Risk factors associated with asthma
\r\n\tThe purpose of the book is to bring together the latest knowledge about genetic diversity by presenting the studies of some of the scientists who are engaged in development of new tools and ideas used to reveal genetic diversity, often from very different perspectives. The book should prove useful to students, researchers and experts in the area of biology, medicine and agriculture.
",isbn:"978-1-80356-945-1",printIsbn:"978-1-80356-944-4",pdfIsbn:"978-1-80356-946-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"0b1e679fcacdec2448603a66df71ccc7",bookSignature:"Prof. Mahmut Çalışkan and Dr. Sevcan Aydin",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11643.jpg",keywords:"PCR Based Methods, Protein Based Methods, Sequencing, Conservation of Genetic Resources, Natural Variation, Molecular Markers, Genetic Manipulation in Animals, Resistance to Disease, Genetic Manipulation in Plants, Use of Microorganisms in Biotechnology, Genetic Differentiation, Gene Therapy and Gene Editing",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 7th 2022",dateEndSecondStepPublish:"June 16th 2022",dateEndThirdStepPublish:"August 15th 2022",dateEndFourthStepPublish:"November 3rd 2022",dateEndFifthStepPublish:"January 2nd 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"16 days",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Professor of genetics and molecular biology and Head of Biotechnology division at İstanbul University in Turkey whose main research areas include plant molecular genetics, microbial biotechnology and characterization and biotechnological use of halophilic archaeal strains.",coeditorOneBiosketch:"Associate Professor of Biotechnology Division in Department of Biology at Istanbul University in Turkey whose main research areas include genetics, environmental biotechnology and bioengineering.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"51528",title:"Prof.",name:"Mahmut",middleName:null,surname:"Çalışkan",slug:"mahmut-caliskan",fullName:"Mahmut Çalışkan",profilePictureURL:"https://mts.intechopen.com/storage/users/51528/images/system/51528.png",biography:"Mahmut Çalışkan is a Professor of Genetics and Molecular Biology in the Department of Biology, Biotechnology Division, Istanbul University, Turkey. 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It is a chronic inflammatory disorder of the airways in which many immunological cells play a role, including mast cells and eosinophils. In susceptible individuals, this inflammation causes symptoms which are usually associated with widespread variable airflow obstruction that is often reversible, either spontaneously or with treatment, and causes an associated airway hyperresponsiveness (AHR) to a variety of stimuli. The clinical features of asthma include dyspnea, wheezing and coughing.
During the last forty years there has been an increased understanding of the wide spectrum of this disease and as a result a number of effective treatments have been developed. Despite these advances, however, the mortality continues to increase and approximately 500 Canadians and 3500 Americans die each year from asthma. It remains a major cause of morbidity, as the leading cause of school absenteeism and the third leading cause of work absenteeism. The prevalence of asthma in North America has been on a constant rise over the last 25 years and it is estimated that currently over 3 million Canadians and 25 million Americans suffer from asthma. Worldwide the prevalence rates of asthma are rising on average by 50% each decade and developing a better understanding of the risk factors associated with this trend is critical. These may be broadly classified as either host genetic factors or environmental factors (Table 1).
