\r\n\tThus, we call for research and review papers on the chemistry and physics of dyes, pigments, and their intermediates, including chemical constituents, spectroscopic aspects, surface, solution, crystal formation, photochemical, and ecological or biological properties. The book will be of interest to a wide variety of researchers worldwide whose work involves various fields of activity such as dyes and pigment synthesis, imaging, sensor, energy, medicine, polymers, food product, toxicological properties, etc.
",isbn:"978-1-83768-114-3",printIsbn:"978-1-83768-113-6",pdfIsbn:"978-1-83768-115-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"fcd069956c2e931195925b19a74ce9a3",bookSignature:"Dr. Brajesh Kumar",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/12081.jpg",keywords:"Heterocycles Pigments, Azo, Nitro, Indigo, Alizarin, Chromophores, Chromophores, Photochemical, Sulphonation, Diazotisation, UV-Vis Spectroscopy, Metal-Ligand",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 19th 2022",dateEndSecondStepPublish:"June 16th 2022",dateEndThirdStepPublish:"August 15th 2022",dateEndFourthStepPublish:"November 3rd 2022",dateEndFifthStepPublish:"January 2nd 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"14 days",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Brajesh Kumar has worked as a faculty member in various universities in India, Ecuador, and South Korea. He has published numerous SCI/SCIE/Scopus research articles and is an active reviewer of more than 50 Journals. Dr. Kumar is a member of the American Chemical Society, the Indian Society of Chemists and Biologists, and the Indian Science Congress Association and holder of two registered patents. He is included in the top 2% of the scientist list prepared by experts at Stanford University,",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"176093",title:"Dr.",name:"Brajesh",middleName:null,surname:"Kumar",slug:"brajesh-kumar",fullName:"Brajesh Kumar",profilePictureURL:"https://mts.intechopen.com/storage/users/176093/images/system/176093.JPG",biography:"Dr. Brajesh Kumar is currently working as an Assistant Professor and Head in the Post Graduate Department of Chemistry, TATA College, Chaibasa, India. He received a Ph.D. in Chemistry from the University of Delhi, India. His research interest is in the development of sustainable and eco-friendly techniques for (a) nanoparticles synthesis and their applications for environmental remediation, (b) active films of organic solar cells, (c) nanomedicine, (d) sensors, (e) natural product extraction, purification, and analysis,(f) natural polymers, (g) peptide chemistry, (h) microwave and ultrasound-assisted organic synthesis and (i) organic synthesis. Dr. Brajesh Kumar has been credited for different national and international fellowships and he has also worked as a faculty member in various universities of India, Ecuador, and South Korea. He has also published numerous SCI/ SCIE/ Scopus research articles (h index = 28, Citations 2690) and is also an active reviewer of more than 50 Journals. He is also included in the top 2% of the scientist list prepared by experts at Stanford University, USA.",institutionString:"TATA College, Kolhan University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"2",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"8",title:"Chemistry",slug:"chemistry"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"444318",firstName:"Nika",lastName:"Karamatic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/444318/images/20011_n.jpg",email:"nika@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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1. Introduction
Cystic Fibrosis (CF) is the most commonly inherited potentially lethal disease amongst the Caucasian ancestry. The prevalence of CF is reported as 0.737 per 10,000 in 27 European Union countries [1]. The United States (US) Cystic Fibrosis Patient Registry reports a similar prevalence of 0.797 CF patients per 10,000 people [2]. It is an autosomal recessive disease and is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) [3]. The most common mutation is caused by deletion of phenylalanine at position 508 (Delta F508) of the CFTR on chromosome 7, which accounts for approximately 70% of CF cases. The primary function of CFTR in many tissues is to regulate and participate in the transport of chloride ions across epithelial cell membranes. To date, more than 1,900 mutations have been described in this gene.
CF is a multisystem disease as CFTR is expressed in different organs [4]; however, the lungs are the predominant organs that bear the brunt of the disease [5]. Recurrent pulmonary infections may start at very early stages in the lives of patients with CF. It has been hypothesised that low airway surface liquid volume and impaired mucociliary clearance are responsible for the pathogenesis of lung infections. These in turn lead to impaired bacterial clearance from respiratory epithelial cells [6]. Pulmonary infections remain the greatest cause of poor life quality, morbidity and mortality in CF that eventually lead to premature death in this condition [7].
Apart from chronic lung disease with recurrent exacerbations, exocrine pancreatic insufficiency is also a feature that leads to malabsorption and subsequently growth retardation and maturation. Endocrine pancreatic insufficiency is another feature of CF with the manifestation of diabetes. Obstructive azoospermia in male CF patients leads to male infertility.
The median survival from CF has taken great strides over the past 40 years as a consequence of the introduction of specialist centre care, nutritional optimisation, prevention and aggressive management of pulmonary exacerbations [8]. In the United Kingdom (UK) CF population in 2012, the median survival was reported as 43.5 years, compared to 38.8 years for the population in 2008 as per the UK CF Registry [9]. It has been postulated that the continuing improvement in survival of CF patients in successive cohorts means that the previous prediction of patients with CF living beyond a median age of 50 years is not impossible. The recent introduction of Ivacaftor to the management of CF patients with G551D CFTR mutations may further enhance the overall survival [10].
Historically, bacteria have been the predominant cause for respiratory exacerbations. The presences of some organisms including Staphylococcus aureus, Pseudomonas aeruginosa and Burkhoderia cepacia in the airways have been shown to lead to clinical deterioration [11-13] and may subsequently lead to morbidity and mortality. Pulmonary exacerbations are associated with acquisition of new organisms and increased concentration of airway flora [14]. The new acquisitions of P. aeruginosa in CF have been demonstrated to occur in the winter months coinciding with the peak of respiratory viral infections [15, 16]. In the event of a pulmonary exacerbation the absence of pyrexia, raised inflammatory markers and systemic response, pathogens other than bacteria can be the potential cause. Respiratory viruses have been implicated by a number of studies in the last 30 years as potentiators for CF exacerbations [17-29]. Influenza is a substantial health threat; it is associated with approximately 36,000 deaths and 220,000 hospitalisations in the USA on an annual basis [30]. The recent emergence of novel influenza virus (H1N1) further heightened the awareness of influenza-like illness. CF Pulmonary exacerbation rates have also been shown to be significantly increased during the winter months and are highly associated with the influenza season [31]. Respiratory viruses that are associated with the exacerbations of CF include influenza A and B, respiratory syncytial virus (RSV), parainfluenza virus (PIV) types 1 to 4, rhinovirus, metapneumovirus, coronavirus and adenovirus.
In the last 30 years, there have been a number of published studies depicting the impact of respiratory viruses in CF. A number of studies have also demonstrated the relationship between respiratory viruses and bacteria in the pathogenesis of CF exacerbations [15, 32]. The introduction of molecular diagnostic technologies has further enhanced the awareness of respiratory viral aetiology in CF exacerbations as they have much higher detection rates than traditional methods. However, further understanding is required to appreciate their relationship in order to allow the development of potential novel treatment. If indeed respiratory virus does lead to secondary bacterial infection in CF, viral vaccinations and anti-viral therapies would be important therapeutic options for CF. On the other hand, the currently commercially available vaccines and anti-virals for the prevention and treatment of respiratory viral infections are limited; they are primarily for influenza infection. The potential development of new vaccines and anti-virals is an exciting field which may offer alternate therapeutic opportunities for CF exacerbations.
This chapter will focus on the literature regarding respiratory viruses in CF and their clinical implications, the detection techniques for viruses and their differences in sensitivities, the interaction between viruses and bacteria, and the management of viral infections.
2. Viral respiratory infections in CF
Early studies looking at respiratory viruses in CF relied on repeated serological testing, either alone [20] or in combination with viral cultures for viral detection [21-25]. These methods are relatively insensitive and more recent studies have utilised molecular-based methodologies [18, 26-28, 33-36]. All these studies produced different results in terms of prevalence of respiratory viruses in CF. The differences can be due to different methodologies, different sampling methods; the differences can also be accountable by different populations studied as the prognosis for CF has improved with each successive birth cohort.
Wang et al. [25] described the relationship between respiratory viral infections and deterioration in clinical status in CF almost 30 years ago. In this 2- year prospective study [25], viruses were identified through serology and nasal lavage in 49 patients with CF (mean age 13.7 years) on a quarterly basis and at the onset of exacerbations. Although the CF patients had more respiratory illnesses than sibling controls (3.7 versus 1.7/year), there were no differences in virus identification rates (1.7/year). The rate of proven virus infection was significantly correlated with the decline in lung functions, nutritional status, radiology score, and frequency and duration of hospitalisation.
More recent studies suggest no difference in the frequency of either upper respiratory tract illness (URTI) episodes [22] or proven respiratory viral infections [24] between children with CF and healthy controls, but children with CF have significantly more episodes of lower airway symptoms than controls [22, 24]. Ramsey et al. [24] prospectively compared the incidence and effect of viral infections on pulmonary function and clinical scores in 15 school-age patients with CF aged between 5 and 21 years and their healthy siblings. Over a 2-year period, samples were taken at regular two monthly intervals and during acute respiratory illnesses (ARI) for pharyngeal culture and serology for respiratory viruses. There was a total of 68 ARI episodes that occurred in the patients with CF and in 19 episodes there was an associated virus identified. A total of 49 infective agents were identified either during ARIs or at routine testing in the patients with CF; 14 were identified on viral isolation (rhinovirus on 11 occasions), whilst 35 were isolated on seroconversion (PIV on 12, RSV on 9 and M.\n\t\t\t\tpneumoniae on 6 occasions). At the time of an ARI, the virus isolation and seroconversion rates were 8.8% and 19.1%, respectively, in children with CF compared to 15.0% and 15.0%, respectively, for the healthy siblings. In contrast, the rates of virus isolation and seroconversion at routine 2 monthly visits were 5.6% and 16.2%, respectively, for children with CF and 7.7% and 20.2%, respectively, for the healthy siblings. There was no significant difference in the rate of viral infections between the patients with CF and their sibling controls, as measured either by culture or serology. The rate of viral infections was higher in younger children (both CF and controls); however, the rate of decline in pulmonary function and severity score was both lower in the younger children with CF and the ones with more viral infections. The authors concluded that there were no significant adverse effects with viral infections in CF.
Likewise, Hiatt [22] assessed respiratory viral infections over three winters in 22 infants less than 2 years of age with CF (30 patient seasons), and 27 age-matched controls (28 patient seasons). The average number of acute respiratory illness per winter was the same in the control and CF groups (5.0 vs. 5.0). However, only 4 of the 28 control infants had lower respiratory tract symptoms in association with the respiratory tract illness, compared with 13 out of the 30 infants with CF (Odd ratio – 4.6; 95% confidence interval 1.3 and 16.5; p-value <0.05); 7 of the infants with CF cultured RSV, of whom 3 required hospitalisation. In contrast, none of the controls required hospitalisation. Pulmonary function measured by rapid chest compression technique was significantly reduced in the infants with CF after the winter months and was associated with two interactions; RSV infection with lower respiratory tract infection and male sex with lower respiratory tract infection.
From previous reports, two viral agents appear to have the greatest effect on respiratory status in CF, namely RSV and influenza, possibly because the uses of viral culture and serology have underestimated the effects of rhinovirus. In younger children, RSV is a major pathogen resulting in an increased rate of hospitalisation. Abman et al. [37] prospectively followed up 48 children with CF diagnosed through newborn screening and documented the effect of RSV infection. Eighteen of the infants were admitted into hospital a total of 30 times over a mean follow-up of 28 months (range 5-59]. In 7 of these infants RSV was isolated, and their clinical course was severe with 3 requiring mechanical ventilation and 5 necessitating chronic oxygen therapy. Over the next 2 years, these infants had significantly more frequent respiratory symptoms and lower Brasfield chest radiograph [38] scores than non-RSV-infected counterparts.
In older children and adults with CF, influenza seems to have the greatest effect. Pribble et al. [23] assessed acute pulmonary exacerbation isolates from 54 patients with CF. Over the year of the study, 80 exacerbations were identified, of which 21 episodes were associated with an identified viral agent (influenza A – 5 episodes; influenza B – 4 episodes; RSV – 3 episodes) with most agents identified on serology. Compared to other respiratory viruses, infection with influenza was associated with a more significant drop in pulmonary function (FEV1 declined by 26% compared with 6%). There were also a higher proportion of patients with a greater than 20% drop in FEV1 within the influenza infected cohort. A retrospective study in older patients with chronic P. aeruginosa infection reported an acute deterioration in clinical status in association with influenza A virus infection, which was confirmed by serology [39].
Over a 1-year period, Smyth et al. [27] prospectively investigated 108 patients with CF (mean age of 7.9 years) using a combination of viral immunofluorescence, culture and seroconversion to identify respiratory viruses. With the exception of rhinovirus, a semi-nested reverse transcriptase PCR technique was used. During the study, 76 subjects had 157 respiratory exacerbations (1.5 episodes/patient/year) and a viral agent was identified in 44 episodes, 25 of which were rhinovirus and an equal distribution of other viruses was identified almost always on seroconversion. Rhinovirus identification was associated with significantly more days of intravenous antibiotics, whereas, those children in whom a non-rhinovirus was identified had a significantly greater decrease in FEV1 over the year of the study. When all viruses were considered as a whole, patients had significantly greater decline in Shwachman score [40] and days of intravenous antibiotics use.
Collinson et al. [26] followed 48 children with CF over a 15-month period using viral cultures for viral detection, with the exception of picornaviruses where polymerase chain reaction (PCR) was used; 38 children completed the study and there were 147 symptomatic upper respiratory tract infections (URTIs), 2.7 episodes/child/year, with samples available for 119 episodes. Picornaviruses were identified in 51 (43%) of these episodes, of which 21 (18%) were rhinoviruses. In those children old enough to perform spirometry, there was significant reduction in both FVC and FEV1 in association with URTIs, with little difference in severity of reduction whether a picornavirus was identified or not. Maximal mean drop in FEV1 was 16.5%, at 1-4 days after onset of symptoms, but a deficit of 10.3% persisted at 21-24 days. Those with more URTIs appeared to have greater change in total Shwachman score [40] and Chrispin-Norman score [41] over the study. Six children isolated a P.aeruginosa for the first time during the study, 5 at the time of a URTI and only 1 was asymptomatic at the time of first isolation. However, the data from this study have to be handled with care as the term ‘URTI’ does not necessarily imply a positive viral isolation.
Punch et al. [42] used a multiplex reverse transcriptase PCR (RT-PCR) assay combined with an enzyme-linked amplicon hybridization assay (ELAHA) for the identification of seven common respiratory viruses in the sputum of 38 CF patients; 53 sputum samples were collected over 2 seasons and 12 (23%) samples from 12 patients were positive for a respiratory virus (4 for influenza B, 3 for parainfluenza type 1, 3 for influenza A and 2 for RSV). There were no statistical associations between virus status and demographics, clinical variables or isolation rates for P. aeruginosa, S. aureus or A. fumigatus.
Olesen and colleagues [28] obtained sputum and laryngeal aspirates from children with CF over a 12-month period in outpatient clinics. They achieved a viral detection rate of 16%, with rhinovirus being the most prevalent virus. FEV1 was significantly reduced during viral infection (-12.5%, p=0.048), with the exception of rhinovirus infection. The authors were not able to demonstrate a positive correlation between respiratory viruses and bacterial infections in their studied population as the type or frequency of bacterial infection during or after viral infections were not altered. They also concluded that clinical viral symptoms had a very poor predictive value (0.39) for a positive viral test.
Our group in 2004 [36] utilised ‘real-time’ multiplex Nucleic Acid Sequenced Based Amplification to examine the role of respiratory viruses in CF children. Over an 18-month period, a viral detection rate of 46% was achieved during reported episodes of respiratory illness. The results compared favourably with previous studies and it may be that earlier studies relied heavily on repeated serological testing, either alone [20] or in combination with viral isolation [21-25]. The viral detection rate was 18.3% from routine nasal samples. However, this was comparable to the seroconversion rate of 12.3% as reported by Wang et al. [25]. Ramsey and colleagues [24] also achieved a similar seroconversion rate of 16.2% from asymptomatic samples. These results suggest that a laboratory method with a higher sensitivity for viral detection does not increase the detection rate in asymptomatic samples, implying that false positives are not necessarily more common than less sensitive diagnostic methods. Influenza A and B viruses were the major viruses in causing respiratory exacerbations in CF and both viruses are more commonly detected during pulmonary exacerbations; 22 of 88 [23%) viruses found in this study were influenza viruses (A & B). The result is consistent with majority of the previous studies which showed that influenza virus represented between 12% and 27% of all viruses detected. However, the findings are in contrast with other studies where rhinovirus is the major virus in CF exacerbations [26, 28, 43]. The influenza vaccine uptake rate during the study period was up to 70% [36]. It is possible that the detection rate for influenza virus could have been higher had the vaccine coverage not been this high.
Asner et al. [44] performed an observational cross-sectional study of CF children from a large paediatric referral centre investigating the association between respiratory viruses and pulmonary exacerbations by taking mid-turbinate swabs, sputum and throat swab samples that were tested by a direct immunofluorescent antibody assay and a multiplex PCR panel. Forty-three patients were recruited into the study. Pulmonary function tests, quality of life and severity scores were recorded. Sputum cell counts, bacterial density and cytokines were measured. Twenty-six (60.5%) subjects were tested positive for at least one respiratory virus by any diagnostic method applied to any sample type. Of the 26 virus positive subjects, 17 (65.4%) were positive for one virus and the remaining 9 (34.6%) were positive for two or more viruses. Coxsackie/echovirus was the most commonly identified pathogen (29.4%) amongst the 17 subjects that were positive for one virus. Virus-positive patients were younger (p=0.047) and more likely to be male (p=0.029). They were also more likely to present with fever (p=0.019), have higher CF clinical severity (p=0.041) and lower quality of life scores (p=0.022). However, virus-positive and negative patients had similar IL-8, neutrophil percentage, elastase levels and 26 additional cytokines levels between both groups. The authors reported a higher rate of viral detection with mid-turbinate swabs than with sputum samples. The study was primarily conducted in the outpatient setting and subjects may have milder form of exacerbations which may in turn explain the lack of inflammatory response in virus-positive subjects. There was also a significant median age difference between the virus-positive and negative groups (6.9 vs. 13 years, p=0.047), with respiratory viral infection being more common in younger children presumably related to the delay maturation of the immune system.
A CF centre in Milan (Italy) led by Esposito and colleagues [43] showed that human rhinovirus was the most frequently isolated virus from CF patients <25 years of age during respiratory exacerbations and when subjects were clinically stable over a 1-year period. Molecular techniques were utilised to isolate viruses from nasopharyngeal samples. The authors demonstrated that human rhinovirus was more common among patients with pulmonary exacerbations than among clinically stable patients. The human rhinovirus viral load was however similar in subjects with or without acute respiratory exacerbations (p=0.46). There were no correlations between the associated clinical condition and viral load as well as between bacterial colonisation, colonising bacterial, and viral infections between the 2 groups. This finding is similar to de Almeida et al. [17] who did not show a difference in viral infection between the exacerbation and clinically stable groups. Therefore, this raises a possibility that isolation of rhinovirus from nasopharyngeal swabs does not always indicate that it is a cause of exacerbation as it may be explained by a coincidental upper airways infection, a carrier state, or prolonged shedding of a pathogen that caused a previous infection [45].
