbon compounds and many studies show that the production of surface-active compounds makes an important contribution. In a recent study, G. amicalis HS-11 was able to remove 92.85% of the diesel oil provided as the sole carbon source after 16 days of incubation, with a corresponding reduction in surface tension due to the production of extracellular surfactants. Microscopy suggested that these surfactants play a role in the emulsification and uptake of the hydrocarbons. Plant-based bioassays also showed that toxicity of the diesel oil decreased. This illustrates the potential of this strain and perhaps other gordoniae for use in the bioremediation of contaminated environments, or industrial wastewaters [82].
The properties and actions of biosurfactants make them particularly relevant to the petroleum industry. MEOR is perhaps the most well-known application in this area. Biosurfactants, or biosurfactant-producing microorganisms, are used to extract some of the oil remaining in reservoirs after primary and secondary processing has been carried out. Mechanisms include reduction of capillary forces holding the oil in porous rock, stabilisation of desorbed oil in water and increased viscosity of oil for easier removal [83]. Dietzia sp. ZQ-4, a hydrocarbon-degrading, surfactant-producing MACA isolated from an oil reservoir, demonstrated potential for use in ex situ oil recovery. Fermentation broth significantly increased oil displacement efficiency by 18.82% in rock cores and performed well within the range reported for other strains. However, injection of the strain itself was not so successful, and field trials testing nutrient injection did not always result in an increase in the population of Dietzia sp. ZQ-4, indicating that an in-situ approach may not be viable although it may be possible to optimise this strategy further [72]. Biosurfactants produced by various rhodococci strains recovered from oil-polluted soils have been shown to be effective at recovering trapped oil from oil-saturated sand packs. Glycolipids produced by strain ST-5 recovered up to 86% [84] and a mix of glycolipids and extracellular lipids produced by strain TA6 up to 86% [24] using the sand pack column method. Studies on biosurfactant produced by R. ruber IEGM 231 showed that 2.5 times greater washing activity could be achieved than with synthetic surfactant Tween-60 in soil columns spiked with polyaromatic carbons (PAHs) and alkanes. The biosurfactant maintained activity at a high (5% w/w) contamination level and consistently removed 0.3–0.5 g PAHs per kg dry soil in a single run of washing [71].
Biosurfactants may also be used to de-emulsify water–oil emulsions that form during oil production in the oilfields, as well as during transportation, and processing and offer a more ecologically friendly solution than chemically synthesized de-emulsifiers. A lipopeptide bio-demulsifier produced by Dietzia sp. strain S-JS-1 grown on waste frying oil achieved 88.3% of oil separation ratio in water/oil emulsion and 76.4% of water separation ratio in oil/water emulsion [75].
Biosurfactants have been shown to reduce phytotoxicity of heavy metals, and pre-treatment of seeds could allow plants to be grown successfully in contaminated soil, facilitating phytoremediation of the environment. Crude biosurfactant from R. ruber IEGM 231 mitigated the toxic effects of high concentrations of molybdenum on oat, white mustard, and vetch seeds. Germination increased up to 4.5 times and shoot and/or root length up to 2.5 times when seeds were pre-treated with a biosurfactant emulsion and grown under conditions of molybdenum contamination [85]. Similar results have been recorded for other heavy metals such as copper [86].
The use of biosurfactants in environmental and industrial applications is limited by the current high costs of production, and the large amounts of biosurfactant required. However, using waste and/or renewable substrates would be cheaper, and a highly purified product is not essential so costs of downstream processing can also be reduced. In addition, different approaches such as selective stimulation of biosurfactant producers in situ, and inoculation of biosurfactant-producing cultures, are being explored [87]. This could potentially overcome some of the challenges associated with accessing the cell-bound biosurfactants produced by MACA such as Rhodococcus spp.
5.3 Challenges to commercialisation
Currently, commercial production of biosurfactants is not economically competitive with chemical surfactant production as there are various challenges to overcome. Bioprocesses presently achieve low biosurfactant productivity and yield and substrates are expensive [6]. Foam formation can cause serious operational issues and downstream biosurfactant recovery can be technically involved and costly. Development work to optimise bioprocesses should focus on enhancing biosurfactant yield and potency. Approaches include the search and discovery of novel biosurfactant-producing organisms and strain improvement by various genetic engineering methods and/or stress-fermentation including co-cultivation [84]. Yield can also be enhanced through the optimisation of culture conditions and costs reduced through the introduction of renewable or waste products [6, 28, 77] as cheaper feed stocks. The effects of biosurfactants on human health and the environment also require further assessment to ensure safe production and use.