\n\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
Atopy Gender Genetic predisposition Race/ethnicity | \n\t\t\t\t\t\tSmoking Allergens Occupational sensitizers Respiratory infections Parasitic infections Perinatal risk factors Diet and nutrition | \n\t\t\t\t\t
Risk factors associated with asthma
One of the marked risk factors of asthma associated with the westernized lifestyle is our changing diet and/or nutritional status. It has been hypothesized that the significant change in our diet plays a dominant role in the etiology of asthma. Seaton
Oxidative stress is important in the pathophysiology of asthma [2] and development of AHR [3]. A large number of epidemiologic studies have reported the protective effects of dietary antioxidants such as micronutrients vitamin A, C, and E, polyphenol, and carotenoids against the development of asthma and decline of lung function. In a study on American children higher levels of antioxidants beta-carotene and Vitamin C, along with antioxidant trace mineral selenium is associated with a lower risk of asthma [4]. Dietary vitamin C intake is positively associated with 1 Second Forced Expiratory Volume (FEV1) in children and adults [5-8] but less frequently with asthma or wheeze in children and adults [4, 9-11]. Dietary vitamin E intake is positively associated with ventilatory function [5, 6, 12] but negatively associated with asthma and wheeze in children [13], adult-onset wheeze [11] and the likelihood of atopic sensitization in adults [14]. Fresh fruits intake is inversely associated with wheeze [15] and chronic lung disease onset [16] and is positively associated with FEV1 [17]. Total fruit and vegetable intake is inversely related to asthma prevalence [18] but not to FEV1 [19] or airway obstruction [20]. Vegetables may protect against chronic bronchitis, asthma [21], and wheeze [22]. Moreover, dietary polyphenols intake are associated with lower disease risk with beneficial clinical outcomes attributed to both the antioxidants and anti-inflammatory properties of polyphenols [23]. Polyphenols consist of a large group of natural antioxidants extracted from plants and flavonoids comprise the most studied group.
In addition to antioxidants, intake of fats, particularly the changing composition of polyunsaturated fatty acids (PUFA) in westernized diets, has been implicated in the etiology of asthma. There has been a reduced intake of saturated fat accompanied by an increase in n-6 PUFA consumption, particularly linoleic acid and arachidonic acid. In addition, there has been a decrease in consumption of n-3 PUFA such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Thus, it has been postulated that the increased ratio of n-6:n-3 PUFA in diets of industrialized countries may also contributed to the increased asthma incidence.
Ancient Egyptian papyrus writings contain prescriptions for asthma that include several herbs suggesting that naturally occurring bioactive compounds may been used to effectively treat asthma. This chapter summarizes the current knowledge on the effects of dietary compounds and nutrients on allergy and asthma, with a focus on the mechanisms involved, wherever possible.
\n\t\tAirway inflammation in asthma is a complex process involving the interactions between immunological mediators produced by inflammatory cells such as mast cells, eosinophils, basophils, neutrophils, dendritic cells and lymphocytes [24]. This inflammation leads to structural and architectural changes in the airways of asthmatic patients including collagen and fibronectin deposition, wall thickening, subepithelial fibrosis and hypertrophy, goblet and airway smooth muscle cell hyperplasia, and angiogenesis, all of which collectively contribute to the phenomenon known as airway remodeling [25].
Allergic inflammation is often classified into four phases [26]:
\n\t\t\tInduction of allergic reaction involving antigen uptake, processing and presentation (Figure 1),
Early-phase asthmatic reaction (EAR, Figure 2),
Late-phase asthmatic reactions (LAR, Figure 3), and
Chronic allergic inflammation (Figure 4)\n\t\t\t\t\t
AHR and bronchial inflammation starts with the inhalation of an allergen. The allergen enters tissues through disrupted epithelium. It is then captured by antigen-presenting cells (APCs), usually dendritic cells (DCs), but also alveolar macrophages and B cells [
The EAR occurs within 30 min of allergen exposure and is principally initiated by mast cell and basophil activation [
The LAR typically develops 2-6 hr following allergen challenge, often peaks after 6-9 hr, and has a more severe and prolonged phase. In general, allergen activated mast cells release various