In 2009, a novel swine pandemic influenza A virus (H1N1) was identified. Nash et al. [46] showed that the symptoms of CF patients infected with H1N1 tend to be mild. There was no significant reduction in FEV1 % predicted, FVC % predicted and body mass index regardless of whether the patients were positive or negative for H1N1. Colombo et al. [47] performed a multi-centre survey showing that diagnostic testing did not identify clinical characteristics specifically associated with H1N1 infections. Similarly, they did not show a significant decline in lung function associated with this infection. To date, the significance of H1N1 infection in CF remains undefined.
In contrast, the data regarding respiratory viral infection in adults is sparse. An observational study conducted by Hoek et al. [48] over a 1-year period amongst adult CF patients yielded a viral isolation rate of 33% [8/24] utilising molecular techniques and conventional methods. Etherington and colleagues [18] from an adult CF centre published a retrospective case control study looking at the prevalence of respiratory viruses during exacerbations. Viral throat swabs were taken from all patients presenting with an acute pulmonary exacerbation requiring intravenous antibiotic treatment over a 12-month period. Viral isolation was performed by PCR. There were 432 pulmonary exacerbations in 180 adults. In total, there was a total positive viral isolation in 42 exacerbations indicating a prevalence of 9.7%. Rhinovirus was the commonest isolated virus and was found on 29 occasions (69%). Influenza A/H1N1 was isolated in seven patients (16.7%). They demonstrated a measurable impact of viral infections in CF as exacerbations associated with a positive viral PCR had a greater fall in lung function at presentation with higher levels of inflammatory markers. These patients also received more days of intravenous antibiotics, showed less response to treatment and had a shorter time to next pulmonary exacerbation compared to matched controls.
Flight et al. [35] followed up 100 adult CF patients prospectively for 12 months. Sputum, nose swabs and throat swabs were collected every 2 months and at the onset of pulmonary exacerbation for virus detection. PCR assays for adenovirus, influenza A&B, human metapneumovirus, parainfluenza 1-3, respiratory syncytial virus and human rhinovirus were performed on each sample. Symptom scores, spirometry and inflammatory markers were measured at each visit. Overall, virology results were available for 626 of 649 completed study visits. Of these, 191 (30.5%) were positive for a respiratory virus including 9 episodes of dual viral infection. Human rhinovirus accounted for 72.5% of viruses. Overall incidence of viral respiratory infection (VRI) was 1.66 (95% CI 1.39 to 1.92) cases/patient-year. VRI was associated with increased risk of pulmonary exacerbation (OR=2.19; 95% CI 1.56 to 3.08; p<0.001) and prescription of antibiotics (OR=2.26; 95% CI 1.63 to 3.13; p<0.001). Virus-positive visits were associated with higher respiratory symptom scores and greater C-reactive protein levels. Virus-positive exacerbations had a lower acute fall in FEV1 than virus-negative exacerbations (12.7% vs. 15.6%; p=0.040). The incidence of exacerbations, but not VRI, was associated with greater lung function decline over 12 months (-1.79% per pulmonary exacerbation/year; 95% CI -3.4 to -0.23; p=0.025).
Experimental data on the effects of viral infections in CF are limited. Toll-like receptors (TLRs) have recently been identified as key mediators of the innate response and they recognise pathogens through detection of conserved microbial structures that are absent from the host. Kurt-Jones et al. [49] found that RSV persisted longer in the lungs of infected TLR4-deficient mice compared to normal mice. Haynes et al. [50] also demonstrated that TLR4-deficient mice when challenged with RSV exhibited impaired natural killer cell trafficking and impaired virus clearance compared to normal ones. Limited human studies have demonstrated the important role of TLRs in host response against many major groups of mammalian pathogens [51]. The relationship between TLR and respiratory virus including RSV in humans will require further studies before it can be established.
Some studies have suggested a higher viral replication when there is an impairment of the innate host defence in CF. Influenza titres were significantly increased in a mouse model which were chronically infected with P. aeruginosa compared to control model [52]. This in turn led to an increase in susceptibility to fatal streptococcus pneumonia infection. Increased virus replication was also found after PIV infection of CF human airway epithelial cells, compared to controls [53]. One of the possible causes of increased virus replication and of virus persistence might be a reduced production of respiratory nitric oxide (NO), which is a vital part of innate antiviral defence mechanism [54]. Increased production of NO protects against viral infections. In CF patients, expression of the NO producing enzyme NO synthase type 2 (NOS2) is considerably reduced.
Xu et al. [55] showed that CF cells that were infected with influenza A had less IFN-related antiviral gene induction at 24 h but more significant inflammatory cytokine gene induction at 1 h after infection. Therefore, the lesser antiviral and greater early inflammatory response may explain the severe respiratory illness of CF patients with viral infections. Sutanto and co-workers [56] showed that CF airway epithelial cells had a marked increase in IL-8 production, a reduction in apoptosis and an increased viral replication compared with airway epithelial cells from healthy children following exposure to human rhinovirus. This is despite the fact that CF and healthy airway epithelial cells have similar basal and stimulated expression of IL-8 in response to pro-inflammatory stimuli. The increment of IL-8, together with a reduction of apoptotic responses by CF cells to human rhinovirus, could contribute to augmented airway inflammation in the setting of recurrent viral infections early in life.
Azithromycin has previously been shown to offer anti-rhinoviral activity in bronchial epithelial cells and, during rhinovirus infection by increasing the production of interferon-stimulated genes [57]. However, the role of anti-viral properties of Azithromycin in CF is not clearly defined. Schögler et al. [58] showed that primary bronchial epithelial cells from CF children that were pre-treated with Azithromycin had a seven-fold reduction in rhinovirus replication without inducing cell death. Azithromycin also increased RV-induced pattern recognition receptor, IFN and IFN-stimulated gene mRNA levels when measured by real-time quantitative PCR. Therefore, it is likely that Azithromycin pre-treatment reduces RV replication in CF bronchial epithelial cells, possibly through the amplification of the antiviral response mediated by the IFN pathway.
3. Detection of respiratory viruses
The diagnostic accuracy and sensitivity of respiratory viral detection is determined by several factors:
Appropriate respiratory specimen for testing – Nasal swabs, nasopharyngeal aspirates, nasal swabs and mid-turbinate sampling are reasonable sampling methods in young children who may not be able to expectorate. However, in older patients, sputum is easy to obtain, painless and quick. Bronchoalveolar lavage (BAL) is a useful intervention to obtain specimen in the distal airways but it is more invasive. However, it can provide useful information regarding the activities of respiratory viruses and bacteria in the distal airways.
Appropriate specimen transport method – There are recognised procedures for transporting clinical specimens for diagnostic virology testing. These procedures should be adhered to closely to enhance the chances of isolating the viral organism. For instance, nasal swabs should be transported in viral transport medium and all specimens should be refrigerated if there is a delay of more than 2 hours in reaching the laboratory.
Detection methods – Molecular techniques have superseded many conventional methods such as viral culture and serology as they are far more sensitive and specific; in addition, they have a more rapid turn-around, allowing diagnostic technology to have an immediate impact on clinical management. The advantages of such technology will allow the appropriate utilisation of anti-virals, many of which are virus-specific; it may play a role in complying with hospital infection control policy; finally, it can provide useful information to public health authorities such that public health policies can be adjusted accordingly, e.g. the outbreak of SARS and influenza H5N1 virus.
Utilisation of real-time multiplex amplification technique allows multiple viruses being quantified even if the copy number of the viral target is low.
More recently, Virochip has been shown to be a pan-virus microarray platform that is capable of detection of known as well as novel viruses in a single assay simultaneously [59]. Probes chosen for Virochip can identify nodes in the viral taxonomy at the family, genus and species levels. As the Virochip probes are updated regularly, the extent of probes that can be covered are ever increasing, up to 36,000. It has a diagnostic sensitivity comparable to PCR for detecting respiratory genomes at levels as low as 100 genome copies. At the present time, Virochip is very much a research tool, and several issues must be addressed before it can be used as a routine test for virus detection in the clinical setting, including cost, diagnostic accuracy, repeatability, and sensitivity/specificity for virus detection. In addition, the clinical implication of novel viruses in the human respiratory tract is not yet defined. Therefore, the accurate interpretation of Virochip in the clinical setting remains a formidable task. For example, where specimens are polymicrobial or viral material are present at low levels, clinical and epidemiological information might be required to draw clinically meaningful conclusions.
4. Interaction between respiratory viruses and bacteria
In a 25-year retrospective review from the Danish CF clinic, the first isolation of P. aeruginosa was most likely between October and March [16] coinciding with the peak of the RSV season. However, there are a number of other possible viral agents that would broadly fit the winter season, most notably influenza, rhinovirus and metapneumovirus; therefore, these findings must be interpreted with caution.
An increase in immunoglobulin A (IgA) antibodies to the O-antigen of P. aeruginosa is noted in 62% of viral infections [60]. This suggests a possible ‘microbial synergism’ between bacterial infections and infections with respiratory viruses in CF.
The first bacterial isolation of a given organism in CF has also been shown to often follow a viral infection. In the 17-month prospective study reported by Collinson et al. [26], 5 of the 6 first isolations of P. aeruginosa were made during the symptomatic phase of an upper respiratory tract infection or three weeks thereafter. In contrast, only one of the 6 initial infections with P. aeruginosa was identified during the asymptomatic period. Similarly, H. influenzae was recovered for the first time from 3 children within 3 weeks of an upper respiratory tract infection and the one new S. aureus infection was identified immediately following a viral infection.
Armstrong and colleagues have reported that 50% of CF respiratory exacerbations requiring hospitalisation are associated with isolation of a respiratory virus [21]. In their prospective study of repeated BAL in infants over a 5-year period, a respiratory virus was identified in 52% of infants hospitalised for a respiratory exacerbation, most commonly RSV; 11 of the 31 hospitalised infants (35%) acquired P. aeruginosa in the subsequent 12-60 month follow-up, compared to 3 of 49 (6%) non-hospitalised infants (Relative risk 5.8). This indicates that RSV infection was identified immediately following a viral infection.
Respiratory viruses can disrupt the airway epithelium and precipitate bacterial adherence. Influenza A infection has been shown to cause epithelial shedding to basement membrane with submucosal oedema and neutrophil infiltrate [61], while both influenza and adenovirus have a cytopathic effect on cultured nasal epithelium leading to destruction of the cell monolayer [62]. This epithelial damage results in an increase in the permeability of the mucosal layer [63, 64] and possibly facilitating bacterial adherence. Bacteria can also utilise viral glycoproteins and other virus-induced receptors on host cell membrane as bacterial receptors in order to adhere to virus-infected cells [65, 66].
Kim et al. [67] found that invariant natural killer T cells induce a type of macrophage activation driving the secretion of interleukin-13 leading to the production of globlet cell metaplasia and airway hyperactivity following infection with Sendai virus. The term ‘invariant’ stems from the fact that all invariant natural killer T cells in humans and mice use a unique T cell receptor that is essential for interaction with CD1d. CD1d molecules present lipid antigens to T lymphocytes rather than peptide antigens as in the case of major histocompatibility complex (MHC) class I and II molecules. Historically, MHC class II dependent CD4 and T lymphocytes, through their response to stimulation by environmental allergens, are keys to the pathogenesis of human asthma. The findings by the authors lead to the notion of the use of anti-interleukin-13 therapy as a potential therapy in patients.
Viral infections might predispose to secondary bacterial infections by impairing mucociliary function and triggering host inflammatory receptors [68, 69]. This phenomenon has been demonstrated both in vivo and in vitro [70, 71]. Avadhanula et al. [72] showed that different respiratory viruses use different mechanisms to enhance the adherence of bacteria to respiratory epithelial cells. In particular, RSV and PIV type 3 up-regulate intercellular adhesion molecule-1 (ICAM-1), carcinoembryonic adhesion molecule 1 (CEACAM1) and platelet activating factor receptor (PAFr) but not mucin on the surfaces of A549, BEAS-2B and NHBE but not SAE cell lines. Much of the increased bacterial adhesion following RSV infection could be blocked by antibodies directed against these receptors. A549 and BEAS-2B are transformed cell lines derived from type II alveolar and normal bronchial cells, respectively. NHBE and SAE cells are primary epithelial cells obtained from bronchi and distal bronchial tree and are likely to include a heterogeneous population of cells.
Mechanisms independent of the expression of conventional receptors for bacteria, such as binding to viral proteins, could be responsible for enhanced adhesion [73]. Immunofluorescence microscopy demonstrates that bacteria binding to RSV-infected A549 cells adhere not only to these cells expressing viral antigens but also to uninfected epithelial cells. These data suggest that the ability to augment bacterial adhesion may result from a factor served by infected cells that exert a paracrine effect on adjacent epithelium. Cytokines or other inflammatory molecules are potential good candidates for such a mediator.
Rhinovirus has been shown to potentiate bacterial infections by inhibiting the secretion of TNF alpha and interleukin-8 by macrophages in vitro following co-infection with gram negative bacterial products, lipopolysaccharide (LPS), and gram positive bacterial products, lipoteichoic acid (LTA) [74]. This rhinovirus-dependent impairment of the macrophage immune response was not mediated by autocrine production of the anti-inflammatory cytokines interleukin-10 and PGE2, or by down-regulation of the cell surface receptor for LTA and LPS. In addition, the authors also show that rhinovirus inhibit the phagocytosis of bacterial products by macrophages. These findings support the notion that rhinovirus exposure resulted in a reduced ability to innate and adaptive immune responses against bacterial products, hence promoting the occurrence of bacterial and viral co-infections.
The lower respiratory tract is protected by local mucociliary mechanisms that involve the integration of the ciliated epithelium, periciliary fluid and mucus. Mucus acts as a physical and chemical barrier onto which particles and organisms adhere. Cilia lining the respiratory tract propel the overlying mucus to the oropharynx where it is either swallowed or expectorated. Influenza viral infection has been shown to precipitate the loss of cilial beat, and shedding of the columnar epithelial cells generally within 48 hours of infection [75]. Pittet et al. [76] showed that a prior influenza infection of tracheal cells in vivo does not increase the initial number of pneumococci found during the first hour of infection, but it does significantly reduce mucociliary velocity, and thereby reduces pneumococcal clearance during the first 2 hours after pneumococcal infection at both 3 and 6 days after an influenza infection. The defects in pneumococcal clearance were greatest at 6 days after influenza infection. Changes to the tracheal epithelium induced by influenza virus may increase susceptibility to a secondary S. pneumoniae infection by increasing pneumococcal adherence to the tracheal epithelium and/or decreasing the clearance of S. pneumoniae via the mucociliary escalator of the trachea, and thus increasing the risk of secondary bacterial infection.
De Vrankrijker et al. [77] showed that mice that were co-infected with RSV and P. aeruginosa had a 2,000 times higher colony-forming units (CFU) count of P. aeruginosa in the lung homogenates compared to mice that were infected with P. aeruginosa alone. Co-infected mice also had more severe lung function changes. These results suggest that RSV can facilitate the initiation of acute P. aeruginosa infection.
Another study also showed that H. influenzae and S. pneumoniae bind to both free RSV virions and epithelial cells transfected with cell-membrane-bound G protein, but not to secreted G protein. Pre-incubation with specific anti-G antibody significantly reduces bacterial adhesion to G protein-transfected cells [78].
Stark et al. [79] showed that mice that were exposed to RSV had significantly decreased S. pneumonia, S. aureus or P. aeruginosa clearance 1 to 7 days after RSV exposure. Mice that were exposed to both RSV and bacteria had a higher production of neutrophil-induced peroxide but less production of myeloperoxidase compared to mice that were exposed to S. pneumoniae alone. This suggests that functional changes in the recruited neutrophils may contribute to the decreased bacterial clearance.
More recently, Chattoraj et al. [15] demonstrated that acute infection of primary CF airway epithelial cells with rhinovirus liberates planktonic bacteria from biofilm. Superinfection with rhinovirus stimulates robust chemokine responses from CF airway epithelial cells that were pre-treated with mucoid P. aeruginosa. The authors also showed that these chemokine responses lead to a liberation of bacteria from mucoid P. aeruginosa biofilm and transmigration of planktonic bacteria from the apical to the basolateral surface of mucociliary-differentiated CF airway epithelial cells. Planktonic bacteria, which are more pro-inflammatory than their biofilm counterparts, stimulate increased chemokine responses in CF airway epithelial cells which, in turn, may contribute to the pathogenesis of CF exacerbations and subsequent prolonged intravenous antibiotic use and hospitalisation.
Contrary to the above reports, Chin et al. [32] performed a prospective study over a 2-year period on 35 adult CF patients. P. aeruginosa sputum density was analysed during stable, exacerbation and post-exacerbation assessments. PCR was used to detect respiratory viruses during exacerbations. The sputum density of P. aeruginosa in patients with or without a viral infection was compared using quantitative culture or by PCR. Twenty-two patients experienced 30 exacerbations during the study period; 50% were associated with a viral infection. There was no change in sputum density of P. aeruginosa from the stable to exacerbation state. Virus-associated exacerbations did not result in significant increases in P. aeruginosa sputum density compared to non-viral exacerbations.
Contrary to the above findings, Asner et al. [44] found the mean total bacterial density in sputum samples in virus-positive patients being two logs lower than that found in virus-negative patients (p=0.299). However, this could be explained by the fact that the median age of the virus-positive group was significantly lower than the virus-negative group. Virus-positive and virus-negative patients had similar IL-8, neutrophil percentage and neutrophil elastase levels.
Similarly, Kieninger et al. [80] performed a comprehensive investigation of the inflammatory response of CF airway epithelial cells on virus infection. Strong cytokine production was found in all cells studied, with the magnitude and type of inflammation differing depending on cell type and virus used. There was no exaggerated inflammatory response in CF, either during cytokine production or at the transcriptional level. Instead, there was a trend towards lower cytokine production in CF airway epithelial cells after virus infection, which was associated with increased cell death. The lower inflammatory response in CF can also be explained by additional pathophysiological mechanisms, such as interactions between anti-viral and pro-inflammatory pathways, which are likely to be involved [81]. It could also be speculated that because of chronic activation of pro-inflammatory pathways, CF airway epithelial cells are not able to respond sufficiently to further stimuli, such as virus infections. This might, in turn, lead to a lack of recruitment of effector immune cells resulting in longer duration and more severe respiratory symptoms.
TLRs are key mediators of type I interferon (IFN) during viral infections by recognizing various viral components. TLR7 and TLR9 have become apparent as universally important in inducing type I IFN during infection with most viruses, particularly by plasmacytoid dendritic cells [82]. New intracellular viral pattern recognition receptors leading to type I IFN production have been identified. CFTR mutations have been shown to affect the epithelial induction of type I IFN expression by airway cells in response to P. aeruginosa infection [83]. This is achieved by abolishing this signalling pathway, an important component of the innate immune system that protects mucosal surfaces. Based on available evidence, chronic colonisation of P. aeruginosa in CF airways can be hypothesised to increase the predisposition of viral infections; however, more in-depth studies are required to elucidate this hypothesis.
Taken together, these findings suggest conflicting data regarding the inflammatory response of the CF airway epithelium on virus infection and to some extent the symbiotic relationship between viruses and bacteria. Nonetheless, respiratory viruses may lead to epithelial disruption, increase neutrophil influx, inhibition of macrophage phagocytosis, destruction of mucociliary escalator, down-regulation of cilia beat, liberation of pro-inflammatory planktonic P. aeruginosa from biofilm and increased neutrophil-induced peroxide release, indirectly facilitating bacterial infection of the airway.
5. Prevention and treatment for respiratory viruses
The diversity of viral serotypes in causing infection has made vaccine preparation very difficult. Frequent mutations of viral proteins of RNA viruses (e.g. genetic drift and shift of influenza) have further hampered the prevention of the illness.