6. Conclusions
Biosurfactants offer an attractive proposition for biotechnological application across various sectors and are considered superior to synthetic surfactants. Diverse MACA produce biosurfactants with interesting properties that have been explored in the context of biomedicine and environmental remediation. However, many MACA have not yet been investigated for biosurfactant production and various potential applications are yet to receive significant research. Rapid, reliable methods for high throughput screening for biosurfactant production are essential as are robust standard methods for biosurfactant purification and characterisation. Efforts to evaluate and expand the knowledge of structural characteristics and gene regulation of biosurfactants are warranted to improve their effectiveness and productivity. Commercial-scale production will need to employ various existing and new strategies to become economic and sustainable. Cutting-edge technologies such high-throughput omics-based tools should accelerate the development of commercial production of biosurfactants. Furthering our understanding of biosurfactants produced by MACA will facilitate their commercial exploitation thereby contributing to a sustainable bio-based economy.
Conflict of interest
The authors declare that there is no conflict of interest.
\n',keywords:"actinobacteria, antimicrobial, bioemulsifiers, bioremediation, biosurfactants, biotechnology, Corynebacteriales, mycolic acids, Rhodococcus",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/81978.pdf",chapterXML:"https://mts.intechopen.com/source/xml/81978.xml",downloadPdfUrl:"/chapter/pdf-download/81978",previewPdfUrl:"/chapter/pdf-preview/81978",totalDownloads:6,totalViews:0,totalCrossrefCites:0,dateSubmitted:"October 19th 2021",dateReviewed:"March 21st 2022",datePrePublished:"May 27th 2022",datePublished:null,dateFinished:"May 27th 2022",readingETA:"0",abstract:"The Actinobacteria produce an array of valuable metabolites including biosurfactants which are gaining increased attention in the biotechnology industries as they are multifunctional, biorenewable and generally superior to chemically synthesized compounds. Biosurfactants are surface-active, amphipathic molecules present at the microbial cell-surface or released extracellularly and in a variety of chemical forms. The mycolic acid-containing actinobacteria (MACA), classified in the order Corynebacteriales, represent a potentially rich source of biosurfactants for novel applications and undiscovered biosurfactant compounds. Members of the mycolate genus Rhodococcus produce various well-characterised glycolipids. However, other mycolate genera including Corynebacterium, Dietzia, Gordonia and Tsukamurella although less extensively investigated also possess biosurfactant-producing strains. This chapter captures current knowledge on biosurfactant production amongst the MACA, including their chemical structures and producer organisms. It also provides an overview of approaches to the recovery of biosurfactant producing MACA from the environment and assays available to screen for biosurfactant production. Methodologies applied in the extraction, purification, and structural elucidation of the different types of biosurfactants are also summarised. Potential future applications of MACA-derived biosurfactants are highlighted with particular focus on biomedical and environmental possibilities. Further investigation of biosurfactant production by MACA will enable the discovery of both novel producing strains and compounds with the prospect of biotechnological exploitation.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/81978",risUrl:"/chapter/ris/81978",signatures:"Fiona M. Stainsby, Janki Hodar and Halina Vaughan",book:{id:"10893",type:"book",title:"Actinobacteria",subtitle:null,fullTitle:"Actinobacteria",slug:null,publishedDate:null,bookSignature:"Prof. Wael N. Nabil Hozzein",coverURL:"https://cdn.intechopen.com/books/images_new/10893.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-097-8",printIsbn:"978-1-80355-096-1",pdfIsbn:"978-1-80355-098-5",isAvailableForWebshopOrdering:!0,editors:[{id:"189233",title:"Prof.",name:"Wael N.",middleName:"Nabil",surname:"Hozzein",slug:"wael-n.-hozzein",fullName:"Wael N. Hozzein"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1 Biosurfactant properties",level:"2"},{id:"sec_2_2",title:"1.2 Mycolic acid-containing actinobacteria",level:"2"},{id:"sec_4",title:"2. Biosurfactants produced by MACA",level:"1"},{id:"sec_5",title:"3. Habitats, recovery, and growth requirements of MACA",level:"1"},{id:"sec_6",title:"4. Detection and characterisation of biosurfactants",level:"1"},{id:"sec_6_2",title:"4.1 Biosurfactant screening methods",level:"2"},{id:"sec_7_2",title:"4.2 Extraction and structural analysis of biosurfactants",level:"2"},{id:"sec_9",title:"5. Potential applications of biosurfactants from MACA",level:"1"},{id:"sec_9_2",title:"5.1 Biomedical applications",level:"2"},{id:"sec_10_2",title:"5.2 Environmental applications",level:"2"},{id:"sec_11_2",title:"5.3 Challenges to commercialisation",level:"2"},{id:"sec_13",title:"6. Conclusions",level:"1"},{id:"sec_17",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Mnif I, Ghribi D. Lipopeptides biosurfactants: Mean classes and new insights for industrial, biomedical, and environmental applications. Biopolymers. 