\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
Preformed Mediators | \n\t\t\t\t\t\tHistamine, heparin | \n\t\t\t\t\t\tIncrease vascular permeability, smooth muscle contraction | \n\t\t\t\t\t
Enzymes | \n\t\t\t\t\t\tTryptase, chymase, cathepsin G, carboxypeptidase | \n\t\t\t\t\t\tRemodel tissue matrix | \n\t\t\t\t\t
Cytokines | \n\t\t\t\t\t\tIL-4, IL-13 | \n\t\t\t\t\t\tStimulate Th2 cell response | \n\t\t\t\t\t
\n\t\t\t\t\t\t | IL-3, IL-5, GM-CSF | \n\t\t\t\t\t\tPromote eosinophil production and activation | \n\t\t\t\t\t
\n\t\t\t\t\t\t | Tumor necrosis factor (TNF) | \n\t\t\t\t\t\tPromotes inflammation and cytokine release by immune cells | \n\t\t\t\t\t
Chemokines | \n\t\t\t\t\t\tCCL2, CCL3, CCL4, CXCL1, CXCL2, CXCL3, CXCL10 | \n\t\t\t\t\t\tAttract monocytes, macrophages and neutrophils | \n\t\t\t\t\t
Lipid Mediators | \n\t\t\t\t\t\tProstaglandin D2, E2 Leukotriene B4, C4 | \n\t\t\t\t\t\tCause smooth muscle contraction, increase vascular permeability, stimulate mucus secretion | \n\t\t\t\t\t
\n\t\t\t\t\t\t | Platelet-activating factor | \n\t\t\t\t\t\tAttracts leukocytes, amplifies production of lipid mediators, activates neutrophils, eosinophils and platelets | \n\t\t\t\t\t
Mast cell-derived proinflammatory mediators
Inspite of the advances made in the field of asthma treatments, some patients remain less responsive to conventional therapies than others. Current treatment strategy includes the combinations of bronchodilators, particularly short or long acting β2-adrenergic agonists (SABA, LABA), and inhaled and oral corticosteroids. The current approach to the management of asthma includes the addition of drugs in a stepwise fashion based on the severity of symptoms, however the stronger drugs include more severe side effects. The treatment aims to reverse airflow obstruction and reduces asthma exacerbations thus improving quality of life. However, long-term use of high dose inhaled corticosteroids therapy may lead to detrimental effects, such as cataracts [46], osteoporosis in elderly patients [47], and stunting of growth in children [48]. Moreover, the combination therapy may not modify the disease progression and are not curative.
The limited efficacy and side effects associated with conventional treatments has lead to the introduction of nutraceuticals as a “safer“alternative therapy and for those whom symptoms are not improved with current therapies. Nutraceuticals is a very general term which encompasses many classifications of food products and derivatives that have the potential to either prevent or treat pathological conditions in humans or animals. For example, micronutrients such as vitamins and minerals and non-nutritive components of plant products such as polyphenols have some anti-inflammatory activity and have been used to supplement some foods to improve their health benefits. Table 3 summarizes some of the major nutraceuticals used to treat allergy and asthma currently.
The following sections discuss the current knowledge on the effects of nutraceuticals on inflammation associated with asthma with a focus on the cellular and molecular mechanism involved.
\n\t\t\tAnti-mediator agents are a group of drugs that antagonize the release of granule-associated preformed mediators, lipid mediators, cytokines, chemokines, and growth factors released by allergen-activated inflammatory cells. Several important groups of specific inhibitors against many of these inhibitors have been developed.
\n\t\t\t\tMontelukast is a current FDA approved drug used in asthma treatment and serves a prototypical drug for Lipid Mediator Blocking class of drugs. Its mechanism of actions works through the blocking of the CysLT receptor for leukotriene D4 which reduces bronchoconstriction and inflammation. Zileuton, a related drug in the same class, is a 5-lipoxygenase inhibitor which blocks the synthesis of cysLTs and leukotriene B4. These drugs while not natural products serve as a models in the search for nutraceuticals whom may share same or related mechanism of action and therefore may prove useful in asthma management. Antagonists of the prostaglandin D2 receptors DP1 and CRTH2 reduce inflammation in a murine model of asthma, possibly by inhibiting prostaglandin synthesis [49, 50]. Antagonist of the leukotriene B4 receptor BLT1 (R05101576) prevents airway inflammation and AHR in animal models and non-human primates [51]. Quercetin and luteolin, flavonoids found in fruits, vegetables and wine, inhibit the release of leukotrienes and PGD
Some of the dietary nutraceuticals indicated in asthma prevention.