In the UK, it has been reported that 2,150 deaths during the 2011/12 season was attributable to influenza [84], though some of the deaths may be attributed to RSV. Influenza vaccines are the only commercially available vaccines against common respiratory viruses. They have been used since the mid-1940s and they now have an established role in the prevention of influenza A and B infections. Inactivated influenza vaccine is effective even in young children including those younger than 2 years [85]. The waning of vaccine-induced immunity over time requires annual re-immunisation even if the vaccine antigens are unchanged.
Recent vaccines contain antigens of two influenza A subtypes, strains of the currently circulating H3N2 and H1N1 (Swine flu) subtypes, and one influenza B virus. The current recommendation for influenza vaccination in the UK is to offer it to those over the age of 65, those with chronic heart, respiratory (including CF) or renal diseases and those who are diabetic or immunosuppressed.
Our group [34] recently showed that influenza vaccination provides protection against influenza acquisition in patients with CF, with 1 of 41 patients vaccinated having a positive nasal swab for influenza compared to 4 of the 22 non-vaccinated patients (p=0.046). Although influenza vaccination does not appear to have any impact on respiratory exacerbation rates, it does have a role in preventing live infections. In our study, respiratory exacerbation rates in the preceding 10 months before the study between the vaccinated and non-vaccinated groups were similar, indicating that these were unlikely to be the reasons influencing the decision on immunisation. The decision may be secondary to a combination of patient/parent education, social background, awareness of vaccination and accessibility of vaccination.
Due to the lack of randomised controlled studies looking at the efficacy of influenza vaccine in CF, the Cochrane review recommends clinicians to make their own judgements on the benefits and risks of this therapy in this cohort of patients [86]. In addition to vaccine, neuraminidase inhibitors have been shown to have a role in preventing influenza A and B infections [87].
Rhinovirus has more than 100 serotypes; therefore, it will be unlikely that a unifying vaccine can be developed. VP4, one of the non-enveloped capsids, is highly conserved among all of the rhinoviruses; anti-VP4 antibodies have recently been generated and been shown to have the potential for future vaccine development [88].
The development of an RSV vaccine has been hampered by the experience with formalin-inactivated whole RSV vaccine in the 1960s, as it caused 80% of RSV vaccinees to become hospitalised compared with 5% of controls, as well as two fatalities [89]. Current major research work has focused on a prophylaxis using a humanised mouse monoclonal antibody, Palizivumab. In patients with CF, monthly Palizivumab injection significantly reduced the hospitalisation rate for acute respiratory illness during the RSV season compared to those who were not immunised (p<0.05). The former group also had fewer hospital days for acute respiratory illness [90]. However, the Cochrane database systematic reviews were not able to draw any firm conclusions on the safety and tolerability of RSV prophylaxis with Palivizumab in infants with cystic fibrosis up to 2 years of age due to a lack of randomised controlled studies [91]. Further studies are required to evaluate the safety and effectiveness of this treatment in CF patients.
There is currently no licensed PIV vaccine. The formalin-inactivated vaccine generated in the 1960s was not able to prevent PIV infection and was soon abandoned. Recently, recombinant bovine PIV type 3 and human PIV type 3 attenuated vaccines are being evaluated in animal models as vectors for the delivery of other viral antigens such as RSV-G and RSV-F proteins. This bivalent vaccine combination provides high level of resistance to challenges with PIV type 3 and RSV in animal models [92].
The conventional methods of vaccination are via the intramuscular and subcutaneous routes. Mucosal immunisation has recently been introduced as it represents an attractive manner of delivering vaccines. It is fast, simple, non-invasive and can be carried out by unskilled individuals. The use of mucosal vaccination seems logical in that most of respiratory viral infections initially start at the mucosal sites and therefore induce local immunity. In the autumn/winter of 2014/15 the annual nasal spray flu vaccine (Fluenz Tetra) became available for children aged 2, 3 and 4 year as part of the UK NHS childhood vaccination programme. The nasal spray flu vaccine is also for children aged 2-18 years who are “at risk” from flu, such as children with long-term health conditions.
Amantadine has been the conventional anti-viral against influenza. However, it is strain-specific as it is only effective against influenza A and has common side effects such as insomnia, poor concentration and irritability. It is now largely being replaced by neuraminidase inhibitors such as Zanamivir and Oseltamivir, which are licensed for the treatment of influenza A and B, including avian flu H5N1 and swine flu H1N1. However, Amantadine still has a role in dealing with Oseltamivir-resistant H1N1 virus. In children and adults, early initiation of neuraminidase inhibitors within 48 hours of the onset of symptoms can reduce the duration of flulike symptoms by 0.5 to 2.5 days [93]. Early use of these medications can also reduce development of complications such as pneumonia [94]. The 2009 pandemic H1N1 virus remains susceptible to neuraminidase inhibitors, and Oseltamivir has been used extensively for treatment related to this viral infection. Resistance to Oseltamivir has been reported with H1N1 viral infection but this is mainly restricted to immunocompromised individuals [95]. Zanamivir has a poor oral bioavailability, and intranasal application has been shown to be effective in treating experimental influenza infection with the reduction in symptoms caused, virus shedding and development of otitis media [96]. Intravenous use of Peramivir or Zanamivir could be life-saving in critically ill patients with influenza infection [97, 98]. However, currently the Cochrane database of systematic reviews does not recommend the routine use of neuraminidase inhibitors in influenza infection in CF because of the absence of high level evidence for the effectiveness of these interventions [99].
Ribavarin, a synthetic guanosine nucleoside that has a broad spectrum of anti-viral activity, has been used for treatment of infections related to RSV, metapneumovirus, and parainfluenza and influenza viruses [100]. Potential benefits of ribavarin therapy include the inhibition of RSV-specific IgE production in nasal secretions, which has been associated with the development of hypoxaemia and wheezing [101] and it has improved pulmonary functions [102]. Controlled studies also show that the use of ribavarin is effective in reducing the clinical severity score, duration of mechanical ventilation, supplemental oxygen use and days of hospitalisation [103]. Aerosolised ribavarin has been used for the treatment of RSV-related bronchiolitis and pneumonia. Intravenous formulation could be used for treatment of severe pneumonia, caused by infection RSV, metapneumovirus, or parainfluenza virus, on the basis of experience in immunocompromised patients [104]. Bonney et al. have shown that metapneumovirus can be successfully treated with a combination of intravenous ribavarin and immunoglobulin [105].
Although rhinovirus is the major cause of colds, its vast amount of serotypes has made development of anti-virals against it problematic. A 90% of rhinovirus serotypes gain entry into epithelial cells using ICAM-1 cellular receptors, and blockade of these receptors in experimental studies has shown reduced infection severity [106], but further study is required before this treatment option becomes widely available. Macrolide antibiotics, Bafilomycin A1 and Erythromycin have been shown to inhibit ICAM-1 epithelial expression and hypotheses about their potential as anti-inflammatory agents have yet to be definitive, as clinical proof is either negative or inconclusive [107].
Recently, an anti-rhinoviral agent known as Plecoranil, which acts by inhibiting the uncoating of Picornaviruses [108], the RV 3C protease inhibitor, Ruprintrivir[109] and soluble ICAM-1, Tremacamra[106] have shown promising results in early-stage clinical trials, but each of these medications was derailed by a combination of cost, pharmacokinetics, toxicity, drug interactions, and limited efficacy [110].
A previous study suggests that the increased morbidity in CF patients after virus infection is not due to an exaggerated inflammatory response of the airway epithelium but rather linked to increased cell death. Thus, they provide a rationale for implementing therapies aimed at controlling viruses and their replication rather than primarily targeting inflammation. In this respect, a promising candidate is the macrolide-antibiotic azithromycin, which is increasingly used in CF patients as a beneficial immunomodulatory agent [111] and has recently been shown to possess anti-viral properties [57].
6. Conclusion
As we become increasingly knowledgeable about the impact of respiratory virus infections in the context of CF exacerbations, screening for respiratory viruses should be part of the routine investigations for any CF patients that present with exacerbation symptoms. Using the appropriate sampling method in conjunction with sensitive and specific diagnostic technology will enable us to make appropriate clinical decisions surrounding the use of anti-virals and antibiotics.
Gaining further understanding in the pathogenesis of virus-induced respiratory exacerbations in CF may allow the development of new therapeutic techniques. If viral infection does predispose to bacterial infection, then influencing the interaction between viruses and bacteria could be a next pathway to diminish respiratory morbidity in patients with CF. The development of novel therapies will be exciting and this may improve their quality of life and prolong the lifespan of patients with CF.
However, there are still a number of research dilemmas that remain unanswered:
What are the standardised definitions of CF pulmonary exacerbation and pulmonary exacerbation severity score?
What is the optimal way for viral sampling?
What is the role of Virochip in routine viral identification?
How do respiratory viruses influence bacterial activities in chronically infected airways?
What influences the rate of respiratory viral clearance in CF respiratory tract?
What are the roles of anti-virals in CF?
What are the anti-viral properties of Azithromycin in CF?
Further understanding in the pathogenesis of viral infection in CF would be beneficial as this may provide insight to the above unresolved mysteries. At the moment, influenza vaccination and the use of neuraminidase inhibitors remain the only evidence based practice, albeit weak for the management of viral infections in CF.
\n',keywords:"Cystic fibrosis, respiratory virus, bacteria, Pseudomonas aeruginosa",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/48831.pdf",chapterXML:"https://mts.intechopen.com/source/xml/48831.xml",downloadPdfUrl:"/chapter/pdf-download/48831",previewPdfUrl:"/chapter/pdf-preview/48831",totalDownloads:1225,totalViews:340,totalCrossrefCites:1,totalDimensionsCites:1,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:60,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"November 4th 2014",dateReviewed:"May 26th 2015",datePrePublished:null,datePublished:"August 24th 2015",dateFinished:"July 27th 2015",readingETA:"0",abstract:"Life expectancy in Cystic Fibrosis (CF) has improved dramatically in the last few decades; this is very much due to the emergence of disease-modifying treatments, optimisation of nutritional status and the inception of specialist CF units. However, progressive obstructive lung disease characterised by chronic inflammation, bacterial colonisation and recurrent infections of the lung, resulting in irreversible pulmonary damage, remains the major cause of mortality in individuals with CF. Historically, bacterial infections are the major pathogens accounting for clinical deterioration in CF. More recently, there has been emerging evidence to support respiratory viruses being accountable for the colonisation of bacteria and progression of lung disease in CF. This chapter sought to provide an overview on the impact of respiratory viruses in CF lung disease, the interaction between viruses and bacteria, the preventative and therapeutic measures that are currently available for the management of viral lung disease in CF.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/48831",risUrl:"/chapter/ris/48831",book:{id:"4649",slug:"cystic-fibrosis-in-the-light-of-new-research"},signatures:"Dennis Wat",authors:[{id:"92549",title:"Dr.",name:"Dennis",middleName:null,surname:"Wat",fullName:"Dennis Wat",slug:"dennis-wat",email:"dennis.wat@lhch.nhs.uk",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/92549/images/system/92549.jpg",institution:{name:"Liverpool Heart and Chest Hospital",institutionURL:null,country:{name:"United Kingdom"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Viral respiratory infections in CF",level:"1"},{id:"sec_3",title:"3. Detection of respiratory viruses",level:"1"},{id:"sec_4",title:"4. Interaction between respiratory viruses and bacteria",level:"1"},{id:"sec_5",title:"5. Prevention and treatment for respiratory viruses",level:"1"},{id:"sec_6",title:"6. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Farrell PM. The prevalence of cystic fibrosis in the European Union. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2008;7(5):450-3.'},{id:"B2",body:'2005 U.S. Cystic Fibrosis Foundation Annual Data Report to the Center Directors.. 2006.'},{id:"B3",body:'Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245(4922):1066-73.'},{id:"B4",body:'Vawter GF, Shwachman H. Cystic fibrosis in adults: an autopsy study. Pathol Annu. 1979;14 Pt 2:357-82.'},{id:"B5",body:'Oppenheimer EH, Esterly JR. 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In: Richman D, Whiyley R, Hayden F, editors. Clinical virology, 3rd edition. Washington: ASM Press; 2009. p. 217-64.'},{id:"B101",body:'Rosner IK, Welliver RC, Edelson PJ, Geraci-Ciardullo K, Sun M. Effect of ribavirin therapy on respiratory syncytial virus-specific IgE and IgA responses after infection. J Infect Dis. 1987;155(5):1043-7.'},{id:"B102",body:'Hiatt PT, D Laber, L. Pulmonary function (PF) following treatment with ribavarin in infants hospitalised with RSV bronchiolitis. Am Rev Respir Dis. 1990;141:A624.'},{id:"B103",body:'Smith DW, Frankel LR, Mathers LH, Tang AT, Ariagno RL, Prober CG. A controlled trial of aerosolized ribavirin in infants receiving mechanical ventilation for severe respiratory syncytial virus infection. N Engl J Med. 1991;325(1):24-9.'},{id:"B104",body:'Hopkins P, McNeil K, Kermeen F, Musk M, McQueen E, Mackay I, et al. Human metapneumovirus in lung transplant recipients and comparison to respiratory syncytial virus. 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J Virol. 2004;78(7):3663-74.'},{id:"B109",body:'Hayden FG, Turner RB, Gwaltney JM, Chi-Burris K, Gersten M, Hsyu P, et al. Phase II, randomized, double-blind, placebo-controlled studies of ruprintrivir nasal spray 2-percent suspension for prevention and treatment of experimentally induced rhinovirus colds in healthy volunteers. Antimicrobial agents and chemotherapy. 2003;47(12):3907-16.'},{id:"B110",body:'Turner RB. New considerations in the treatment and prevention of rhinovirus infections. Pediatr Ann. 2005;34(1):53-7.'},{id:"B111",body:'Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet. 2002;360(9338):978-84.'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Dennis Wat",address:"Dennis.Wat@lhch.nhs.uk",affiliation:'
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1. Introduction
Mushrooms are a group of fungi with a distinctive fruiting body that can be either epigeous or hypogenous and large enough to be seen with the naked eye and picked by hand [1]. They are either saprophytic, parasitic or mycorrhizal. Out of these three categories, the majority of them are saprophytic and they play an important role in the biodegradation and bioremediation of recalcitrant substances [2]. Notably, there are about 14,000 mushroom species that have been reported to date and a further 126,000 species more are yet to be discovered [3]. The majority of mushroom species are edible and over 400 species are poisonous [4]. Out of these more than 2000 edible species, 5–6 species are grown on a mass scale, 40 species are produced commercially and 80 species are cultivated experimentally (Figure 1). Edible mushrooms have very minimal calorie value as they contain less amounts fat and carbohydrate and are also cholesterol-free. In addition, edible mushrooms are rich in other vital nutrients like niacin, vitamin D, proteins, selenium, potassium, riboflavin. Mushrooms also contain a significant amount of fiber which helps in the appropriate digestion of food (Table 1) [1]. The active compounds in common mushrooms and the nutritional value of these mushrooms and their activities were showed in Table 2 and Figure 2.
Oxidative stress (OS) is one of the major causes of any disease such as neurodegenerative (NDs), cardiovascular (CDs) and reproductive diseases (RDs), and diabetes [17]. Inflammation is the progressive result of the severe burden of OS. Any biomolecules with anti-oxidative and anti-inflammatory activity show a better response in the treatment of the above diseases [18]. The polyphenols, terpenoids, alkaloids, and other important biomolecules found in edible mushrooms prove their efficacy in therapeutics with minimal side effects [19]. Mushrooms and their biomolecules are known to have been used to cure diabetes by Indian and Chinese patents from ancient times [20]. The active components in these mushroom species; Ganoderma lucidum, Lentinus edodes, Pleurotus ostreatus, Pleurotus sajor-caju, Grifola frondosa, Poriacocos, have exhibited potent anti-diabetic activity [21]. For example, the polysaccharides derived from Pleurotus ostreatus exhibits potent antidiabetic activity in the streptozotocin-persuaded Diabetic Rat model [22]. β-glucans and several other biomolecules present in edible mushrooms show strong anti-diabetic activity [23]. Recently the edible oyster mushroom Pleurotus fossulatus aqueous extract improved liver and kidney function in the streptozotocin-induced diabetic rats, besides reducing blood glucose levels, total cholesterol (TC), triglyceride (TG), and high-density lipoprotein (HDL) [24].
Disorders related to the heart and blood vessels are grouped into cardiovascular diseases (CVDs) [25]. Mushrooms and their bioactive components can prevent CVDs [26]. Being functional foods, edible mushrooms contain a significant number of bioactive compounds that show strong potential in the treatment of CVDs [27]. The antioxidant and anti- inflammatory biomolecules present in mushrooms reduce the atherosclerosis risk which is directly related to CVDs [28]. Diseases related to the reproductive systems are very common now a day. Abnormalities in the endocrine system are mainly responsible for the progression of reproductive diseases (RDs). Several RDs like reproductive tract infections, prostate cancer, breast cancer, ovarian cancer, etc. are most common in different populations [29]. Mushrooms and their bioactive molecules show anti-tumor activity which can be immensely beneficial in the treatment of different RDs. RDs commonly lead to different types of cancer and several biomolecules present in edible mushrooms can prevent metastasis toward cancer [1, 26]. Neurodegenerative diseases (NDs) like Huntington’s disease (HD), Alzheimer’s disease (AD), and Parkinson’s disease (PD), etc. have been effectively treated by edible mushrooms through their bioactive components [30]. Progression of the NDs is the main cause of death which can be significantly inhibited by the biomolecules present in edible mushrooms [31]. Polyphenols, alkaloids, and several other biomolecules in edible mushrooms prove their efficacy in the treatment of different neurodegenerative diseases [32]. Similarly, a different form of cancer can also be treated by the biomolecules found in edible mushrooms [23]. This review discusses the role of mushrooms and their biomolecules to be utilized for the treatment of some most common diseases like CVDs, RDs, NDs, diabetes, and the different forms of cancer.