2015;104:129-147. DOI: 0.1002/bip.22630'},{id:"B2",body:'Goodfellow M, Jones AL. Corynebacteriales ord. nov. In: Whitman WB, editor. Bergey’s Manual of Systematics of Archaea and Bacteria. New Jersey: Wiley; 2015. p. 14. DOI: 10.1002/9781118960608.obm00009'},{id:"B3",body:'Bognolo G. Biosurfactants as emulsifying agents for hydrocarbons. Colloids and Surfaces A: Physicochemical and Engineering Aspects. 1999;152(1-2):41-52. 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Department of Life Sciences, School of Applied Sciences, Edinburgh Napier University, Edinburgh, UK
Department of Life Sciences, School of Applied Sciences, Edinburgh Napier University, Edinburgh, UK
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IntechOpen’s Academic Editors and Authors have received funding for their work through many well-known funders, including: the European Commission, Bill and Melinda Gates Foundation, Wellcome Trust, Chinese Academy of Sciences, Natural Science Foundation of China (NSFC), CGIAR Consortium of International Agricultural Research Centers, National Institute of Health (NIH), National Science Foundation (NSF), National Aeronautics and Space Administration (NASA), National Institute of Standards and Technology (NIST), German Research Foundation (DFG), Research Councils United Kingdom (RCUK), Oswaldo Cruz Foundation, Austrian Science Fund (FWF), Foundation for Science and Technology (FCT), Australian Research Council (ARC).
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Please be aware that you must be a member, or grantee, of the institutions/funders listed in order to apply for their Open Access publication funds.
Open Access publication costs can often be designated directly in the grants or in specific budgets allocated for that purpose. Many of the most important funding organisations encourage, and even request, that the projects they fund are made available at no cost to the wider public. IntechOpen strives to maintain excellent relationships with these funders and ensures compliance with mandates.
\n\n
In order to help Authors identify appropriate funding agencies and institutions, we have created a list, based on extensive research on various OA resources (including ROARMAP and SHERPA/JULIET) of organizations that have funds available. Before consulting our list we encourage you to petition your own institution or organization for Open Access funds or check the specifications of your grant with your funder to ascertain if publication costs are included. Where you are in receipt of a grant you should clarify:
\n\n
\n\t
Does your institution already have a budget for covering Open Access publication costs?
\n\t
Does your grant list Open Access publication fees as legitimate direct/indirect costs?
\n
\n\n
If you are associated with any of the institutions in our list below, you can apply to receive OA publication funds by following the instructions provided in the links. Please consult the Open Access policies or grant Terms and Conditions of any institution with which you are linked to explore ways to cover your publication costs (also accessible by clicking on the link in their title).
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Please note that this list is not a definitive one and is updated regularly. To suggest possible modifications or the inclusion of your institution/funder, please contact us at funders@intechopen.com
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We tried to elaborate general guidelines on how to diagnose and some anticipations for emergency treatments tailored by the type of congenital heart disease in neonates. Stabilization consists of medical treatment including emergent prostaglandin institution in some types of duct dependent lesion. The role of interventional catheterization such as patent ductus arteriosus (PDA) stent, balloon pulmonary valvotomy, etc. as modalities for stabilization before surgery was also elaborated. Some general and specific guidelines based on the type of surgeries for postoperative management were also discussed.",book:{id:"5473",slug:"pediatric-and-neonatal-surgery",title:"Pediatric and Neonatal Surgery",fullTitle:"Pediatric and Neonatal Surgery"},signatures:"Eva Miranda Marwali, Beatrice Heineking and Nikolaus A. 