Phytochemical inhibitors of lipid mediators
Cytokines exhibit pleiotropy and have overlapping functions in the pathogenesis of asthma, making them a major target for new asthma therapies. Allergic inflammation is driven by an imbalance between Th1 and Th2 cytokines, favoring the Th2 arm of the immune response and inhibition of Th2 cytokines IL-4, IL-5 and IL-13 prevents asthma progression in animal models. Anti-IL-4 administration in mice prevents development of acute and chronic allergic inflammation [53], therefore, natural products that specifically target cytokines or their receptors have the potential to be effective asthma treatments.
Our current pharmacological approach include the use humanized monoclonal antibodies against specific cytokine or receptor targets. This class of drugs, known as the biologics, has been approved for use in treatment of cancer, autoimmune and inflammatory diseases. Omalizumab is a drug currently approved for the management of asthma and is antibody targeting IgE. While not specifically a cytokine blocker it functions through the same mechanism of action. These drugs while very effective carry the risk of unforeseen side effects and under current production treatment costs remain very high ranging upwards from $15,000 to 60,000 per annum. Others examples including humanized IL-4-specific antibodies that block IL-4 receptor α that are under clinical trial [54]. Neutralizing antibodies against IL-5 (Mepolizumab and Reslizumab) and IL-5 receptor α (MEDI-563) remarkably inhibits IL-5 related pathways resulting in reduction of asthma exacerbations [55]. Tralokinumab, an anti-IL-13 monoclonal antibody, prevents the development of asthmatic phenotype, both in murine model as well asthmatic patients [56]. Suplatast tosilate inhibits IL-4 and IL-5 production from T cells and reduces AHR in asthmatic patients.
Some of the phytochemicals and potential treatments indicated against cytokines function are listed in Table 5. These products if proved to be effective, could be cost effective alternatives and being natural products have the potential to have less side effects.
\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t
Vitamin A | \n\t\t\t\t\t\t\t\tInhibits release of Th2 cytokines IL-4, IL-5 and IL-13 | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t |
Vitamin C | \n\t\t\t\t\t\t\t\tEffect on Th1/Th2 balance controversial. | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t |
Vitamin E | \n\t\t\t\t\t\t\t\tInhibits IL-1β, IL-6 and TNF response of human monocytes in asthmatic patients. Suppresses IL-4 levels in lungs of experimental allergic mice. | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t |
\n\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t |
Apigenin | \n\t\t\t\t\t\t\t\tReduces airway inflammation by down-regulating Th2 cytokines IL-4 and IL-13. Suppresses the expression of Th2 cytokines (IL-4, IL-13 and IL-5) in human basophils. Inhibits production of TNF, IL-6 and GM-CSF in HMC-1 cells. | \n\t\t\t\t\t\t\t\t[57, 58] | \n\t\t\t\t\t\t\t