2. Mushroom active compounds against cardiovascular diseases (CVDs)
Cardio Vascular Diseases (CVDs) are a category of heart and blood diseases, including coronary heart disease, cerebrovascular disease, rheumatic heart disease, and other diseases. CVDs are the leading cause of death worldwide. In the past few decades, researchers have shown the use of mushrooms and their bioactive compounds as therapeutic agents for CVDs. In 2010, Guillamon et al. reported the potentially positive effects of mushroom consumption on risk markers for CVDs and identified some potential bioactive compounds responsible for their therapeutic activity. Several studies have shown the influence of mushroom intake on some metabolic markers (total low-density lipoproteins (LDL), high-density lipoproteins (HDL): cholesterol, fasting triacylglycerol, homocysteine, blood pressure) which could potentially reduce the risk of cardiovascular disease. Relevant nutritional aspects of mushrooms include high fiber content, low-fat content, and low trans isomers of unsaturated fatty acids. Mushrooms also have low sodium concentrations and other significant components, such as eritadenine, phenolic compounds, sterols (such as ergosterol), chitosan, triterpenes, etc., which are considered to be potential agents for some previously healthy properties. The intake of mushrooms has a cholesterol-lowering or hypocholesterolemic effect which has been elucidated by different mechanisms, such as lowering of very-low-density lipoproteins (VLDL), improving lipid metabolism, inhibiting the activity of HMG-CoA reductase and therefore, prevents the development of atherosclerosis (Figure 3). Antioxidants and anti-inflammatory compounds found in mushrooms also reduce the risk of atherosclerosis [26]. Ganoderma lucidum play a curicral role in mitigating the toxicity of Adriamycin, where, Adriamycin treatment raised the number of marker enzymes found in serum including aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), and lactate dehydrogenase (LDH). In order to increase lipid peroxidation (LPO), adriamycin significantly decreased antioxidant enzymes in the cardiac tissues, including glutathione-S-transferase (GST), glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). Adriamycin has also been shown to considerably lower glutathione (GSH) levels. This study has shown that G. Lucidum extracts have significant antioxidant properties and protect the heart from the free radical-mediated toxicity of adriamycin. G. Lucidum extract retrieves free radicals and also increases the levels of glutathione and antioxidant enzymes [33]. Important findings show that the edible mushrooms could be used as possible sources of novel hypocholesterolemia agents. Few studies have identified the levels of sterols, b-glucans, and HMGCoA-red as inhibitors in mushrooms. Ergosterol was the most plentiful sterol recorded in all the samples examined, apart from G. lucidum, which had identical levels of ergosterol and ergosta-7,22-dienol. P. ostreatus, G. lucidum, A. aegerita, and L. edodes mushrooms had high levels of b-glucan content, whereas A. Blazeii, A. Bisporus, and L. procera had low levels of β-glucan content. Because of the presence of lovastatin, a statin found in mycelia broths and its fruiting bodies, the oyster mushroom (Pleurotus spp.) reduces blood cholesterol levels. As a result, a mixture of bioactive supplements improves the nutritional ability of different mushrooms to lower serum cholesterol levels [31]. A study has assessed the effect of different mushroom-like Lentinus edodes, Auricularia polytricha, and Flammulina velutipes preparations on the levels of cholesterol in the rats which showed that the preparation of dried mushrooms significantly reduced plasma cholesterol levels. Lentinus edodes was more effective, while Auricularia polytricha (Jews-ear) and Flammulina velutipes were less effective than L. edodes, Kohshin. However, ergosterol supplements have caused a marked decrease in hepatic cholesterol levels [34]. A previous study, focusing on the hypolipidemic effects of polysaccharides, isolated from Pholiota Nameko (PNPS-1) was conducted on hyperlipidemic Wistar rats. The rats were treated with PNPS-1 at different doses which reduced very-low-density: lipoprotein/low-density lipoprotein cholesterol, triacylglycerol, phospholipids, and increased the atherogenic index and high-density lipoprotein cholesterol in the serum. PNPS-1 also improved pathological changes in the coronary arteries of hyperlipidemic rats. These results suggest that PNPS-1 significantly reduces the development of hyperlipidemia and could be used as a potential therapeutic agent for CVD [35]. Anti-atherogenic and antiatherosclerotic effects of different mushrooms belonging to the genera: Armillaria, Agaricus, Boletus, Collybia, Cortinfrius, Coriolus, Flammulina, Hirneola, Lentinus, Ganoderrna, Lyophyllurn, Sarcodon, Pleurotus, Tricholoma, and Trenella were detected in human intima aortic culture. The results showed that anti-atherosclerotic, anti-atherogenic, and hypolipidemic effects of certain species of mushrooms allow us to speculate that these edible fungi are beneficial dietary supplements that might be utilized in prophylactics and to a limited extent, in atherosclerotic medicines. Furthermore, the extraction and purification of the active substance from these mushrooms may result in the development of a strong anti-atherosclerotic medicine [36]. Among the Pleurotus species, P. ostreatus was the best candidate for the prevention and treatment of atherosclerosis because it has been shown to contain a large number of antiatherosclerotic agents such as ergothionein, lovastatin, and chrysin [37].
Figure 3.
Mushroom active compounds against cardiovascular diseases (CVDs).
3. Antidiabetic activity of mushroom biomolecules
Mushrooms are fungi that either grow above or below the ground. These are the macro fungi that can be easily seen with the naked eye. Mushrooms have been used since ancient times by the people of India and China or their medicinal properties. Nowadays many countries are consuming mushrooms for not only their unique flavor but also for their culinary effects. As many studies have revealed that mushrooms are rich sources of: proteins, carbohydrates, vitamins (B1, B2, B12, C, D, and E) and minerals like Mn, Mg, Se, Ca, Na, Cu, K, and Fe [38]. These nutritional factors in mushrooms have made it very efficient to fight diabetes. In vitro and in vivo studies have shown that the extract of mushrooms can reduce the expression of proinflammatory cytokines, induced by lipopolysaccharides which further improved the glucose uptake in skeletal muscle cell lines [39].
One of the most active biomolecules of mushrooms is β-glucans, a polysaccharide that can protect the pancreatic tissue from damage and restore the function of b-cells which helps to lower the blood glucose levels [40]. The low energy, lack of cholesterol and fats, less carbohydrates, and high minerals, proteins and vitamins made mushrooms an ideal food for diabetic patients. The consumption of mushrooms for a few days only can help to manage the low-density lipoproteins, total cholesterol, high-density lipoprotein, triglycerides levels in serum [10]. Besides bioactive molecules, mushrooms are very good in antioxidants activity and are also a good source of dietary fibers and water. Some of the most culinary properties containing mushrooms are Agaricus bisporus, Agaricus subrufescens, Cordyceps millitaris, Cordyceps sinensis, Grifola frondosa, Ganoderma lucidum, Phellinus linteus, Pleurotus flabellatus, Pleurotus citrinopileatus, Pleurotus ostreatus, Poria cocos [10, 41]. Extracts of Ganoderma lucidum contain: polysaccharides, triterpenoids, proteoglycans, and proteins which have been shown to reduce blood glucose levels. The proteoglycans of G. lucidum inhibit the tyrosine phosphatase 1B protein in diabetic patients. G. lucidum has proven to be very effective in controlling diabetes. Moreover, the triterpenoid from G. lucidum inhibits the aldose reductase and a-glucosidase enzymes which are responsible for the elevation of postprandial glucose levels [42]. Polysaccharides from G. atrum (PSG-1) increase insulin sensitivity and lower the serum lipid by increasing and decreasing the expression levels of Bcl-2 and Bax, respectively in pancreatic cells [43].
Heteropolysaccharides are one of the bioactive molecules of Pleurotus ostreatus that control diabetes by activating the Glycogen synthase kinase 3 (GSK3) by phosphorylation and facilitating the translocation of glucose transporter type 4 (GLUT4) in streptozotocininduced diabetic rats [44]. Lentinula edodes promote the growth of gut microbiota, which play a very important role to balance the energy in diabetic patients. Another mushroom, Hirsutellas inensis shows antidiabetic, antiobesogenic effects in high-fat-diet feed-mice by modification of the components of gut microbiota. The polysaccharides and fibers of mushrooms act as prebiotics that helps in the treatment of diabetic patients [45]. Recently, researchers have found the potential effects of mushrooms in diabetic nephropathy conditions. Polysaccharides from Auricularia auricula are very helpful in promoting the oxidation of glucose. This polysaccharide protects against diabetic nephropathy by the regulation of creatinine, inflammatory factors, blood urea nitrogen, and urine protein. Polysaccharides isolated from Flammulina velutipes provided protection against reactive oxygen species (ROS) and reduced the level of malondialdehyde (MDA) in the kidney. The studies have also revealed that the proteoglycans from Ganoderma lucidum can restore kidney function by providing antioxidant activity [46]. According to a study conducted by Chou, Kan, Chang, Peng, Wang, Yu, Cheng, Jhang, Liu and Chuu [47], low molecular weight polysaccharide of Inonotus obiquus (LIOP) significantly reduces the expression of NF-jB and Transforming growth factor-beta (TGF-b) in a dose-dependent manner [48]. They find that LIOP treatment can improve glucolipotoxicity induced renal fibrosis in diabetic nephropathy mice. Hypsizigusm armoreus have been used to examine its protective effect on the liver, kidney, and pancreas. The spent mushroom compost polysaccharide (SCP), its enzymatic lysates (ESCP), and acid-based hydrolyzed SCP (ASCP) were tested in streptozotocin-induced mice and found that it increased the: catalase, superoxide dismutase, and glutathione peroxidase activity whereas, it reduced the lipid peroxide and malonaldehyde levels [49]. a-glucosidase inhibiting polysaccharide (ePS-F4-1) with triterpenoids had been purified from Coriolus versicolor. Another bioactive molecule, MT-a-glucan (polysaccharide) from Grifola frondosa increases the expression of Interleukin-2 (IL-2) and prevents the injury of b-cells [50]. Submerged cultured mycelium of Agaricus brasiliensis and G. lucidum has shown a protective effect on red blood cells (RBCs) in Streptozotocin (STZ)-induced diabetic rats [51].
4. Anticancer activity
Reproductive system diseases are responsible for several types of cancers like: prostate cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, colorectal cancer etc. The bioactive compounds present in the mushroom are playing an important role in the treatment of reproductive disease-associated cancers. There are several medicinal mushrooms like Ganoderma lucidum, Trametes versicolor, Inonotus obliquus, Fomitopsis officinalis, etc. which are frequently used in the treatment of cancer. Prostate cancer is the third leading cause of cancer deaths in men worldwide and the utmost common male malignancy in several western countries. The incidence rate of prostate cancer is highest in the United States, lower in European countries and lowest in Asia [52]. The common risk factor related to prostate cancer is age, obesity, family history, environmental factors and dietary factors [53]. Retinoblastoma (Rb) and p53 (tumor suppressor gene) play a vital role in the progression of prostate cancer [54]. The anomalous expression in growth factors and receptors such as: transforming growth factor-a (TGF-a), epidermal growth factor (EGF), transforming growth factor-b (TGF-b), HER-2/neu, and c-erbB-3 oncogenes [41] also lead to the malignant prostate cancer. To combat these problems, natural compounds and fungal metabolites can be used as inhibitors for targeting cancerous cells in certain cancers [55, 56, 57, 58]. Ganoderma lucidum belongs to the Ganoderma genus, oriental medicinally mushroom, which have been widely used in Asian countries for centuries to cure different diseases including cancer. Plenty of species of this genus have antiviral, antibacterial, antifungal, anticancer, and immune-stimulating activities [59]. These activities were due to the production of various bioactive compounds present in medicinally mushrooms such as proteins [60, 61, 62], terpenes, sterols, and polyphenols, etc. The dried powder of G. lucidum is used as dietary supplements and is also used as a chemotherapeutic agent for cancer therapy. It induced the apoptosis of prostate cancer (PC-3) cells by lowering the expression of NF-jB-mediated Bcl-2 and Bcl-xl expression while the upregulation of the Bax protein [63]. The extracts of G. lucidum suppress the proliferation of cells and induce the G1 cell cycle in prostate cancer and breast cancer cells line [64]. Trametes versicolor, is a medicinal mushroom, belongs to the class Agaricomycetes shows anti-proliferative effects upon hepatocellular carcinoma cells (HCC), prostate cancer (DU145) and human breast cancer (4 T1) [42]. Several studies suggested that in T. versicolor β-glucan-based polysaccharopeptide fraction (PSP) and polysaccharide fraction (PSK) are present which are used as immunotherapeutic anticancer agents [65]. PSP activates cells of the immune system by enhancing the secretion of histamine, chemokines and cytokines such as interleukins (IL-1b and IL-6), TNF-a and prostaglandin E which excites dendrite and T-cell infiltration into tumor and lowers the damaging undesirable effects of chemotherapy [66]. Breast cancer is becoming one of the most common leading causes of mortality among women. The molecular subtypes of breast cancer are identified by gene expression profiles and lead to the identification of biomarkers that may ease the prognosis and treatment of cancer [67]. The molecular and pathological marker for the treatment of breast cancer is based on the presence or absence of progesterone receptors (PR), estrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2) [67]. To overcome this problem, the medicinally mushroom is widely utilized in modern integrative oncology and given to patients regularly. The clinical results suggested that T. versicolor inhibits the human triple-negative breast cancer cells (MDA-MB-231) in the in vitro culture and reduced their growth [68] and is used as a supplement in the treatment of breast cancer. The mushroom Inonotus obliquus, often known as Chaga mushroom, belongs to the Agaricomycetes class and is widely used as traditional medicine for cancer therapy in Korea, China, Japan, and Russia [69]. Scientists illustrated that the water extracts of Chaga mushroom have shown cytotoxic and antimitotic activity on HeLa cells. The polysaccharides from I. obliquus inhibit the migration of cancer cell lines and shows anti-metastatic activities in vitro. The polysaccharide suppressed the NF-jB, PI3K/AKT and MAPKs signaling pathways by blocking activity and the expression of matrix metalloproteinases 2 and 9 (MMP) [70]. The studies confirmed that the Chaga mushroom has Wnt/β- catenin-inhibitory properties due to the presence of one major compound namely inotodiol which suppressed the breast cancer proliferation via the Wnt-dependent signaling pathway in a diabetic rat model [71].
The bioactive compounds present in the Ganoderma species are a viable alternative to fight breast cancer. The aqueous extracts of G. lucidum, G. sinense and G. tsugae were widely used against breast cancer cells. The data illustrated that the aqueous extract of these species has anti-proliferative activities against MCF-7 cells and MDA-MB-231 cells. However, the aqueous extract of G. tsugae was most effective against MCF-7 cells, although the activity of other Ganoderma species is similar to MDA-MB-231 cells. It also established that the extract did not show any cytotoxic activity against human noncancerous epithelial cells [72]. Several results showed that G. lucidum suppressed the proliferation of MDA-MB-231 cells in a dose and time-dependent manner [64]. The spore powder of G. lucidum also exhibited potent cytotoxic effects in the MDA-MB-468, triple-negative breast cancer cell lines, and SUM-102cell line and overexpressing the HER2 gene in MDA-MB435 [73]. Fomitopsis officinalis belongs to the family Polyporaceae and is generally known as ‘Agarikon.’ The fruiting bodies of mushrooms are used as a medicine in Western Europe, North America, and Asian countries for the treatment of gastric cancer, asthma, cough, and pneumonia [74]. Some auspicious evidence illustrated that using fungal extracts can help prevent breast and gastrointestinal cancers. Some studies confirmed antiviral, antibacterial, anticancer, and anti-inflammatory activity of crude extract of F. officinalis in different forms of cancers [75]. In F. officinalis extract, Lanostane-type triterpenoids, was reported which showed promising anticancer activity. Scientists showed that the ethanol extracts of F. officinalis are more effective in comparison with water extract against human breast cancer (MDAMB-231) cells, colon cancer (HCT-116), lung cancer (A549), mouse sarcoma 180 (S-180) and hepatoma (HepG2) cells [75].
Figure 4 shows the therapeutic activity of mushrooms and their biomolecules in the treatment of different forms of cancer. The immune system plays a very contributing role in the progression of tumors toward cancer. Mushroom shows its therapeutic activity by targeting the components of the immune system and also modulates the apoptotic processes. Figure 4 suggests the therapeutic activity of mushrooms by modulating the different components of the immune system and also regulates the apoptotic processes in cancerous cells [76, 77, 78].
Figure 4.
Antitumor mechanism of bioactive compounds in medicinal mushroom.
5. Biomolecules of mushrooms in neurodegenerative diseases (NDs)
Bioactive molecules in mushrooms also prevent the progression of different NDs. Motor symptoms linked with Parkinson’s disease (PD) are significantly prevented by a diet rich in mushroom supplements. In addition, the clinical symptoms of PD were also alleviated by mushroom supplements rich in phytochemicals, minerals, and vitamins [79]. Anti-inflammatory and antioxidative activity is exhibited by dietary mushrooms containing significant quantities of carotenoids, polysaccharides, minerals, polyphenols, and vitamins [80]. The two major factors that are responsible for the progression of PD are oxidative stress and neuroinflammation. Thus, the biomolecules present in edible mushrooms offer significant neuroprotection by their anti-oxidative and anti-inflammatory activity by preventing the progressive degeneration of dopaminergic neurons [79]. One of the major factors responsible for the generation of neuroinflammation in PD is the activation of microglial cells. Ganoderma lucidum extract (GLE) inhibited the activation of these microglial cells and ultimately preventing the progressive degeneration of dopaminergic neurons in PD. Tumor necrosis factoralpha (TNF-a) and interleukin-1b (IL-1b) are the examples of some important proinflammatory cytokines whose expression was downregulated by GLE in a dose-dependent manner and can be treated by natural antibiotics reported in [81]. Further progression of PD is prevented by inhibition of these proinflammatory cytokines by GLE. Thus, the treatment of PD, GLE should be utilized as an effective anti-inflammatory medication [82]. For the treatment of PD, niacin-rich food can be very beneficial and offers significant protective activity. Niacin-rich mushroom content offers potential therapeutic efficacy in the treatment of PD [83]. In the rotenone intoxicated model of PD, neuroprotective activity was shown by the Agaricus blazei extract (ABE). ABE also improves rotenone-induced non-motor and motor complications in PD. Therefore, for the treatment of PD, ABE might also be utilized as a nutritional supplement [84]. Some herbal plants like Tinospora cordifolia, Withania somnifera, Mucuna pruriens (Mp), and the essential oils also exhibit neuroprotective activity similar to mushrooms in toxin-induced PD mouse models [85, 86, 87]. In addition, bioactive components of Mp like Ursolic acid also exhibits potent antioxidative and anti-inflammatory property in toxin-induced PD model [88, 89, 90]. Chlorogenic acid also exhibits a similar AntiParkinsonian activity in the mouse model of PD [91]. Similar to PD, in Alzheimer’s disease (AD), nutritional mushroom provides important biomolecules that help to improve the quality of AD patients. Neuroinflammation along with oxidative stress mainly contributes to the pathogenesis of AD. The redox status in the cell of AD is significantly impaired [1]. Mushrooms have all the essential components that restore the normal balance of the redox system in AD models and patients. Proper and accurate functioning of mitochondria is required to maintain energy homeostasis. The synthesis of vital energy equivalents is hampered by abnormal mitochondrial functioning. In the neuroprotective network, inflammasome is an example of a very vital component. In AD, mitochondrial functioning was improved by Coriolus and Hericium. Normal redox balance was also maintained by these two nutritional mushrooms. Thus, energy homeostasis in AD was maintained by the above-mentioned two mushrooms by their antioxidative and anti-inflammatory properties [92]. One of the best examples of both medicinal and edible mushrooms is the Hericium erinaceus (HE). Both in vitro and in vivo model systems show the neuroprotective activity of HE. The aqueous extract of HE rich in a mycelium polysaccharide shows potent anti-apoptotic activity in l-glutamic acid (l-Glu)-induced differentiated PC12 (DPC12) cell lines. The AD mouse model induces by the combination of AlCl3 with D-galactose. The aqueous extract of HE prevents the further progression of AD by its neuroprotective potential. Behavioral abnormalities were also improved by the aqueous extract of HE in the AD mouse model. In a dosedependent manner, HE is responsible for the enhancement of choline acetyltransferase (ChAT) and acetylcholine (Ach) in serum and hypothalamus. To avert the pathogenesis of AD, the hypothalamus and serum level of Ach and ChAT is very vital. HE could be an efficient neuroprotective agent in AD and for some other neurodegenerative diseases [22]. For the treatment of different diseases, Coriolus versicolor (CV) mushroom is also widely utilized as a nutritional supplement. The oxidative stress and neuroinflammation were considerably reduced by the CV in AD. CV also improve the quality of mitochondria and restores the normal redox balance [92]. Human wellness was effectively maintained by the bioactive molecules present in prebiotics such as legumes [93, 94, 95], spirulina [96], biological nanoparticles [93, 97], mushroom [30]. Similar to PD, some herbal plants like Bacopa monnieri, Withania somnifera, Eclipta alba, Moringa oleifera and cucumber also improves cognitive function as suggested by some researchers [98, 99, 100, 101, 102, 103]. In addition, the neuroinflammatory pathways are also significantly modulated by a variety of medicinal mushrooms in AD [104]. In Huntington’s disease (HD), the therapeutic efficacy was also shown by medicinal, non-edible, and edible mushrooms and their bioactive components. Cognitive dysfunction is the very basic clinical feature of HD. In the edible mushroom Polyozellus multiplex, Polyozellin is a very important biomolecule having significant therapeutic activity. In the HD model, glutamate-induced mouse hippocampal neuronal HT22 cell death was significantly ameliorated by Polyozellin by apoptosis and the MAPK pathway. In HT22 cells, biochemical anomalies like lipid peroxidation and reactive oxygen species (ROS) were reduced by Polyozellin. Therefore, Polyozellin might be utilized for the treatment of HD patients in near future [105]. In the animal model of multiple sclerosis (MS), the disease conditions were ameliorated by Piwep, a mushroom extract from Phellinus igniarius. The dietary mushrooms and their bioactive components also improve the disease pathology in MS as with other NDs [106]. NFjB and Nrf2 mediated neuroinflammatory pathways are mainly responsible for mitochondrial dysfunction and ultimately cause progressive neurodegeneration in all NDs. Thus, the biomolecules of mushrooms play a very potential role to reduce the pathogenesis associated with NDs. Further studies will need to characterize more biomolecules in mushrooms and test their efficacy in several NDs.