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It is more common during the neonatal period than at any other age with the estimated incidence of 0.25 per 1000 live births. The absence of specific clinical presentation makes diagnosis of meningitis more difficult in neonates than in older children. Culture of cerebrospinal fluid is the traditional gold standard for diagnosis of bacterial meningitis, so all newborn infants with proven or suspected sepsis should undergo lumbar puncture. However, deciding when to perform lumbar puncture and interpretation of the results are challenging. Although the pathophysiology of neonatal meningitis is complex and not fully understood, researches on diagnostic and prognostic tools are ongoing. Prevention of neonatal sepsis, early recognition of infants at risk, development of novel, rapid diagnostics and adjunctive therapies, and appropriate and aggressive antimicrobial treatment to sterilize cerebrospinal fluid as soon as possible may prevent the lifelong squeal of bacterial meningitis in newborn infants.",book:{id:"7527",slug:"neonatal-medicine",title:"Neonatal Medicine",fullTitle:"Neonatal Medicine"},signatures:"Mehmet Şah İpek",authors:[{id:"267903",title:"Associate Prof.",name:"Mehmet Şah",middleName:null,surname:"İpek",slug:"mehmet-sah-ipek",fullName:"Mehmet Şah İpek"}]},{id:"71427",title:"Factors Influencing Maternal Decision-Making on Infant Feeding Practices",slug:"factors-influencing-maternal-decision-making-on-infant-feeding-practices",totalDownloads:984,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The decision to formula feed or breastfeed a child typically begins with an established prenatal intention. This chapter will examine the multiple dimensions influencing maternal decision-making in regards to the feeding practices of infants including 1) individual maternal characteristics, 2) organizational factors, 3) hospital/provider recommendations, and 4) systematic/policy factors. The chapter will also examine the impact of infant feeding practices on early infant and childhood health outcomes. Research has demonstrated the benefits of breastfeeding on infants and early childhood which includes but is not limited to protection against common illnesses and infections, improved IQ , and even increased school attendance. Moreover, the World Health Assembly global nutrition objectives focus on encouraging breastfeeding support across all sectors in addition to implementing tailored community-based approaches, limiting the excessive marketing of infant formula, and enforcing supportive breastfeeding legislation. The aim of this chapter is to provide an overview of the dynamic interplay between individual, interpersonal, community, and societal factors, such as policies that impact breastfeeding rates and more specifically the health of infants.",book:{id:"9805",slug:"infant-feeding-breast-versus-formula",title:"Infant Feeding",fullTitle:"Infant Feeding - Breast versus Formula"},signatures:"Whitney N. Hamilton",authors:[{id:"313554",title:"Dr.",name:"Whitney",middleName:null,surname:"Hamilton",slug:"whitney-hamilton",fullName:"Whitney Hamilton"}]},{id:"73181",title:"Introductory Chapter: Impact of First 1000 Days Nutrition on Child Development and General Health",slug:"introductory-chapter-impact-of-first-1000-days-nutrition-on-child-development-and-general-health",totalDownloads:781,totalCrossrefCites:0,totalDimensionsCites:0,abstract:null,book:{id:"9805",slug:"infant-feeding-breast-versus-formula",title:"Infant Feeding",fullTitle:"Infant Feeding - Breast versus Formula"},signatures:"Isam Jaber AL-Zwaini, Zaid Rasheed AL-Ani and Walter Hurley",authors:[{id:"30993",title:"Prof.",name:"Isam Jaber",middleName:null,surname:"Al-Zwaini",slug:"isam-jaber-al-zwaini",fullName:"Isam Jaber Al-Zwaini"},{id:"136109",title:"Dr.",name:"Walter",middleName:null,surname:"Hurley",slug:"walter-hurley",fullName:"Walter Hurley"},{id:"317690",title:"Dr.",name:"Zaid Rasheed",middleName:null,surname:"Al-Ani",slug:"zaid-rasheed-al-ani",fullName:"Zaid Rasheed Al-Ani"}]}],onlineFirstChaptersFilter:{topicId:"1108",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:106,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:3,numberOfUpcomingTopics:0,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:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}}]},series:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 29th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:32,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. She is an author of about 90 publications (According to Scopus: H-Index: 23; According to WOS: H-Index: 20) on peer-reviewed journals, a member of the “Società Italiana di Biochimica e Biologia Molecolare,“ and a Consultant Reviewer for International Journal of Molecular Science, Journal of Chromatography A, COPD, Plos ONE and Nutritional Neuroscience.