Baicalein | \n\t\t\t\t\t\t\t\tDecreases inflammatory cytokines such as TNF and IL-6 in allergic inflammation. Inhibits production of IL-6 in activated human mast cells, and GM-CSF from human cultured mast cells. | \n\t\t\t\t\t\t\t\t[52, 59] | \n\t\t\t\t\t\t\t
Bicalin | \n\t\t\t\t\t\t\t\tReduces TNF and IL-6 levels in plasma and BALF in cigarette smoke-induced COPD rat model. | \n\t\t\t\t\t\t\t\t[60] | \n\t\t\t\t\t\t\t
Chrysin | \n\t\t\t\t\t\t\t\tDownregulates IL-4 and IL-13 expression and production in allergen-sensitized mice. Inhibits TNF, IL-1β, IL-4 and IL-6 expression in RBL-2H3 and HMC-1 cells. | \n\t\t\t\t\t\t\t\t[61] | \n\t\t\t\t\t\t\t
Chrysol | \n\t\t\t\t\t\t\t\tInhibits IL-4 production in antigen-stimulated RBL-2H3 cells. | \n\t\t\t\t\t\t\t\t[62] | \n\t\t\t\t\t\t\t
Daidzein | \n\t\t\t\t\t\t\t\tMast cell stabilizer; inhibits Th2 cytokines production. | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t |
Fisetin | \n\t\t\t\t\t\t\t\tInhibits IL-13 production in RBL-2H3 cells, and TNF, IL-6, IL-4 and IL-1β production in HMC-1 cells. Suppresses the expression of Th2 cytokines (IL-4, IL-13 and IL-5)in human basophils. Attenuates LPS-induced TNF, IL-6 and IL-10 release in leukocytes of patients with COPD. | \n\t\t\t\t\t\t\t\t[57, 63-65] | \n\t\t\t\t\t\t\t
Genistein | \n\t\t\t\t\t\t\t\tInhibits TNF production in PBMCs from asthmatic patients. | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t |
Ginkgetin | \n\t\t\t\t\t\t\t\tInhibits TNF expression in activated macrophages. | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t |
Isoliquiritigenin | \n\t\t\t\t\t\t\t\tInhibits the release of TNF and IL-6 in activated inflammatory cells. | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t |
Kaempferol | \n\t\t\t\t\t\t\t\tImpairs Th2 cytokines production (IL-5 and IL-13) in OVA-sensitized mice. Suppresses the release of IL-4 and TNF in RBL-2H3 cells and macrophages. Inhibits IgE-mediated TNF and IL-6 release in hCBMCs. | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t |
Kuraridin | \n\t\t\t\t\t\t\t\tSuppresses expression of TNF and IL-1β in LPS-stimulated macrophages (40 μM). | \n\t\t\t\t\t\t\t\t[66] | \n\t\t\t\t\t\t\t
Kurarinone | \n\t\t\t\t\t\t\t\tSuppresses expression of TNF and IL-1β in LPS-stimulated macrophages (40 μM). | \n\t\t\t\t\t\t\t\t[66] | \n\t\t\t\t\t\t\t
Luteolin | \n\t\t\t\t\t\t\t\tReduces the levels of TNF and IL-1β in LPS-stimulated macrophages (8 & 16 μM). Inhibits induction of TNF, IL-6 and GM-CSF in HMC-1 cells (10 & 50 μM). Inhibits Th2 cytokines (IL-4, IL-5 and IL-13) expression in murine asthma model (50 & 100 mg/kg body wt.). Inhibits myelin basic protein-induced IL-6, TGF-β1, and TNF release in hCBMCs (10 & 100 μM). Decreases TNF (IC50 7.9±4.6 μM) and IL-1β (IC50 5.1±0.4 μM) in PBMCs. Reduces IL-4 and IL-5 levels in BALF of murine asthma model (0.1 mg/kg body wt.). Inhibits antigen-IgE-mediated TNF (IC50 5.8 μM) and IL-4 (IC50 3.7 μM) production in RBL-2H3 cells. | \n\t\t\t\t\t\t\t\t[57, 67-73] | \n\t\t\t\t\t\t\t
Morin | \n\t\t\t\t\t\t\t\tInhibits IgE-mediated TNF and IL-6 release in hCBMCs (10 & 100 μM). Inhibits TNF secretion in LPS-activated macrophages. | \n\t\t\t\t\t\t\t\t[74, 75] | \n\t\t\t\t\t\t\t