\n',keywords:"mushroom, species, bioactive components, anticancer, antidiabetic",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/81926.pdf",chapterXML:"https://mts.intechopen.com/source/xml/81926.xml",downloadPdfUrl:"/chapter/pdf-download/81926",previewPdfUrl:"/chapter/pdf-preview/81926",totalDownloads:6,totalViews:0,totalCrossrefCites:0,dateSubmitted:"February 26th 2022",dateReviewed:"March 2nd 2022",datePrePublished:"June 13th 2022",datePublished:null,dateFinished:"May 24th 2022",readingETA:"0",abstract:"Apposite energy is required for body activity. Energy is derived from the oxidation of various biomolecules like carbohydrates, lipids, and proteins. These bio-molecules in the proper amount are essential for the structural and functional activities of any living being. Certain vitamins and enzymes are also needed for the maintenance of biochemical processes. Our daily food is the major source of these biomolecules. From the last few decades, researchers have placed giant effort into searching for a food material that can provide nearly all the essential components required to maintain the energy need and consequently, balancing the body’s homeostasis. Mushrooms have the potential to address the above-raised issues. Besides their pleasant flavor and culinary value, mushrooms are an important source of biomolecules that include large macromolecules (protein, carbohydrate, lipid, and nucleic acid) as well as small molecules (primary metabolites, secondary metabolites, and natural products). This chapter discusses the bioactive compounds in edible mushroom and their activities.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/81926",risUrl:"/chapter/ris/81926",signatures:"Ahmed M. Saad, Mahmoud Z. Sitohy, Belal A. Omar, Mohamed T. El-Saadony and Basel Sitohy",book:{id:"11363",type:"book",title:"Functional Food",subtitle:null,fullTitle:"Functional Food",slug:null,publishedDate:null,bookSignature:"Dr. Naofumi Shiomi and Ph.D. Anna Savitskaya",coverURL:"https://cdn.intechopen.com/books/images_new/11363.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-793-9",printIsbn:"978-1-80355-792-2",pdfIsbn:"978-1-80355-794-6",isAvailableForWebshopOrdering:!0,editors:[{id:"163777",title:"Dr.",name:"Naofumi",middleName:null,surname:"Shiomi",slug:"naofumi-shiomi",fullName:"Naofumi Shiomi"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Mushroom active compounds against cardiovascular diseases (CVDs)",level:"1"},{id:"sec_3",title:"3. Antidiabetic activity of mushroom biomolecules",level:"1"},{id:"sec_4",title:"4. Anticancer activity",level:"1"},{id:"sec_5",title:"5. 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Type 2 diabetes mellitus, oxidative stress and inflammation: Examining the links. International Journal of Physiology, Pathophysiology and Pharmacology. 2019;11(3):45'},{id:"B19",body:'Dasgupta A, Acharya K. Mushrooms: An emerging resource for therapeutic terpenoids. 3. Biotech. 2019;9(10):1-14'},{id:"B20",body:'Lee K-H, Morris-Natschke SL, Yang X, Huang R, Zhou T, Wu S-F, et al. Recent progress of research on medicinal mushrooms, foods, and other herbal products used in traditional Chinese medicine. Journal of Traditional and Complementary Medicine. 2012;2(2):1-12'},{id:"B21",body:'Ganeshpurkar A, Rai G, Jain AP. Medicinal mushrooms: Towards a new horizon. Pharmacognosy Reviews. 2010;4(8):127'},{id:"B22",body:'Zhang Y, Hu T, Zhou H, Zhang Y, Jin G, Yang Y. Antidiabetic effect of polysaccharides from Pleurotus ostreatus in streptozotocin-induced diabetic rats. International Journal of Biological Macromolecules. 2016;83:126-132'},{id:"B23",body:'Chaturvedi VK, Agarwal S, Gupta KK, Ramteke PW, Singh M. Medicinal mushroom: Boon for therapeutic applications. 3 Biotech. 2018;8(8):1-20'},{id:"B24",body:'Dubey S, Yadav C, Bajpeyee A, Singh MP. Effect of Pleurotus fossulatus aqueous extract on biochemical properties of liver and kidney in streptozotocin-induced diabetic rat. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2020;13:3035'},{id:"B25",body:'Cao S-Y, Zhao C-N, Gan R-Y, Xu X-Y, Wei X-L, Corke H, et al. Effects and mechanisms of tea and its bioactive compounds for the prevention and treatment of cardiovascular diseases: An updated review. Antioxidants. 2019;8(6):166'},{id:"B26",body:'Guillamón E, García-Lafuente A, Lozano M, Rostagno MA, Villares A, Martínez JA. Edible mushrooms: Role in the prevention of cardiovascular diseases. Fitoterapia. 2010;81(7):715-723'},{id:"B27",body:'Elkhateeb WA, Daba GM, Sheir D, El-Dein AN, Fayad W, Elmahdy EM, et al. GC-MS analysis and in-vitro hypocholesterolemic, anti-rotavirus, anti-human colon carcinoma activities of the crude extract of a Japanese Ganoderma spp. Egyptian Pharmaceutical Journal. 2019;18(2):102-110'},{id:"B28",body:'Tan BL, Norhaizan ME, Liew W-P-P, Sulaiman Rahman H. Antioxidant and oxidative stress: A mutual interplay in age-related diseases. Frontiers in Pharmacology. 2018;9:1162'},{id:"B29",body:'Hunt PA, Sathyanarayana S, Fowler PA, Trasande L. Female reproductive disorders, diseases, and costs of exposure to endocrine disrupting chemicals in the European Union. The Journal of Clinical Endocrinology & Metabolism. 2016;101(4):1562-1570'},{id:"B30",body:'Phan C-W, Tan EY-Y, Sabaratnam V. Bioactive molecules in edible and medicinal mushrooms for human wellness. In: Mérillon J-M, Ramawat KG, editors. Bioactive Molecules in Food. Springer International Publishing AG; 2018. pp. 1-24. DOI: 10.1007/978-3-319-54528-8_83-1'},{id:"B31",body:'Gil-Ramirez A, Clavijo C, Palanisamy M, Soler-Rivas C, Ruiz-Rodriguez A, Marín FR, Reglero G, et al. Edible mushrooms as potential sources of new hypocholesterolemic compounds. Villenave d’Ornon Cedex, France: Institut National de la Recherche Agronomique (INRA); 2011'},{id:"B32",body:'Phan C-W, David P, Sabaratnam V. Edible and medicinal mushrooms: Emerging brain food for the mitigation of neurodegenerative diseases. Journal of Medicinal Food. 2017;20(1):1-10'},{id:"B33",body:'Rajasekaran M, Kalaimagal C. Cardioprotective effect of a medicinal mushroom, Ganoderma lucidum against adriamycin induced toxicity. International Journal of Pharmacology. 2012;8(4):252-258'},{id:"B34",body:'Kaneda T, Tokuda S. Effect of various mushroom preparations on cholesterol levels in rats. The Journal of Nutrition. 1966;90(4):371-376'},{id:"B35",body:'Li H, Zhang M, Ma G. Hypolipidemic effect of the polysaccharide from Pholiota nameko. Nutrition. 2010;26(5):556-562'},{id:"B36",body:'Ryong LH, Tertov VV, Vasil’ev AV, Tutel’yan VA, Orekhov AN. Antiatherogenic and antiatherosclerotic effects of mushroom extracts revealed in human aortic intima cell culture. Drug Development Research. 1989;17(2):109-117'},{id:"B37",body:'Abidin MHZ, Abdullah N, Abidin NZ. Therapeutic properties of Pleurotus species (oyster mushrooms) for atherosclerosis: A review. International Journal of Food Properties. 2017;20(6):1251-1261'},{id:"B38",body:'Lee DH, Yang M, Giovannucci EL, Sun Q , Chavarro JE. Mushroom consumption, biomarkers, and risk of cardiovascular disease and type 2 diabetes: A prospective cohort study of US women and men. The American Journal of Clinical Nutrition. 2019;110(3):666-674'},{id:"B39",body:'Yang H, Hwang I, Kim S, Hong EJ, Jeung EB. Lentinus edodes promotes fat removal in hypercholesterolemic mice. Experimental and Therapeutic Medicine. 2013;6(6):1409-1413'},{id:"B40",body:'Xiao C, Wu Q , Tan J, Cai W, Yang X, Zhang J. Inhibitory effects on-glucosidase and hypoglycemic effects of the crude polysaccharides isolated from 11 edible fungi. Journal of Medicinal Plants Research. 2011;5(32):6963-6967'},{id:"B41",body:'Lu X, Chen H, Dong P, Fu L, Zhang X. Phytochemical characteristics and hypoglycaemic activity of fraction from mushroom Inonotus obliquus. Journal of the Science of Food and Agriculture. 2010;90(2):276-280'},{id:"B42",body:'Ma H-T, Hsieh J-F, Chen S-T. Anti-diabetic effects of Ganoderma lucidum. Phytochemistry. 2015;114:109-113'},{id:"B43",body:'Zhu K, Nie S, Li C, Lin S, Xing M, Li W, et al. A newly identified polysaccharide from Ganoderma atrum attenuates hyperglycemia and hyperlipidemia. International Journal of Biological Macromolecules. 2013;57:142-150'},{id:"B44",body:'Ma G, Yang W, Zhao L, Pei F, Fang D, Hu Q. A critical review on the health promoting effects of mushrooms nutraceuticals. Food Science and Human Wellness. 2018;7(2):125-133'},{id:"B45",body:'Martel J, Ojcius DM, Chang C-J, Lin C-S, Lu C-C, Ko Y-F, et al. Anti-obesogenic and antidiabetic effects of plants and mushrooms. Nature Reviews Endocrinology. 2017;13(3):149-160'},{id:"B46",body:'Jiang X, Meng W, Li L, Meng Z, Wang D. Adjuvant therapy with mushroom polysaccharides for diabetic complications. Frontiers in Pharmacology. 2020;11:168'},{id:"B47",body:'Chou Y-J, Kan W-C, Chang C-M, Peng Y-J, Wang H-Y, Yu W-C, et al. Renal protective effects of low molecular weight of Inonotus obliquus polysaccharide (LIOP) on HFD/STZ-induced nephropathy in mice. International Journal of Molecular Sciences. 2016;17(9):1535'},{id:"B48",body:'Sitohy MZ, Ramadan MF. Granular properties of different starch phosphate monoesters. Starch-Stärke. 2001;53(1):27-34'},{id:"B49",body:'Liu M, Song X, Zhang J, Zhang C, Gao Z, Li S, et al. Protective effects on liver, kidney and pancreas of enzymatic-and acidic-hydrolysis of polysaccharides by spent mushroom compost (Hypsizigus marmoreus). Scientific Reports. 2017;7(1):1-12'},{id:"B50",body:'Inoue A, Kodama N, Nanba H. Effect of maitake (Grifola frondosa) D-fraction on the control of the T lymph node Th-1/Th-2 proportion. Biological and Pharmaceutical Bulletin. 2002;25(4):536-540'},{id:"B51",body:'Vitak T, Yurkiv B, Wasser S, Nevo E, Sybirna N. Effect of medicinal mushrooms on blood cells under conditions of diabetes mellitus. World Journal of Diabetes. 2017;8(5):187'},{id:"B52",body:'Rawla P. Epidemiology of prostate cancer. World Journal of Oncology. 2019;10(2):63'},{id:"B53",body:'Baillargeon J, Platz EA, Rose DP, Pollock BH, Ankerst DP, Haffner S, et al. Obesity, adipokines, and prostate cancer in a prospective population-based study. Cancer Epidemiology and Prevention Biomarkers. 2006;15(7):1331-1335'},{id:"B54",body:'Hickman ES, Moroni MC, Helin K. The role of p53 and pRB in apoptosis and cancer. Current Opinion in Genetics & Development. 2002;12(1):60-66'},{id:"B55",body:'Ali H, AbdelMageed M, Olsson L, Israelsson A, Lindmark G, Hammarström M-L, et al. Utility of G protein-coupled receptor 35 expression for predicting outcome in colon cancer. Tumor Biology. 2019;41(6):1010428319858885'},{id:"B56",body:'El-Sayed AS, Fathalla M, Yassin MA, Zein N, Morsy S, Sitohy M, et al. Conjugation of aspergillus flavipes taxol with porphyrin increases the anticancer activity of taxol and ameliorates its cytotoxic effects. Molecules. 2020;25(2):263'},{id:"B57",body:'Ohlsson L, Hammarström M-L, Lindmark G, Hammarström S, Sitohy B. Ectopic expression of the chemokine CXCL17 in colon cancer cells. British Journal of Cancer. 2016;114(6):697-703'},{id:"B58",body:'El-Sayed AS, Safan S, Mohamed NZ, Shaban L, Ali GS, Sitohy MZ. Induction of Taxol biosynthesis by aspergillus terreus, endophyte of Podocarpus gracilior Pilger, upon intimate interaction with the plant endogenous microbes. Process Biochemistry. 2018;71:31-40'},{id:"B59",body:'Abdelbacki AM, Taha SH, Sitohy MZ, Abou Dawood AI, Hamid MM, Rezk AA. Inhibition of tomato yellow leaf curl virus (TYLCV) using whey proteins. Virology Journal. 2010;7(1):1-6'},{id:"B60",body:'Osman A, El-Didamony G, Sitohy M, Khalifa M, Enan G. Soybean glycinin basic subunit inhibits methicillin resistant-vancomycin intermediate Staphylococcus aureus (MRSA-VISA) in vitro. International Journal of Applied Research in Natural Products. 2016;9(2):17-26'},{id:"B61",body:'Sitohy M, CHOBERT JM, Haertlé T. Study of factors influencing protein esterification using β-lactoglobulin as a model. Journal of Food Biochemistry. 2000;24(5):381-398'},{id:"B62",body:'Sitohy M, Mahgoub S, Osman A. Controlling psychrotrophic bacteria in raw buffalo milk preserved at 4 C with esterified legume proteins. LWT-Food Science and Technology. 2011;44(8):1697-1702'},{id:"B63",body:'Jiang J, Slivova V, Harvey K, Valachovicova T, Sliva D. Ganoderma lucidum suppresses growth of breast cancer cells through the inhibition of Akt/NF-κB signaling. Nutrition and Cancer. 2004;49(2):209-216'},{id:"B64",body:'Lu Q-Y, Jin Y-S, Zhang Q , Zhang Z, Heber D, Go VLW, et al. Ganoderma lucidum extracts inhibit growth and induce actin polymerization in bladder cancer cells in vitro. Cancer Letters. 2004;216(1):9-20'},{id:"B65",body:'Cui J, Chisti Y. Polysaccharopeptides of Coriolus versicolor: Physiological activity, uses, and production. Biotechnology Advances. 2003;21(2):109-122'},{id:"B66",body:'Chang Y, Zhang M, Jiang Y, Liu Y, Luo H, Hao C, et al. Preclinical and clinical studies of Coriolus versicolor polysaccharopeptide as an immunotherapeutic in China. Discovery Medicine. 2017;23(127):207-219'},{id:"B67",body:'Reis-Filho JS, Pusztai L. Gene expression profiling in breast cancer: Classification, prognostication, and prediction. The Lancet. 2011;378(9805):1812-1823'},{id:"B68",body:'Jiang J, Thyagarajan-Sahu A, Loganathan J, Eliaz I, Terry C, Sandusky GE, et al. BreastDefend™ prevents breast-to-lung cancer metastases in an orthotopic animal model of triple-negative human breast cancer. Oncology Reports. 2012;28(4):1139-1145'},{id:"B69",body:'Handa N, Yamada T, Tanaka R. An unusual lanostane-type triterpenoid, spiroinonotsuoxodiol, and other triterpenoids from Inonotus obliquus. Phytochemistry. 2010;71(14-15):1774-1779'},{id:"B70",body:'Lee KR, Lee JS, Kim YR, Song IG, Hong EK. Polysaccharide from Inonotus obliquus inhibits migration and invasion in B16-F10 cells by suppressing MMP-2 and MMP-9 via downregulation of NF-κB signaling pathway. Oncology Reports. 2014;31(5):2447-2453'},{id:"B71",body:'Zhang X, Bao C, Zhang J. Inotodiol suppresses proliferation of breast cancer in rat model of type 2 diabetes mellitus via downregulation of β-catenin signaling. Biomedicine & Pharmacotherapy. 2018;99:142-150'},{id:"B72",body:'Yue GG, Fung K-P, Tse GM, Leung P-C, Lau CB. Comparative studies of various Ganoderma species and their different parts with regard to their antitumor and immunomodulating activities in vitro. Journal of Alternative & Complementary Medicine. 2006;12(8):777-789'},{id:"B73",body:'Suárez-Arroyo IJ, Rios-Fuller TJ, Feliz-Mosquea YR, Lacourt-Ventura M, Leal-Alviarez DJ, Maldonado-Martinez G, et al. Ganoderma lucidum combined with the EGFR tyrosine kinase inhibitor, erlotinib synergize to reduce inflammatory breast cancer progression. Journal of Cancer. 2016;7(5):500'},{id:"B74",body:'Grienke U, Zöll M, Peintner U, Rollinger JM. European medicinal polypores—A modern view on traditional uses. Journal of Ethnopharmacology. 2014;154(3):564-583'},{id:"B75",body:'Wu H-T, Lu F-H, Su Y-C, Ou H-Y, Hung H-C, Wu J-S, et al. In vivo and in vitro anti-tumor effects of fungal extracts. Molecules. 2014;19(2):2546-2556'},{id:"B76",body:'Sitohy B, Chang S, Sciuto TE, Masse E, Shen M, Kang PM, et al. Early actions of anti-vascular endothelial growth factor/vascular endothelial growth factor receptor drugs on Angiogenic blood vessels. The American Journal of Pathology. 2017;187(10):2337-2347'},{id:"B77",body:'Sitohy B, El-Salhy M. Changes in the colonic enteric nervous system in rats with chemically induced colon dysplasia and carcinoma. Acta Oncologica. 2002;41(6):543-549'},{id:"B78",body:'Sitohy B, El-Salhy M. A comparison between double and triple therapies of octreotide, galanin and serotonin on a rat colon carcinoma. Histology and Histopathology. 2003;1:103-110'},{id:"B79",body:'Ciulla M, Marinelli L, Cacciatore I, Stefano AD. Role of dietary supplements in the management of Parkinson’s disease. Biomolecules. 2019;9(7):271'},{id:"B80",body:'Kozarski M, Klaus A, Jakovljevic D, Todorovic N, Vunduk J, Petrović P, et al. Antioxidants of edible mushrooms. Molecules. 2015;20(10):19489-19525'},{id:"B81",body:'Abd El-Hack ME, El-Saadony MT, Elbestawy AR, Nahed A, Saad AM, Salem HM, et al. Necrotic enteritis in broiler chickens: Disease characteristics and prevention using organic antibiotic alternatives—A comprehensive review. Poultry Science. 2021;101(2):101590'},{id:"B82",body:'Zhang R, Xu S, Cai Y, Zhou M, Zuo X, Chan P. Ganoderma lucidum protects dopaminergic neuron degeneration through inhibition of microglial activation. Evidence-based Complementary and Alternative Medicine. 2011:1-9'},{id:"B83",body:'Aaseth J, Dusek P, Roos PM. Prevention of progression in Parkinson’s disease. Biometals. 2018;31(5):737-747'},{id:"B84",body:'Venkateshgobi V, Rajasankar S, Johnson WMS, Prabu K, Ramkumar M. Neuroprotective effect of agaricus blazei extract against rotenone-induced motor and nonmotor symptoms in experimental model of parkinson’s disease. International Journal of Nutrition, Pharmacology, Neurological Diseases. 2018;8(2):59'},{id:"B85",body:'Birla H, Rai SN, Singh SS, Zahra W, Rawat A, Tiwari N, et al. Tinospora cordifolia suppresses neuroinflammation in parkinsonian mouse model. Neuromolecular Medicine. 2019;21(1):42-53'},{id:"B86",body:'Rai SN, Birla H, Singh SS, Zahra W, Patil RR, Jadhav JP, et al. Mucuna pruriens protects against MPTP intoxicated neuroinflammation in Parkinson’s disease through NF-κB/pAKT signaling pathways. Frontiers in Aging Neuroscience. 2017;9:421'},{id:"B87",body:'Abd El-Hack ME, El-Saadony MT, Saad AM, Salem HM, Ashry NM, Ghanima MMA, et al. Essential oils and their nanoemulsions as green alternatives to antibiotics in poultry nutrition: A comprehensive review. Poultry Science. 2021;101(2):101584'},{id:"B88",body:'Rai SN, Mishra D, Singh P, Vamanu E, Singh M. Therapeutic applications of mushrooms and their biomolecules along with a glimpse of in silico approach in neurodegenerative diseases. Biomedicine & Pharmacotherapy. 2021;137:111377'},{id:"B89",body:'Rai SN, Zahra W, Singh SS, Birla H, Keswani C, Dilnashin H, et al. Anti-inflammatory activity of ursolic acid in MPTP-induced parkinsonian mouse model. Neurotoxicity Research. 2019;36(3):452-462'},{id:"B90",body:'Zahra W, Rai SN, Birla H, Singh SS, Rathore AS, Dilnashin H, et al. Neuroprotection of rotenone-induced parkinsonism by ursolic acid in PD mouse model. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders). 2020;19(7):527-540'},{id:"B91",body:'Singh SS, Rai SN, Birla H, Zahra W, Rathore AS, Dilnashin H, et al. Neuroprotective effect of chlorogenic acid on mitochondrial dysfunction-mediated apoptotic death of DA neurons in a Parkinsonian mouse model. Oxidative Medicine and Cellular Longevity; 2020:1-14'},{id:"B92",body:'Trovato Salinaro A, Pennisi M, Di Paola R, Scuto M, Crupi R, Cambria MT, et al. Neuroinflammation and neurohormesis in the pathogenesis of Alzheimer’s disease and Alzheimer-linked pathologies: Modulation by nutritional mushrooms. Immunity & Ageing. 