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null}]},overviewPageOFChapters:{paginationCount:36,paginationItems:[{id:"82195",title:"Endoplasmic Reticulum: A Hub in Lipid Homeostasis",doi:"10.5772/intechopen.105450",signatures:"Raúl Ventura and María Isabel Hernández-Alvarez",slug:"endoplasmic-reticulum-a-hub-in-lipid-homeostasis",totalDownloads:2,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"82409",title:"Purinergic Signaling in Covid-19 Disease",doi:"10.5772/intechopen.105008",signatures:"Hailian Shen",slug:"purinergic-signaling-in-covid-19-disease",totalDownloads:3,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82374",title:"The Potential of the Purinergic System as a Therapeutic Target of Natural Compounds in Cutaneous Melanoma",doi:"10.5772/intechopen.105457",signatures:"Gilnei Bruno da Silva, Daiane Manica, Marcelo Moreno and Margarete Dulce Bagatini",slug:"the-potential-of-the-purinergic-system-as-a-therapeutic-target-of-natural-compounds-in-cutaneous-mel",totalDownloads:9,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Purinergic System",coverURL:"https://cdn.intechopen.com/books/images_new/10801.jpg",subseries:{id:"17",title:"Metabolism"}}},{id:"82103",title:"The Role of Endoplasmic Reticulum Stress and Its Regulation in the Progression of Neurological and Infectious Diseases",doi:"10.5772/intechopen.105543",signatures:"Mary Dover, Michael Kishek, Miranda Eddins, Naneeta Desar, Ketema Paul and Milan Fiala",slug:"the-role-of-endoplasmic-reticulum-stress-and-its-regulation-in-the-progression-of-neurological-and-i",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}}]},overviewPagePublishedBooks:{paginationCount:32,paginationItems:[{type:"book",id:"7006",title:"Biochemistry and Health Benefits of Fatty Acids",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7006.jpg",slug:"biochemistry-and-health-benefits-of-fatty-acids",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Viduranga Waisundara",hash:"c93a00abd68b5eba67e5e719f67fd20b",volumeInSeries:1,fullTitle:"Biochemistry and Health Benefits of Fatty Acids",editors:[{id:"194281",title:"Dr.",name:"Viduranga Y.",middleName:null,surname:"Waisundara",slug:"viduranga-y.-waisundara",fullName:"Viduranga Y. Waisundara",profilePictureURL:"https://mts.intechopen.com/storage/users/194281/images/system/194281.jpg",biography:"Dr. Viduranga Waisundara obtained her Ph.D. in Food Science\nand Technology from the Department of Chemistry, National\nUniversity of Singapore, in 2010. She was a lecturer at Temasek Polytechnic, Singapore from July 2009 to March 2013.\nShe relocated to her motherland of Sri Lanka and spearheaded the Functional Food Product Development Project at the\nNational Institute of Fundamental Studies from April 2013 to\nOctober 2016. She was a senior lecturer on a temporary basis at the Department of\nFood Technology, Faculty of Technology, Rajarata University of Sri Lanka. She is\ncurrently Deputy Principal of the Australian College of Business and Technology –\nKandy Campus, Sri Lanka. She is also the Global Harmonization Initiative (GHI)",institutionString:"Australian College of Business & Technology",institution:null}]},{type:"book",id:"6820",title:"Keratin",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/6820.jpg",slug:"keratin",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Miroslav Blumenberg",hash:"6def75cd4b6b5324a02b6dc0359896d0",volumeInSeries:2,fullTitle:"Keratin",editors:[{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",slug:"miroslav-blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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She is also a UNESCO-trained International Bioethics Facilitator.",institutionString:"University of the Witwatersrand",institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419588",title:"Ph.D.",name:"Sergio",middleName:"Alexandre",surname:"Gehrke",slug:"sergio-gehrke",fullName:"Sergio Gehrke",position:null,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",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:"1",type:"subseries",title:"Oral Health",keywords:"Oral health, Dental care, Diagnosis, Diagnostic imaging, Early diagnosis, Oral cancer, Conservative treatment, Epidemiology, Comprehensive dental care, Complementary therapies, Holistic health",scope:"
\r\n This topic aims to provide a comprehensive overview of the latest trends in Oral Health based on recent scientific evidence. Subjects will include an overview of oral diseases and infections, systemic diseases affecting the oral cavity, prevention, diagnosis, treatment, epidemiology, as well as current clinical recommendations for the management of oral, dental, and periodontal diseases.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/1.jpg",hasOnlineFirst:!0,hasPublishedBooks:!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,series:{id:"3",title:"Dentistry",doi:"10.5772/intechopen.71199",issn:"2631-6218"},editorialBoard:[{id:"267724",title:"Dr.",name:"Febronia",middleName:null,surname:"Kahabuka",slug:"febronia-kahabuka",fullName:"Febronia Kahabuka",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZpJQAW/Profile_Picture_2022-06-27T12:00:42.JPG",institutionString:null,institution:null}]},onlineFirstChapters:{paginationCount:7,paginationItems:[{id:"82405",title:"Does Board Structure Matter in CSR Spending of Commercial Banks? 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