Myricetin | \n\t\t\t\t\t\t\t\tInhibits TNF (30 μM) and IL-6 (30 μM) production in HMC-1 cells. Inhibits IgE-mediated TNF (10 & 100 μM) and IL-6 (1, 10 & 100 μM) release from hCBMCs. | \n\t\t\t\t\t\t\t\t[75, 76] | \n\t\t\t\t\t\t\t
Naringenin | \n\t\t\t\t\t\t\t\tSuppresses Th2 cytokines production from CD4 T cells (0.8 mg/kg body wt.). Reduces IL-4 (25, 50 & 100 mg/kg body wt.) and IL-13 (50 & 100 mg/kg body wt.) levels in BALF of murine asthma model. Suppresses LPS-induced IL-1β (10, 25 & 50 μg/mL), IL-6 (5, 10, 25 & 50 μg/mL), and TNF (25 & 50 μg/mL) production in macrophages and human whole-blood samples. | \n\t\t\t\t\t\t\t\t[77-79] | \n\t\t\t\t\t\t\t
Pedalitin | \n\t\t\t\t\t\t\t\tInhibits TNF and IL-12 production in LPS-activated macrophages (40 μM). | \n\t\t\t\t\t\t\t\t[80] | \n\t\t\t\t\t\t\t
Quercetin | \n\t\t\t\t\t\t\t\tInhibits IgE-mediated TNF (10 & 100 μM) and IL-6 (1, 10 & 100 μM) release from hCBMCs. | \n\t\t\t\t\t\t\t\t[75] | \n\t\t\t\t\t\t\t
Resveratrol | \n\t\t\t\t\t\t\t\tInhibits increase in Th2 cytokines (IL-4 and IL-5) in plasma and BALF in asthmatic mouse model (30 mg/kg body wt.). Inhibits TNF induced GM-CSF and VEGF release in HASM cells. Inhibits PMA- and A23187-induced TNF and IL-6 release in HMC-1 cells. Decreases production of IL-1β in lung tissue of mice with LPS-induced acute lung injury (1 mg/kg body wt.). Attenuates C5a-induced TNF, IL-1β and IL-6 production in mouse model (10 mg/kg body wt.). | \n\t\t\t\t\t\t\t\t[68, 81-86] | \n\t\t\t\t\t\t\t
Scutellarein | \n\t\t\t\t\t\t\t\tInhibits TNF and IL-12 production in LPS-activated macrophages (40 μM). | \n\t\t\t\t\t\t\t\t[80] | \n\t\t\t\t\t\t\t
Silibinin | \n\t\t\t\t\t\t\t\tPolarizes Th1/Th2 balance towards Th1 by increasing IFN-γ (200 & 400 mg/kg body wt.) and decreasing IL-4 levels (200 & 400 mg/kg body wt.) in asthmatic mouse model. | \n\t\t\t\t\t\t\t\t[87] | \n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t |
Caffeic acid | \n\t\t\t\t\t\t\t\tInhibits increase in TNF and Th2 cytokines (IL-4 and IL-5) in BALF in asthmatic mouse model (10 mg/kg body wt. IP). Inhibits IL-10 expression in allergic patients’ DCs (10 μM). Suppresses TNF and IL-6 levels in asthmatic patients (13% solution). | \n\t\t\t\t\t\t\t\t[88-90] | \n\t\t\t\t\t\t\t
Curcumin | \n\t\t\t\t\t\t\t\tAttenuates the expression of IL-4 and IL-5 in BALF in asthmatic mouse model (20 mg/kg body wt.). Inhibits release of IL-10, TNF and IL-1β in HDM-activated eosinophils and bronchial epithelial cells (10 μM). Inhibits IL-5, GM-CSF and IL-4 production in lymphocytes from bronchial asthmatics (10 μM). Inhibits TNF secretion in activated HMC-1 cells (10 & 100 μM/L). Inhibits tryptase-induced IL-6 release in eosinophils (25 μM). | \n\t\t\t\t\t\t\t\t[91-95] | \n\t\t\t\t\t\t\t
EGCG | \n\t\t\t\t\t\t\t\tReduces TNF in BALF in asthmatic guinea pigs (25 mg/kg body wt. SC). Inhibits TNF and IL-6 production in HMC-1 cells (100 μM). Attenuates production of TNF in lungs of mice with LPS-induced acute lung injury (10 mg/kg body wt. IP). | \n\t\t\t\t\t\t\t\t[96-99] | \n\t\t\t\t\t\t\t