2018;15(1):1-8'},{id:"B93",body:'Abd El-Hack ME, El-Saadony MT, Shafi ME, Alshahrani OA, Saghir SA, Al-Wajeeh AS, et al. Prebiotics can restrict Salmonella populations in poultry: A review. Animal Biotechnology; 2021:1-10. DOI: 10.1080/10495398.2021.1883637'},{id:"B94",body:'Saad AM, Elmassry RA, Wahdan KM, Ramadan FM. Chickpea (Cicer arietinum) steep liquor as a leavening agent: Effect on dough rheology and sensory properties of bread. Acta Periodica Technologica. 2015;46:91-102'},{id:"B95",body:'Saad AM, Sitohy MZ, Ahmed AI, Rabie NA, Amin SA, Aboelenin SM, et al. Biochemical and functional characterization of kidney bean protein alcalase-hydrolysates and their preservative action on stored chicken meat. Molecules. 2021;26(15):4690'},{id:"B96",body:'Abdel-Moneim A-ME, El-Saadony MT, Shehata AM, Saad AM, Aldhumri SA, Ouda SM, et al. Antioxidant and antimicrobial activities of Spirulina platensis extracts and biogenic selenium nanoparticles against selected pathogenic bacteria and fungi. Saudi Journal of Biological Sciences. 2022;29(2):1197-1209'},{id:"B97",body:'El-Saadony MT, Saad AM, Taha TF, Najjar AA, Zabermawi NM, Nader MM, et al. Selenium nanoparticles from lactobacillus paracasei HM1 capable of antagonizing animal pathogenic fungi as a new source from human breast milk. Saudi Journal of Biological Sciences. 2021;28(12):6782-6794'},{id:"B98",body:'Chaudhari KS, Tiwari NR, Tiwari RR, Sharma RS. Neurocognitive effect of nootropic drug Brahmi (Bacopa monnieri) in Alzheimer’ disease. Annals of Neurosciences. 2017;24(2):111-122'},{id:"B99",body:'Mahaman YAR, Huang F, Wu M, Wang Y, Wei Z, Bao J, et al. Moringa oleifera alleviates homocysteine-induced Alzheimer’s disease-like pathology and cognitive impairments. Journal of Alzheimer’s Disease. 2018;63(3):1141-1159'},{id:"B100",body:'Mehla J, Gupta P, Pahuja M, Diwan D, Diksha D. Indian medicinal herbs and formulations for alzheimer’s disease, from traditional knowledge to scientific assessment. Brain Sciences. 2020;10(12):964'},{id:"B101",body:'Sehgal N, Gupta A, Valli RK, Joshi SD, Mills JT, Hamel E, et al. Withania somnifera reverses Alzheimer’s disease pathology by enhancing low-density lipoprotein receptor-related protein in liver. Proceedings of the National Academy of Sciences. 2012;109(9):3510-3515'},{id:"B102",body:'El-Saadony MT, Saad AM, Elakkad HA, El-Tahan AM, Alshahrani OA, Alshilawi MS, et al. Flavoring and extending the shelf life of cucumber juice with aroma compounds-rich herbal extracts at 4° C through controlling chemical and microbial fluctuations. Saudi Journal of Biological Sciences. 2022;29(1):346-354'},{id:"B103",body:'Saad AM, El-Saadony MT, Mohamed AS, Ahmed AI, Sitohy MZ. Impact of cucumber pomace fortification on the nutritional, sensorial and technological quality of soft wheat flour-based noodles. International Journal of Food Science & Technology. 2021;56(7):3255-3268'},{id:"B104",body:'Kushairi N, Tarmizi NAKA, Phan CW, Macreadie I, Sabaratnam V, Naidu M, et al. Modulation of neuroinflammatory pathways by medicinal mushrooms, with particular relevance to Alzheimer’s disease. Trends in Food Science & Technology. 2020;104:153-162'},{id:"B105",body:'Yang E-J, Song K-S. Polyozellin, a key constituent of the edible mushroom Polyozellus multiplex, attenuates glutamate-induced mouse hippocampal neuronal HT22 cell death. Food & Function. 2015;6(12):3678-3686'},{id:"B106",body:'Li L, Wu G, Choi BY, Jang BG, Kim JH, Sung GH, et al. A mushroom extract Piwep from Phellinus igniarius ameliorates experimental autoimmune encephalomyelitis by inhibiting immune cell infiltration in the spinal cord. BioMed Research International; 2014:1-14'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Ahmed M. Saad",address:"ahmedm4187@gmail.com",affiliation:'
Department of Biochemistry, Faculty of Agriculture, Zagazig University, Egypt
'},{corresp:null,contributorFullName:"Mahmoud Z. Sitohy",address:null,affiliation:'
Department of Biochemistry, Faculty of Agriculture, Zagazig University, Egypt
'},{corresp:null,contributorFullName:"Belal A. Omar",address:null,affiliation:'
Department of Biochemistry, Faculty of Agriculture, Zagazig University, Egypt
'},{corresp:null,contributorFullName:"Mohamed T. El-Saadony",address:null,affiliation:'
Department of Agricultural Microbiology, Faculty of Agriculture, Zagazig University, Egypt
Department of Radiation Sciences, Norrlands universitetssjukhus Umeå universitet, Sweden
Department of Clinical Microbiology, Infection and Immunology, Umeå University, Sweden
'}],corrections:null},book:{id:"11363",type:"book",title:"Functional Food",subtitle:null,fullTitle:"Functional Food",slug:null,publishedDate:null,bookSignature:"Dr. Naofumi Shiomi and Ph.D. Anna Savitskaya",coverURL:"https://cdn.intechopen.com/books/images_new/11363.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-793-9",printIsbn:"978-1-80355-792-2",pdfIsbn:"978-1-80355-794-6",isAvailableForWebshopOrdering:!0,editors:[{id:"163777",title:"Dr.",name:"Naofumi",middleName:null,surname:"Shiomi",slug:"naofumi-shiomi",fullName:"Naofumi Shiomi"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},profile:{item:{id:"154742",title:"Dr.",name:"Saule",middleName:null,surname:"Rahimgalieva",email:"saule-ra@mail.ru",fullName:"Saule Rahimgalieva",slug:"saule-rahimgalieva",position:null,biography:null,institutionString:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",totalCites:0,totalChapterViews:"0",outsideEditionCount:0,totalAuthoredChapters:"1",totalEditedBooks:"0",personalWebsiteURL:null,twitterURL:null,linkedinURL:null,institution:null},booksEdited:[],chaptersAuthored:[{id:"43223",title:"Soil Organic Matter Stability as Affected by Land Management in Steppe Ecosystems",slug:"soil-organic-matter-stability-as-affected-by-land-management-in-steppe-ecosystems",abstract:null,signatures:"Elmira Saljnikov, Dragan Cakmak and Saule Rahimgalieva",authors:[{id:"78355",title:"Dr.",name:"Elmira",surname:"Saljnikov",fullName:"Elmira Saljnikov",slug:"elmira-saljnikov",email:"soils.saljnikov@gmail.com"},{id:"85471",title:"Dr.",name:"Dragan",surname:"Cakmak",fullName:"Dragan Cakmak",slug:"dragan-cakmak",email:"cakmakd@yahoo.com"},{id:"154742",title:"Dr.",name:"Saule",surname:"Rahimgalieva",fullName:"Saule Rahimgalieva",slug:"saule-rahimgalieva",email:"saule-ra@mail.ru"}],book:{id:"3224",title:"Soil Processes and Current Trends in Quality Assessment",slug:"soil-processes-and-current-trends-in-quality-assessment",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"56222",title:"Prof.",name:"Zueng-Sang",surname:"Chen",slug:"zueng-sang-chen",fullName:"Zueng-Sang Chen",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Curriculum Vitae\r\nZueng-Sang CHEN\r\nUpdated on Oct 3, 2010\r\n\r\nAssociate Dean\r\nCollege of Bioresources and Agriculture \r\nNational Taiwan University\r\n1, Sect. 4th, Roosevelt road, Taipei 10617, Taiwan.\r\nTel: (college office) (+886-2) 3366-4205) \r\nFax: (college office) (+886-2) 2391-9626\r\nE-mail: soilchen@ntu.edu.tw \r\n\r\nDistinguished Professor\r\nPedology and soil environmental quality\r\nSoil Survey and Remediation Laboratory\r\nDepartment of Agricultural Chemistry\r\nNational Taiwan University\r\n1, Sect. 4th, Roosevelt road, Taipei 10617, Taiwan.\r\nTel: (Office) (+886-2) 2369-8349 (or 3366-2117) \r\nFax: (Office) (+886-2) 2392-4335\r\nE-mail: soilchen@ntu.edu.tw \r\nLab. Website: http://Lab.ac.ntu.edu.tw/soilsc/ \r\n\r\nMain Contributions \r\nHe have published more than 37 International SCI papers, 68 local journal papers, 117 international conference full paper, 61 local workshop full papers, 37 book chapters, and 62 technical reports in his career. \r\n\r\nHe contributed to East and Southeastern Federation of Soil Science Society (ESAFS) as a President for 2 years in 2002-2003, and also as a chairman and well organized the 6th ESAFS International Conference held in November 2003, at Taipei, Taiwan. \r\n\r\nHe served as a part time Soil and Fertilizer Consultant of Food Fertilizer Technology Center for the Asian and Pacific Region (FFTC/ASPAC), for 12 years from 1999 to 2010. He organized more than 10 International workshops or symposiums to maintain the quality of soil resources of the Asia and Pacific region and also to improve the crop productivities and crop quality. \r\n\r\nHis researches especially focus on the technologies of management of agricultural resources, composting, soil and environmental quality, newly developed innovative technologies on soil-crop inventory on heavy metals in the Asian region. \r\n\r\nHe have edited and published 3 technical books, 40 technical bulletin of FFTC and 40 Extension Bulletin of FFTC on Soil and Fertilizer Technology for Asian and Pacific region from 1996 to now. \r\n\r\nHe attended almost all the ESAFS conferences since 1990 and as a representative of Chinese Society of Soil and Fertilizer Sciences (CSSFS) to attend the business meeting of ESAFS and make a valuable contribution on the promotion of the communication and operation processing of the country members of ESAFS. \r\n\r\nHe almost was invited as one of the keynote speakers or speaker of session during the ESAFS conferences held in this region.\r\n\r\nHe initiated to develop the “Asian Soil database and Information Center†in 2008. \r\n\r\nPosition\r\nDirector, Agricultural Exhibition Center of National Taiwan University. (August, 2008-July, 2011).\r\n\r\nAssociate Dean, College of Bioresources and Agriculture, National Taiwan University. (August, 2007 to July, 2011).\r\n\r\nDistinguished Professor, pedology and soil environmental quality, Department of Agricultural Chemistry, National Taiwan University. (August 2007 to July 2010).\r\n\r\nHead of Department, Department of Agricultural Chemistry, National Taiwan University. (August, 2004 to July, 2007). http://www.ac.ntu.edu.tw \r\n\r\nProfessor of pedology and soil environmental quality, Department of Agricultural Chemistry, National Taiwan University. (August, 1989 to July 31, 2007).\r\n\r\nSoil and Fertilizer Consultant, Food and Fertilizer Technology Center for the Asian and Pacific Region (FFTC/ASPAC) http://www.fftc.agnet.org (12 years, March 1999 to February 2011). FFTC is located at Taipei, Taiwan\r\n\r\nInternational Honorable Scientists, RDA, Korea (2004-2006) and International Honorable Green Technology advisor, RDA, Korea (2010-2012)\r\n\r\nAssociate editor, Journal of Food, Agriculture, and Environment (www.world-food.net, 5 years, Jan 01, 2006-Dec 31, 2010). WFL Publisher is located at Helsinki, Finland.\r\n\r\nAssociate Professor, Department of Agricultural Chemistry, National Taiwan University. (August, 1985 to July, 1989)\r\n\r\nNationality: Taiwan \r\n\r\nEducation\r\nPh.D. Graduate Institute of Agricultural Chemistry, Div. of Soils and Plant Nutrition, Taiwan, ROC, June, 1984.\r\n\r\nResaerch and Teaching Distinguished Awards\r\nDistinguished Social Service Award (2009), National Taiwan University\r\n\r\nDistinguished Teaching Professor Award (2004, Top 1%), National Taiwan University\r\n\r\nDistinguished Agricultural Experts Award (2007), KIWANI International-Taiwan Branch\r\n\r\nDistinguished Science Achievement Award (1998), Agricultural Association of China.\r\n\r\nDistinguished Science Achievement Award (1997), Chinese Society of Agricultural Chemistry.\r\n\r\nScience Research Award (1984-2010, 26 times), National Science Council, Taiwan.\r\n\r\nOutstanding Teaching Professor Award (2001-2002, 2010), Natioanl Taiwan University (Top 5% of all faculty members) \r\n\r\nVisiting Professor in 1996\r\nDepartment of Soil Science, North Carolina State University, Raleigh, NC. USA, 1996.\r\n\r\nDepartment of Crop and Soil Environmental Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA., USA. 1996. \r\n\r\nHonorable Presidents of Societies \r\nPresident, East and Southeastern Asian Federation of Soil Science Society (ESAFS) (2002-2003)\r\n\r\nPresident, The Chinese Society of Soil and Fertilizer Sciences (CSSFS) (2002-2006)\r\n\r\nPresident, Taiwan Association of Soil and Groundwater Environmental Protection (2003-2007)\r\n\r\nPresident, The Agricultural Chemical Society of Taiwan (ACST) (2005-2007) \r\n\r\nField of Experts \r\nSoil Morphology, pedogenic processes, and classification\r\n\r\nSoil remediation techniques on cultivated soils contaminated by heavy metals, especially on phytoremediation of trace elements.. \r\n\r\nEnhancing the methodology to establish the criteria and guidelines of soil quality, especially for heavy metals in soils.\r\n\r\nSoil nutrient dynamics of subtropical forest Ecosystem\r\n\r\nResearch\r\nSignificant Findings\r\nDemonstrated the soil morphological characteristics, properties, pedogenic processes and classification of different Soils Orders in Taiwan.\r\n\r\nDemonstrated the data base system and background concentrations of heavy metals in soils-plants system or polluted soils.\r\n\r\nEvaluated the remediation techniques tested in cultivated soils contaminated by heavy metals (cadmium and lead) and make recommendations for EPA.\r\n\r\nPhytoremediation of trace elements in Taiwan rural soils.\r\n\r\nEnhancing the methodology to establish the criteria and guidelines of soil quality, especially for heavy metals in soils.\r\n\r\nSoil nutrient dynamics of subtropical forest Ecosystem in south Taiwan. \r\n\r\nFuture Research Plans\r\nEvaluate the soil remediation technique for soil and sediment contaminated with heavy metals (cadmium, lead, copper, and zinc) or organic materials, especially on phytoremediation of trace elements.\r\n\r\nEvaluate the guidelines of soil quality or criteria in different land uses.\r\n\r\nEnhancing the understanding of genetic processes of cultivated soils (rice-growing soils) and high mountains forest soils, especially on the volcanic soils (Andisols), Ultisols, and Spodosols.\r\n\r\nSoil nutrient balance of agricultural long tern ecologyical site in Taiwan\r\n\r\nInternational Committee Members\r\nInternational Council Meeting Members of International Union of Soil Science (IUSS) (1998-2008)\r\n\r\nInternational Business Meeting Members of East and Southeastern Asian Federation of Soil Science Society (ESAFS) (1995-2009)\r\n\r\nInternational Steering and Auditing Committee Member on International Society for Biogeochemistry of Trace Elements (1997-2005)\r\n\r\nInternational Steering Committee Members on Soil Contamination Research in Asia and the Pacific (SCRAP) Network (1996-1999)\r\n\r\nInternational Organizing Committee Members on National Soil Reference Collections and Databases (NASREC) (ISRIC) (1996-1999)\r\n\r\nWho’s Who Award\r\nVIP members in 2006 MADISON Who’s Who of Executives and Professionals\r\n\r\nMADISON Who’s Who in 2005/2006\r\n\r\nMADISON Who’s Who in 2006/2007\r\n\r\n500 Distinguished Professors & Scholors of the BWW Society/IAPGS (Bibliotheque World Wide, 2004)\r\n\r\n500 GREAT MINDS of the Early 21st Century (Bibliotheque World Wide, 2002)\r\n\r\nMARQUIS Who’s Who in the World (1999 to 2009), 16th to 26th Edition, Marquis Who’s Who. \r\n\r\nProfile in Excellence: 500 Biographies of Inspiration, Dedication and Accomplishment (Bibliotheque World Wide, 2003)\r\n\r\nOutstanding People of the 20th Century Incorporating the Outstanding Achievement Awards (International Biographical Centre, England, 2000)\r\n\r\nThe ASIA 500 Leaders for the New Century (Barons Who’s Who, 2000)\r\n\r\nFive Hundred Leaders of Influence (The American Biographical Institute, 1999)\r\n\r\nServices to review paper submitted in the International Journals\r\nAnalytica Chimica ACTA\r\nAustralian J Soil Research\r\nAnnuals of Tropical Ecology\r\nAnalytica Chimica Acta\r\nArchieves of Environmental contamination and Toxicology (AECT)\r\nChemosphere\r\nCatena\r\nCompost Science & Utilization\r\nDesalination\r\nEnvironmental Science and Technology (ES&T)\r\nGeoderma\r\nGeomorphology\r\nForest Ecology and Management (FE&M)\r\nInternational Journal of Environment and Pollution\r\nInternational Journal of Environmental Analytical Chemistry\r\nInternational Journal of Phytoremediation\r\nEnvironmental Pollution\r\nJournal of Environmental Engineering\r\nJournal Scientia Agricola.\r\nJournal of Environmental Science (Chinese Academy Sciences)\r\nJournal of Environmental Management\r\nPaddy and Water Environment Journal\r\nPedosphere\r\nSoil Science\r\nSoil Science Society of America Journal (SSSAJ)\r\nTalanta\r\nToxicology and Industrial Health\r\nWater, Air, and Soil Pollution",institutionString:null,institution:{name:"National Chung Cheng University",institutionURL:null,country:{name:"Taiwan"}}},{id:"62015",title:"Mr.",name:"Horng-Yuh",surname:"Guo",slug:"horng-yuh-guo",fullName:"Horng-Yuh Guo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"77653",title:"Dr.",name:"Agnieszka",surname:"Rutkowska",slug:"agnieszka-rutkowska",fullName:"Agnieszka Rutkowska",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Institute of Soil Science and Plant Cultivation",institutionURL:null,country:{name:"Poland"}}},{id:"77736",title:"Dr",name:null,surname:"Han",slug:"han",fullName:"Han",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"79674",title:"Dr.",name:"Rui",surname:"Guo",slug:"rui-guo",fullName:"Rui Guo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Institute of Environment and Sustainable Development in Agriculture",institutionURL:null,country:{name:"China"}}},{id:"117438",title:"Dr.",name:"WeiPing",surname:"Hao",slug:"weiping-hao",fullName:"WeiPing Hao",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Institute of Environment and Sustainable Development in Agriculture",institutionURL:null,country:{name:"China"}}},{id:"117439",title:"Dr.",name:"DaoZhi",surname:"Gong",slug:"daozhi-gong",fullName:"DaoZhi Gong",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Institute of Environment and Sustainable Development in Agriculture",institutionURL:null,country:{name:"China"}}},{id:"117440",title:"Dr.",name:"XiuLi",surname:"Zhong",slug:"xiuli-zhong",fullName:"XiuLi Zhong",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Institute of Environment and Sustainable Development in Agriculture",institutionURL:null,country:{name:"China"}}},{id:"155825",title:"Dr.",name:"FengXue",surname:"Gu",slug:"fengxue-gu",fullName:"FengXue Gu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"156225",title:"Ph.D.",name:"Chun-Chih",surname:"Tsui",slug:"chun-chih-tsui",fullName:"Chun-Chih Tsui",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"National Taiwan University",institutionURL:null,country:{name:"Taiwan"}}}]},generic:{page:{slug:"terms-and-conditions",title:"Terms and Conditions",intro:'
These Terms and Conditions outline the rules and regulations pertaining to the use of IntechOpen’s website www.intechopen.com and all the subdomains owned by IntechOpen located at 5 Princes Gate Court, London, SW7 2QJ, United Kingdom.