Eugenol | \n\t\t\t\t\t\t\t\tInhibits IL-1β, TNF and IL-6 release in macrophages. | \n\t\t\t\t\t\t\t\t[100, 101] | \n\t\t\t\t\t\t\t
Gallic acid | \n\t\t\t\t\t\t\t\tInhibits TNF and IL-6 in HMC-1 cells (10 μM). | \n\t\t\t\t\t\t\t\t[102] | \n\t\t\t\t\t\t\t
Gingerol | \n\t\t\t\t\t\t\t\tInhibits IL-1β and IL-12 release in peritoneal macrophages 100 ng/mL) | \n\t\t\t\t\t\t\t\t[103] | \n\t\t\t\t\t\t\t
Hydroxytyrosol | \n\t\t\t\t\t\t\t\tInhibits LPS-induced TNF production in THP-1 cells (25, 50 & 100 μM). Reduces TNF levels in LPS-treated mice. | \n\t\t\t\t\t\t\t\t[104, 105] | \n\t\t\t\t\t\t\t
Rosmarinic acid | \n\t\t\t\t\t\t\t\tReduces IL-4, IL-5 and IL-13 expression in lung of HDM-sensitized asthmatic mouse model (1.5 mg/day PO). Attenuates IL-1β, IL-6, and TNF increase in spleen and nasal mucosa of asthmatic mouse model (4 mg/kg body wt.). Inhibits IL-4 and IFN-γ release from CD4+ T cells (1 & 5 μM). Inhibits diesel exhaust particles-induced IL-1β expression in mice lung (4.6 μg/kg body wt.). | \n\t\t\t\t\t\t\t\t[106-110] | \n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t |
Celastrol | \n\t\t\t\t\t\t\t\tReduced mRNA expression of IL-5, IL-5, IL-13, TNF, and IFN-γ in BAL cells and lung tissue of asthmatic mouse model. | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t |
Costunolide | \n\t\t\t\t\t\t\t\tInhibits production of TNF, IL-1β and IL-6 by LPS-stimulated macrophages (0.1, 0.5 & 1 μM). | \n\t\t\t\t\t\t\t\t[111, 112] | \n\t\t\t\t\t\t\t
Helenalin | \n\t\t\t\t\t\t\t\tInhibits TNF and IL-6 secretion by ASMCs (1 μM). | \n\t\t\t\t\t\t\t\t[113] | \n\t\t\t\t\t\t\t
n-3 PUFA | \n\t\t\t\t\t\t\t\tEPA and DHA Lower BALF concentration of pro-inflammatory cytokines IL-1α, IL-2, IL-5, IL-9, IL-13, G-CSF and RANTES. EPA (120 μM) suppress TNF and IL-1β expression and production in LPS-stimulated alveolar macrophages from asthmatic patients | \n\t\t\t\t\t\t\t\tRef? | \n\t\t\t\t\t\t\t
Phytochemical inhibitors of proinflammatory cytokines
Chemokines (CC) and their receptors (CCR) play a crucial role in the recruitment of inflammatory cells into the airways and development of asthma. CC-chemokine receptor 3 CCR3, CCR4, and CRTH2 antagonists are being targets currently being evaluated for the treatment of asthma. A study found that treatment of asthmatic mice with an anti-CCR3 monoclonal antibody inhibits allergen-induced eosinophilia and CD34+ progenitor cell infiltration into the lung, which is accompanied by reduced AHR [114, 115]. RS-1748, a CCR4 antagonist, inhibits OVA-induced airway inflammation in guinea pigs [116]. The number of CCR4-expressing Th2 cells is increased in the airways of asthmatic patients which can be blocked by a selective CCR4 antagonist [117], and therefore could be an effective therapy for asthma. Ramatroban and closely related TM30089 are antagonists for CRTH2, a chemokine receptor expressed on Th2 cells. They have been shown to attenuate allergen-induced EAR and LAR in animal models of asthma [118, 119]. Some of the phytochemicals indicated against chemokines function are listed in Table 6.