',metaTitle:"Terms and Conditions",metaDescription:"These terms and conditions outline the rules and regulations for the use of IntechOpen Website at https://intechopen.com and all its subdomains owned by Intech Limited located at 7th floor, 10 Lower Thames Street, London, EC3R 6AF, UK.",metaKeywords:null,canonicalURL:"/page/terms-and-conditions",contentRaw:'[{"type":"htmlEditorComponent","content":"
1. Terms
\\n\\n
By accessing the website at www.intechopen.com you are agreeing to be bound by these Terms of Service, all applicable laws and regulations, and agree that you are responsible for compliance with any applicable local laws. Use and/or access to this site is based on full agreement and compliance of these Terms. All materials contained on this website are protected by applicable copyright and trademark laws.
\\n\\n
The following terminology applies to these Terms and Conditions, Privacy Statement, Disclaimer Notice, and any or all Agreements:
\\n\\n
“Client”, “Customer”, “You” and “Your” refers to you, the person accessing this website and accepting the Company’s Terms and Conditions;
\\n\\n
“The Company”, “Ourselves”, “We”, “Our” and “Us”, refers to our Company, IntechOpen;
\\n\\n
“Party”, “Parties”, or “Us”, refers to both the Client and ourselves, or either the Client or ourselves.
\\n\\n
All Terms refer to the offer, acceptance, and consideration of payment necessary to provide assistance to the Client in the most appropriate manner, whether by formal meetings of a fixed duration, or by any other agreed means, for the express purpose of meeting the Client’s needs in respect of provision of the Company’s stated services/products, and in accordance with, and subject to, the prevailing laws of the United Kingdom.
\\n\\n
Any use of the above terminology, or other words in the singular, plural, capitalization and/or he/she or they, are taken as interchangeable.
\\n\\n
2. License
\\n\\n
Unless otherwise stated, IntechOpen and/or its licensors own the intellectual property rights for all materials on www.intechopen.com. All intellectual property rights are reserved. You may view, download, share, link and print pages from www.intechopen.com for your own personal use, subject to the restrictions set out in these Terms and Conditions.
\\n\\n
3. Cookies
\\n\\n
We employ the use of cookies. By using the IntechOpen website you consent to the use of cookies in accordance with IntechOpen’s Privacy Policy. Most modern day interactive websites use cookies to enable the retrieval of user details for each visit. On our site, cookies are predominantly used to enable functionality and ease of use for those visiting the site.
\\n\\n
4. Limitations
\\n\\n
In no circumstances shall IntechOpen or its suppliers be liable for any damages (including, without limitation, damages for loss of data or profit, or due to business interruption) arising out of the use, or inability to use, the materials on IntechOpen's websites, even if IntechOpen or an IntechOpen authorized representative has been notified orally or in writing of the possibility of such damage. Some jurisdictions do not allow limitations on implied warranties, or limitations of liability for consequential or incidental damages; consequently, these limitations may not apply to you.
\\n\\n
5. Accuracy of Materials
\\n\\n
Intechopen.com website content and services are provided on an "AS IS" and an "AS AVAILABLE" basis. Material appearing on www.intechopen.com could include minor technical, typographical, or photographic errors. IntechOpen may make changes to any material contained on its website at any time without notice.
\\n\\n
6. Links
\\n\\n
IntechOpen has no formal affiliation to any external sites that link to www.intechopen.com, unless otherwise specifically stated. As such, it is not responsible for content that appears on any such sites. The inclusion of any link to IntechOpen does not imply endorsement by IntechOpen. Use of any such linked website is done solely at the user's own discretion.
\\n\\n
We reserve the right of ownership over our entire website www.intechopen.com, and all contents. By using our services, you agree to remove all links to our website immediately upon request. We also reserve the right to amend these Terms and Conditions and our linking policy at any time. By continuing to link to our website, you agree to be bound to, and abide by, these linking Terms and Conditions.
\\n\\n
If you find any link on our website, or any linked website, objectionable for any reason, please Contact Us. We will consider all requests to remove links but will have no obligation to do so.
\\n\\n
7. Frames
\\n\\n
Without prior approval and express written permission, you may not create frames around our web pages or use other techniques that alter in any way the visual presentation or appearance of our website.
\\n\\n
8. Modifications
\\n\\n
IntechOpen may revise its Terms of Service for its website at any time without notice. By using this website, you are agreeing to be bound by the current version of all Terms at the time of use.
\\n\\n
9. Governing Law
\\n\\n
These Terms and Conditions are governed by and construed in accordance with the laws of the United Kingdom and you irrevocably submit to the exclusive jurisdiction of the courts in London, United Kingdom.
\\n\\n
Croatian version of Terms and Conditions available here
By accessing the website at www.intechopen.com you are agreeing to be bound by these Terms of Service, all applicable laws and regulations, and agree that you are responsible for compliance with any applicable local laws. Use and/or access to this site is based on full agreement and compliance of these Terms. All materials contained on this website are protected by applicable copyright and trademark laws.
\n\n
The following terminology applies to these Terms and Conditions, Privacy Statement, Disclaimer Notice, and any or all Agreements:
\n\n
“Client”, “Customer”, “You” and “Your” refers to you, the person accessing this website and accepting the Company’s Terms and Conditions;
\n\n
“The Company”, “Ourselves”, “We”, “Our” and “Us”, refers to our Company, IntechOpen;
\n\n
“Party”, “Parties”, or “Us”, refers to both the Client and ourselves, or either the Client or ourselves.
\n\n
All Terms refer to the offer, acceptance, and consideration of payment necessary to provide assistance to the Client in the most appropriate manner, whether by formal meetings of a fixed duration, or by any other agreed means, for the express purpose of meeting the Client’s needs in respect of provision of the Company’s stated services/products, and in accordance with, and subject to, the prevailing laws of the United Kingdom.
\n\n
Any use of the above terminology, or other words in the singular, plural, capitalization and/or he/she or they, are taken as interchangeable.
\n\n
2. License
\n\n
Unless otherwise stated, IntechOpen and/or its licensors own the intellectual property rights for all materials on www.intechopen.com. All intellectual property rights are reserved. You may view, download, share, link and print pages from www.intechopen.com for your own personal use, subject to the restrictions set out in these Terms and Conditions.
\n\n
3. Cookies
\n\n
We employ the use of cookies. By using the IntechOpen website you consent to the use of cookies in accordance with IntechOpen’s Privacy Policy. Most modern day interactive websites use cookies to enable the retrieval of user details for each visit. On our site, cookies are predominantly used to enable functionality and ease of use for those visiting the site.
\n\n
4. Limitations
\n\n
In no circumstances shall IntechOpen or its suppliers be liable for any damages (including, without limitation, damages for loss of data or profit, or due to business interruption) arising out of the use, or inability to use, the materials on IntechOpen's websites, even if IntechOpen or an IntechOpen authorized representative has been notified orally or in writing of the possibility of such damage. Some jurisdictions do not allow limitations on implied warranties, or limitations of liability for consequential or incidental damages; consequently, these limitations may not apply to you.
\n\n
5. Accuracy of Materials
\n\n
Intechopen.com website content and services are provided on an "AS IS" and an "AS AVAILABLE" basis. Material appearing on www.intechopen.com could include minor technical, typographical, or photographic errors. IntechOpen may make changes to any material contained on its website at any time without notice.
\n\n
6. Links
\n\n
IntechOpen has no formal affiliation to any external sites that link to www.intechopen.com, unless otherwise specifically stated. As such, it is not responsible for content that appears on any such sites. The inclusion of any link to IntechOpen does not imply endorsement by IntechOpen. Use of any such linked website is done solely at the user's own discretion.
\n\n
We reserve the right of ownership over our entire website www.intechopen.com, and all contents. By using our services, you agree to remove all links to our website immediately upon request. We also reserve the right to amend these Terms and Conditions and our linking policy at any time. By continuing to link to our website, you agree to be bound to, and abide by, these linking Terms and Conditions.
\n\n
If you find any link on our website, or any linked website, objectionable for any reason, please Contact Us. We will consider all requests to remove links but will have no obligation to do so.
\n\n
7. Frames
\n\n
Without prior approval and express written permission, you may not create frames around our web pages or use other techniques that alter in any way the visual presentation or appearance of our website.
\n\n
8. Modifications
\n\n
IntechOpen may revise its Terms of Service for its website at any time without notice. By using this website, you are agreeing to be bound by the current version of all Terms at the time of use.
\n\n
9. Governing Law
\n\n
These Terms and Conditions are governed by and construed in accordance with the laws of the United Kingdom and you irrevocably submit to the exclusive jurisdiction of the courts in London, United Kingdom.
\n\n
Croatian version of Terms and Conditions available here
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{},profiles:[{id:"396",title:"Dr.",name:"Vedran",middleName:null,surname:"Kordic",slug:"vedran-kordic",fullName:"Vedran Kordic",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/396/images/7281_n.png",biography:"After obtaining his Master's degree in Mechanical Engineering he continued his education at the Vienna University of Technology where he obtained his PhD degree in 2004. He worked as a researcher at the Automation and Control Institute, Faculty of Electrical Engineering, Vienna University of Technology until 2008. His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. 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The literature source was Web of Science and SSCI, SCI-EXPANDED, A&HCI, CPCI-S, CPCI-SSH, and ESCI indexes. Fifty-two articles were reviewed; however, 14 of them were not been included in the study. As a result, 38 articles were examined. Level of education, field of education, and material types of AR used in education and reported educational advantages of AR have been investigated. All articles are categorized according to target groups, which are early childhood education, primary education, secondary education, high school education, graduate education, and others. AR technology has been mostly carried out in primary and graduate education. “Science education” is the most explored field of education. Mobile applications and marker-based materials on paper have been mostly preferred. The major advantages indicated in the articles are “Learning/Academic Achievement,” “Motivation,” and “Attitude”.",book:{id:"6543",slug:"state-of-the-art-virtual-reality-and-augmented-reality-knowhow",title:"State of the Art Virtual Reality and Augmented Reality Knowhow",fullTitle:"State of the Art Virtual Reality and Augmented Reality Knowhow"},signatures:"Rabia M. Yilmaz",authors:[{id:"225838",title:"Dr.",name:"Rabia",middleName:null,surname:"Yilmaz",slug:"rabia-yilmaz",fullName:"Rabia Yilmaz"}]},{id:"63639",doi:"10.5772/intechopen.81086",title:"Cooperative Learning: The Foundation for Active Learning",slug:"cooperative-learning-the-foundation-for-active-learning",totalDownloads:3417,totalCrossrefCites:17,totalDimensionsCites:24,abstract:"The role of instructors is evolving from the presenter of information to the designer of active learning processes, environments, and experiences that maximize student engagement. The more active a lesson, the more students tend to engage intellectually and emotionally in the learning activities. Cooperative learning is the foundation on which many of the active learning procedures are based. Cooperative learning is the instructional use of small groups so that students work together to maximize their own and each other’s learning. Most of the active learning procedures, such as problem-based learning, team-learning, collaborative learning, and PALS, require that students work cooperatively in small groups to achieve joint learning goals. Cooperative learning is based on two theories: Structure-Process-Outcome theory and Social Interdependence theory. Four types of cooperative learning have been derived: formal cooperative learning, informal cooperative learning, cooperative base groups, and constructive controversy. There is considerable research confirming the effectiveness of cooperative learning. To be cooperative, however, five basic elements must be structured into the situation: positive interdependence, individual accountability, promotive interaction, social skills, and group processing.",book:{id:"6929",slug:"active-learning-beyond-the-future",title:"Active Learning",fullTitle:"Active Learning - Beyond the Future"},signatures:"David W. Johnson and Roger T. Johnson",authors:[{id:"259976",title:"Dr.",name:"David",middleName:null,surname:"Johnson",slug:"david-johnson",fullName:"David Johnson"},{id:"263004",title:"Dr.",name:"Roger",middleName:null,surname:"Johnson",slug:"roger-johnson",fullName:"Roger Johnson"}]},{id:"59468",doi:"10.5772/intechopen.74344",title:"Virtual and Augmented Reality: New Frontiers for Clinical Psychology",slug:"virtual-and-augmented-reality-new-frontiers-for-clinical-psychology",totalDownloads:2337,totalCrossrefCites:13,totalDimensionsCites:21,abstract:"In the last decades, the applied approach for the use of virtual reality (VR) and augmented reality (AR) on clinical and health psychology has grown exponentially. These technologies have been used to treat several mental disorders, for example, phobias, stress-related disorders, depression, eating disorders, and chronic pain. The importance of VR/AR for the mental health field comes from three main concepts: (1) VR/AR as an imaginal technology, people can feel “as if they are” in a reality that does not exist in external world; (2) VR/AR as an embodied technology, the experience to feel user’s body inside the virtual environment; and (3) VR/AR as connectivity technology, the “end of geography’. In this chapter, we explore the opportunities provided by VR/AR as technologies to improve people’s quality of life and to discuss new frontiers for their application in mental health and psychological well-being promotion.",book:{id:"6543",slug:"state-of-the-art-virtual-reality-and-augmented-reality-knowhow",title:"State of the Art Virtual Reality and Augmented Reality Knowhow",fullTitle:"State of the Art Virtual Reality and Augmented Reality Knowhow"},signatures:"Sara Ventura, Rosa M. Baños and Cristina Botella",authors:[{id:"106036",title:"Dr.",name:"Rosa Maria",middleName:null,surname:"Baños",slug:"rosa-maria-banos",fullName:"Rosa Maria Baños"},{id:"227763",title:"Ph.D.",name:"Sara",middleName:null,surname:"Ventura",slug:"sara-ventura",fullName:"Sara Ventura"},{id:"229056",title:"Dr.",name:"Cristina",middleName:null,surname:"Botella",slug:"cristina-botella",fullName:"Cristina Botella"}]},{id:"58060",doi:"10.5772/intechopen.72341",title:"Pedagogy of the Twenty-First Century: Innovative Teaching Methods",slug:"pedagogy-of-the-twenty-first-century-innovative-teaching-methods",totalDownloads:8743,totalCrossrefCites:15,totalDimensionsCites:21,abstract:"In the twenty-first century, significant changes are occurring related to new scientific discoveries, informatization, globalization, the development of astronautics, robotics, and artificial intelligence. This century is called the age of digital technologies and knowledge. How is the school changing in the new century? How does learning theory change? Currently, you can hear a lot of criticism that the classroom has not changed significantly compared to the last century or even like two centuries ago. Do the teachers succeed in modern changes? The purpose of the chapter is to summarize the current changes in didactics for the use of innovative teaching methods and study the understanding of changes by teachers. In this chapter, we consider four areas: the expansion of the subject of pedagogy, environmental approach to teaching, the digital generation and the changes taking place, and innovation in teaching. The theory of education, figuratively speaking, has two levels. At the macro-level, in the “education-society” relationship, decentralization and diversification, internationalization of education, and the introduction of digital technologies occur. At the micro-level in the “teacher-learner” relationship, there is an active mix of traditional and innovative methods, combination of an activity approach with an energy-informational environment approach, cognition with constructivism and connectivism.",book:{id:"5980",slug:"new-pedagogical-challenges-in-the-21st-century-contributions-of-research-in-education",title:"New Pedagogical Challenges in the 21st Century",fullTitle:"New Pedagogical Challenges in the 21st Century - Contributions of Research in Education"},signatures:"Aigerim Mynbayeva, Zukhra Sadvakassova and Bakhytkul\nAkshalova",authors:[{id:"201997",title:"Dr.",name:"Aigerim",middleName:null,surname:"Mynbayeva",slug:"aigerim-mynbayeva",fullName:"Aigerim Mynbayeva"},{id:"209208",title:"Dr.",name:"Zukhra",middleName:null,surname:"Sadvakassova",slug:"zukhra-sadvakassova",fullName:"Zukhra Sadvakassova"},{id:"209210",title:"Dr.",name:"Bakhytkul",middleName:null,surname:"Akshalova",slug:"bakhytkul-akshalova",fullName:"Bakhytkul Akshalova"}]},{id:"64583",doi:"10.5772/intechopen.81714",title:"Evaluating a Course for Teaching Advanced Programming Concepts with Scratch to Preservice Kindergarten Teachers: A Case Study in Greece",slug:"evaluating-a-course-for-teaching-advanced-programming-concepts-with-scratch-to-preservice-kindergart",totalDownloads:1408,totalCrossrefCites:13,totalDimensionsCites:18,abstract:"Coding is a new literacy for the twenty-first century, and as a literacy, coding enables new ways of thinking and new ways of communicating and expressing ideas, as well as new ways of civic participation. A growing number of countries, in Europe and beyond, have established clear policies and frameworks for introducing computational thinking (CT) and computer programming to young children. In this chapter, we discuss a game-based approach to coding education for preservice kindergarten teachers using Scratch. The aim of using Scratch was to excite students’ interest and familiarize them with the basics of programming in an open-ended, project-based, and personally meaningful environment for a semester course in the Department of Preschool Education in the University of Crete. For 13 weeks, students were introduced to the main Scratch concepts and, afterward, were asked to prepare their projects. For the projects, they were required to design their own interactive stories to teach certain concepts about mathematics or physical science to preschool-age students. The results we obtained were more satisfactory than expected and, in some regards, encouraging if one considers the fact that the research participants had no prior experiences with computational thinking.",book:{id:"6936",slug:"early-childhood-education",title:"Early Childhood Education",fullTitle:"Early Childhood Education"},signatures:"Stamatios Papadakis and Michail Kalogiannakis",authors:null}],mostDownloadedChaptersLast30Days:[{id:"58060",title:"Pedagogy of the Twenty-First Century: Innovative Teaching Methods",slug:"pedagogy-of-the-twenty-first-century-innovative-teaching-methods",totalDownloads:8743,totalCrossrefCites:15,totalDimensionsCites:21,abstract:"In the twenty-first century, significant changes are occurring related to new scientific discoveries, informatization, globalization, the development of astronautics, robotics, and artificial intelligence. This century is called the age of digital technologies and knowledge. How is the school changing in the new century? How does learning theory change? Currently, you can hear a lot of criticism that the classroom has not changed significantly compared to the last century or even like two centuries ago. Do the teachers succeed in modern changes? The purpose of the chapter is to summarize the current changes in didactics for the use of innovative teaching methods and study the understanding of changes by teachers. In this chapter, we consider four areas: the expansion of the subject of pedagogy, environmental approach to teaching, the digital generation and the changes taking place, and innovation in teaching. The theory of education, figuratively speaking, has two levels. At the macro-level, in the “education-society” relationship, decentralization and diversification, internationalization of education, and the introduction of digital technologies occur. At the micro-level in the “teacher-learner” relationship, there is an active mix of traditional and innovative methods, combination of an activity approach with an energy-informational environment approach, cognition with constructivism and connectivism.",book:{id:"5980",slug:"new-pedagogical-challenges-in-the-21st-century-contributions-of-research-in-education",title:"New Pedagogical Challenges in the 21st Century",fullTitle:"New Pedagogical Challenges in the 21st Century - Contributions of Research in Education"},signatures:"Aigerim Mynbayeva, Zukhra Sadvakassova and Bakhytkul\nAkshalova",authors:[{id:"201997",title:"Dr.",name:"Aigerim",middleName:null,surname:"Mynbayeva",slug:"aigerim-mynbayeva",fullName:"Aigerim Mynbayeva"},{id:"209208",title:"Dr.",name:"Zukhra",middleName:null,surname:"Sadvakassova",slug:"zukhra-sadvakassova",fullName:"Zukhra Sadvakassova"},{id:"209210",title:"Dr.",name:"Bakhytkul",middleName:null,surname:"Akshalova",slug:"bakhytkul-akshalova",fullName:"Bakhytkul Akshalova"}]},{id:"61746",title:"Facilitation of Teachers’ Professional Development through Principals’ Instructional Supervision and Teachers’ Knowledge- Management Behaviors",slug:"facilitation-of-teachers-professional-development-through-principals-instructional-supervision-and-t",totalDownloads:3349,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"With the rise of global competition and the focus on teacher quality, teacher professional development is becoming increasingly crucial, and the stress and challenges for principals are more severe than ever. Teachers can improve their professional abilities through principals’ instructional supervision and their own knowledge-management (KM) behaviors to benefit students. Thus, this chapter analyzes the relationship among principals’ instructional supervision, teachers’ KM, and teachers’ professional development. The author believes that principals’ instructional supervision and effective KM can facilitate the professional development of teachers. The author also believes the readers can know the relationships among them, and teachers’ professional development can be improved through principal’s instructional supervision and teachers’ KM behaviors.",book:{id:"6674",slug:"contemporary-pedagogies-in-teacher-education-and-development",title:"Contemporary Pedagogies in Teacher Education and Development",fullTitle:"Contemporary Pedagogies in Teacher Education and Development"},signatures:"Chien-Chin Chen",authors:[{id:"232569",title:"Ph.D.",name:"Chien Chih",middleName:null,surname:"Chen",slug:"chien-chih-chen",fullName:"Chien Chih Chen"}]},{id:"75908",title:"From the Classroom into Virtual Learning Environments: Essential Knowledge, Competences, Skills and Pedagogical Strategies for the 21st Century Teacher Education in Kenya",slug:"from-the-classroom-into-virtual-learning-environments-essential-knowledge-competences-skills-and-ped",totalDownloads:501,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"As teachers in Kenya begin to migrate from the classroom to virtual learning spaces following COVID 19 pandemic, there is pressing need to realign Teacher Education to requisite Knowledge, competences, skills, and attitudes that will support online teaching. This chapter explores these needs using a combination of lived experiences and literature review that captured a meta-analysis of research trends on e-learning. While trends in Teacher Education indicate progression towards adoption of technology, there are disparities between the theory and practice. Evidence from recent research and reports; and the recollected experiences confirmed knowledge, competence, skills and pedagogical gaps in the implementation of online learning, that have been exacerbated by COVID-19. The researcher recommends that teacher education should sensitize and train teacher trainees on how to access, analyze and use new knowledge emerging with technology; they also should be coached on how learners learn with technology and on fundamentals of the communication process. Particularly the course on educational technology, should focus on how to create and manage online courses. The 5-stage E-Moderator Model and Universal Design for Learning (UDL) are recommended as effective pedagogical scaffold for online teaching.",book:{id:"10229",slug:"teacher-education-in-the-21st-century-emerging-skills-for-a-changing-world",title:"Teacher Education in the 21st Century",fullTitle:"Teacher Education in the 21st Century - Emerging Skills for a Changing World"},signatures:"Catherine Adhiambo Amimo",authors:[{id:"333482",title:"Dr.",name:"Catherine Adhiambo",middleName:null,surname:"Amimo",slug:"catherine-adhiambo-amimo",fullName:"Catherine Adhiambo Amimo"}]},{id:"75224",title:"Decoding the Digital Gap in Teacher Education: Three Perspectives across the Globe",slug:"decoding-the-digital-gap-in-teacher-education-three-perspectives-across-the-globe",totalDownloads:552,totalCrossrefCites:0,totalDimensionsCites:4,abstract:"Educational use of technology is regularly assessed, and results often show a gap between educational policies and what is actually practiced. This chapter will help clarify how teacher educators experience the changing educational contexts due to the digital revolution, how their meaning-making shifts, and how outside forces influence those processes. The results are based on comparative international studies. Central for this study is practitioners’ professional digital competence, their attitudes towards digital technology and the use of digital technology in education. We found that the influence and contribution of digital practice is carried out quite differently across the globe. Our research questions were: How do practitioners experience teaching in a rapidly changing context? How do attitudes change due to top-down governing of education? and What motivates teacher educators to implement digital technology?",book:{id:"10229",slug:"teacher-education-in-the-21st-century-emerging-skills-for-a-changing-world",title:"Teacher Education in the 21st Century",fullTitle:"Teacher Education in the 21st Century - Emerging Skills for a Changing World"},signatures:"Steinar Thorvaldsen and Siri Sollied Madsen",authors:[{id:"332624",title:"Associate Prof.",name:"Siri Sollied",middleName:null,surname:"Madsen",slug:"siri-sollied-madsen",fullName:"Siri Sollied Madsen"},{id:"332626",title:"Prof.",name:"Steinar",middleName:null,surname:"Thorvaldsen",slug:"steinar-thorvaldsen",fullName:"Steinar Thorvaldsen"}]},{id:"75416",title:"Self-Study Research: Challenges and Opportunities in Teacher Education",slug:"self-study-research-challenges-and-opportunities-in-teacher-education",totalDownloads:724,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This article aims to describe what self-study research is, why self-study can be a good approach to teacher educators’ professional development and improvements in practice and highlight some challenges and opportunities in this research approach. In addition, the article will shed light on some methodological aspects related to self-study. Self-study refers to teacher educators who in an intentionally and systematically way examine their practice to improve it, based on a deeper understanding of practice, as well as the context practice takes place. In the article, I argue that engaging in self-study is a learning and development process and an approach to developing personal professionalism, collective professionalism and improvements in practice.",book:{id:"10229",slug:"teacher-education-in-the-21st-century-emerging-skills-for-a-changing-world",title:"Teacher Education in the 21st Century",fullTitle:"Teacher Education in the 21st Century - Emerging Skills for a Changing World"},signatures:"Kåre Hauge",authors:[{id:"332053",title:"Associate Prof.",name:"Kåre",middleName:null,surname:"Hauge",slug:"kare-hauge",fullName:"Kåre Hauge"}]}],onlineFirstChaptersFilter:{topicId:"265",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81937",title:"Socialization Experiences among Undergraduate Students in Higher Learning Institutions (HLI)",slug:"socialization-experiences-among-undergraduate-students-in-higher-learning-institutions-hli",totalDownloads:19,totalDimensionsCites:0,doi:"10.5772/intechopen.99007",abstract:"This work portrays the problems of socialization among undergraduate students in higher learning institutions. The socialization processes in higher learning institution are significant for the successful navigation of students in the academic programs and university environment in preparing the next generation of professional practitioners and scholars. But the undergraduate student socialization experiences of students at university environment are overlooked. To navigate in the higher learning institutions, students should be socialized effectively to the normative contexts of the higher learning institutions. The normative contexts of the higher learning institutions are generally categorized into social and academic contexts, because these context academic and social context integration have been linked to student retention and success. Social integration involves interpersonal relationships, support, interactions with others, and a sense of belonging at a university, which stems from extracurricular activities, informal dealings with peer groups, and interactions with faculty and staff, whereas academic integration is described through grade performance and intellectual development that reflects an ability to meet the standards of the academic system; intellectual development involves a student valuing their education as a process of development in which they gain knowledge and ideas. Students’ background is also the contributing factor for students’ socialization in the University.",book:{id:"10911",title:"Higher Education - New Approaches to Accreditation, Digitalization, and Globalization in the Age of Covid",coverURL:"https://cdn.intechopen.com/books/images_new/10911.jpg"},signatures:"Mulusew Birhanu Ayalew"},{id:"80280",title:"Adoption of Online Learning during the Covid19 Pandemic Lockdown by Universities in Garowe",slug:"adoption-of-online-learning-during-the-covid19-pandemic-lockdown-by-universities-in-garowe",totalDownloads:87,totalDimensionsCites:0,doi:"10.5772/intechopen.99941",abstract:"In response to the Covid-19 outbreak the world closed and therefore countries like Somalia have not been exceptional. The government of Somalia and all higher education institutions adopted crisis intervention measures on implementation of blended learning approaches like online teaching and learning. In this chapter we explore the process and challenges of adopting online learning in response to the world wide lockdown due to the pandemic. Given that this was an abrupt requirement, the survey was interested in finding out whether universities adopted and adapted easily. Researchers compared findings from previous studies and theoretical inclinations on online learning. Results indicate that the adoption of online learning among universities in Garowe was as a matter of crisis management whereby administration, lecturers and students were all not ready and had no prior grounding in this pedagogical learning platform. Just like previous studies online learning implementers have continued to encounter several challenges like intermittent internet network, cost of gadgets and facilities, inadequate skills of both the instructors and students, aspects of communication and satisfaction from stakeholders. With the research survey in Garowe, results show that this is still pervading and therefore need for more rigorous contextualised research on this subject.",book:{id:"10911",title:"Higher Education - New Approaches to Accreditation, Digitalization, and Globalization in the Age of Covid",coverURL:"https://cdn.intechopen.com/books/images_new/10911.jpg"},signatures:"Tumwebaze Alicon Auf and Omer Abdi Hamdi"},{id:"78597",title:"Public-Private Participation in Funding University Education in Sub-Saharan Africa: A Nigerian Case-Study for Sustainable Development",slug:"public-private-participation-in-funding-university-education-in-sub-saharan-africa-a-nigerian-case-s",totalDownloads:132,totalDimensionsCites:0,doi:"10.5772/intechopen.99940",abstract:"The developing countries in Africa still cannot withstand the pressure of the highly competitive global education market. Together with the large numbers of people who make a living in various innovative companies, these countries have solved key contemporary issues affecting global education. For this reason, it is necessary to actively respond to current technological innovation and educational challenges and to eliminate new technology graduates who can effectively interact with students through the responsive expansion of education and training. Expansion of education can produce effective expansion that promotes educational development, but due to budget constraints, most African governments cannot successfully and sustainably implement such educational programs. This is difficult. However, public-private partnership efforts provide a way out of this financial dilemma. The Sub-Saharan Africa initiative has achieved important educational objectives, such as: ensuring relevance for quality; secure funding for sustainability and establish resource mobilization partnerships and connections; and promote international cooperation. This discussion is relevant to the basic conditions for a successful public-private partnership with educational institutions and extended education and sheds light on the impact, lessons, and challenges. The public is increasingly concerned about the importance of higher education in the 21st century. This chapter explores some of the key functions of an innovative education system that supports the development of education in Nigeria and enhances people’s ability to use information. Nigeria’s education system re-emphasizes the importance of public and private universities, but the country does not have a sustainable education system and well-equipped educational institutions to support people’s ability to use information, learning, education, and research activities.",book:{id:"10911",title:"Higher Education - New Approaches to Accreditation, Digitalization, and Globalization in the Age of Covid",coverURL:"https://cdn.intechopen.com/books/images_new/10911.jpg"},signatures:"Lawrence Jones-Esan"},{id:"79197",title:"University Teachers’ Conceptions of What University Is: Implications for the Future of Higher Education",slug:"university-teachers-conceptions-of-what-university-is-implications-for-the-future-of-higher-educatio",totalDownloads:107,totalDimensionsCites:0,doi:"10.5772/intechopen.100813",abstract:"This chapter presents the perception of university teachers about the university, the most recent changes and how they have influenced their activity. The phenomenographic study was conducted with 10 university teachers, nine females and one male with more than 15 years of professional activity. The perception of the university emerges, in the teachers’ voice, focused on the description of its mission, namely as a context for the production and diffusion of knowledge to society, as a space for creative and critical thinking about the world, as an interdisciplinary space and as a system focused on teaching and research. It also includes characteristics related to its structure and functioning, such as the level of hierarchization, bureaucratization, competitiveness, dehumanization and bibliometrics overvaluation. Regarding the perceived changes, they are related to the structural reforms resulting from the Bologna Process, diverse student populations, research and internationalization, new technologies, institutional cooperation, bureaucratization and relationship with the community. Teachers also revealed some dissatisfaction in the way they are experiencing university life due to the overwork resulting from the multiple tasks required in the four activity strands (teaching, research, management and extension) with an impact on quality and innovation, but in line with what the institution demands.",book:{id:"10911",title:"Higher Education - New Approaches to Accreditation, Digitalization, and Globalization in the Age of Covid",coverURL:"https://cdn.intechopen.com/books/images_new/10911.jpg"},signatures:"Elisa Chaleta"},{id:"78595",title:"Globalization and Education: Trends towards Sustainability",slug:"globalization-and-education-trends-towards-sustainability",totalDownloads:57,totalDimensionsCites:0,doi:"10.5772/intechopen.99974",abstract:"Higher Education Institutions (IES) have a very relevant role in the path towards sustainability. The problem of the implementation of curricular sustainability is the disparity of solutions that can be adopted depending on the political and economic situation of each country. The study of a practical case in the south of Honduras allows the student to approach key decisions in a real scenario to bring improvements to a very disadvantaged population, lacking basic services, such as water and electricity, under the premise of sustainability, facing aspects as relevant such as sustainable mobility, water resources management, energy and construction models, in a context where globalization and technological innovation play a very important role. It is essential to know in depth the real context where structural changes will be applied to understand that there is no single reality, that actions are built adapting to specific situations and that the effectiveness of the measures that can be adopted to establish models that prioritize that part of sustainability that best weighs the balance between the environment, society and the economy for each case.",book:{id:"10911",title:"Higher Education - New Approaches to Accreditation, Digitalization, and Globalization in the Age of Covid",coverURL:"https://cdn.intechopen.com/books/images_new/10911.jpg"},signatures:"Maria Olga Bernaldo and Gonzalo Fernandez-Sanchez"},{id:"79255",title:"Higher Education Institutions (HEIs) in Africa Embracing the “New Normal” for Knowledge Production and Innovation: Barriers, Realities, and Possibilities",slug:"higher-education-institutions-heis-in-africa-embracing-the-new-normal-for-knowledge-production-and-i",totalDownloads:127,totalDimensionsCites:1,doi:"10.5772/intechopen.101063",abstract:"If Africa is to remain relevant and competitive in today’s knowledge-based economy, it has to rely on higher education institutions (HEIs) as centers of excellence for knowledge production. HEIs nurture and sustain the production of highly-skilled individuals to support Africa’s growing economies. Among all possible ways, this could be achievable through strategic curricula innovation driven by emerging mobile technologies. Consequently, Africa’s HEIs need to embrace the ‘New Normal’ by optimizing online teaching and learning in their pursuit to expand information and communications technology (ICT) literacy as a means to increase students’ opportunities in higher education (HE). However, Africa’s ability to embrace the ‘New Normal’ has been marred by inadequate ICT infrastructures, low connectivity, unreliable power supply, and national budget constraints that may undermine Africa’s HEIs’ potential to augment knowledge production and innovation.",book:{id:"10911",title:"Higher Education - New Approaches to Accreditation, Digitalization, and Globalization in the Age of Covid",coverURL:"https://cdn.intechopen.com/books/images_new/10911.jpg"},signatures:"Christopher B. 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\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
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\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
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\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
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