\n\t\t\t\t\n\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t
Apigenin | \n\t\t\t\t\t\t\tSuppresses the production of MDC and IP-10 in THP-1 cells (10-6 and 10-5 M). Inhibits release of LPS-induced MCP-1 in J774.2 macrophages (10 & 30 μM). Inhibits production of IL-8 in HMC-1 cells. | \n\t\t\t\t\t\t\t[58, 120, 121] | \n\t\t\t\t\t\t
Baicalein | \n\t\t\t\t\t\t\tInhibits IL-8 and MCP-1 release in activated human mast cells. Inhibits eotaxin production in human dermal fibroblasts (10 μg/mL). | \n\t\t\t\t\t\t\t[59, 122] | \n\t\t\t\t\t\t
Baicalin | \n\t\t\t\t\t\t\tReduces IL-8 levels in plasma and BALF in cigarette smoke-induced COPD rat model. Inhibits eotaxin production in human dermal fibroblasts (10 μg/mL). | \n\t\t\t\t\t\t\t[60, 122] | \n\t\t\t\t\t\t
Chrysin | \n\t\t\t\t\t\t\tInhibits TNF-induced IL-8 expression in HEK 293 cells (20, 40 & 80 μM). | \n\t\t\t\t\t\t\t[123] | \n\t\t\t\t\t\t
Chrysol | \n\t\t\t\t\t\t\tInhibits MCP-1 production in antigen-stimulated RBL-2H3. | \n\t\t\t\t\t\t\t[62] | \n\t\t\t\t\t\t
Fisetin | \n\t\t\t\t\t\t\tInhibits TNF-induced IL-8 expression in HEK 293 (20, 40 & 80 μM). Inhibits IL-8 production in HMC-1 cells. | \n\t\t\t\t\t\t\t[65, 123] | \n\t\t\t\t\t\t
Genistein | \n\t\t\t\t\t\t\tBlocks HDM-induced IL-8 release in human lung epithelial cells (50 μM). Inhibits IL-8 release in TNF-stimulated human keratinocytes (60 μM). Inhibits chemokine-stimulated eosinophil adherence (10-7, 10-6 and 10-5 M). | \n\t\t\t\t\t\t\t[124-126] | \n\t\t\t\t\t\t
Isoliquiritigenin | \n\t\t\t\t\t\t\tInhibits eotaxin-1 secretion in human fetal lung fibroblasts (IC50 0.92±0.05 μg/mL). | \n\t\t\t\t\t\t\t[127] | \n\t\t\t\t\t\t
Kaempferol | \n\t\t\t\t\t\t\tSuppresses LPS-induced production of MDC, IP-10 and IL-8 in THP-1. Inhibits MCP-1 production in antigen-stimulated RBL-2H3 and J774.2 macrophages (10 & 30 μM). Inhibits TNF-induced IL-8 expression in HEK 293 (20, 40 & 80 μM). | \n\t\t\t\t\t\t\t[62, 123, 128, 129] | \n\t\t\t\t\t\t
Kuraridin | \n\t\t\t\t\t\t\tSuppresses expression of MCP-1 in LPS-stimulated macrophages (40 μM). | \n\t\t\t\t\t\t\t[66] | \n\t\t\t\t\t\t
Kurarinone | \n\t\t\t\t\t\t\tInhibits MCP-1-induced chemotaxis of THP-1 cells (IC50 19.2 µg/mL). Suppresses expression of MCP-1 in LPS-stimulated macrophages (40 μM). | \n\t\t\t\t\t\t\t[130] | \n\t\t\t\t\t\t
Luteolin | \n\t\t\t\t\t\t\tInhibits TNF-induced expression of MCP-1 (10, 20 & 30 μM) and CXCL-1 (20 & 30 μM) expression in keratinocytes. Inhibits induction of IL-8 in activated HMC-1 cells (50 μM) and hCBMCs. | \n\t\t\t\t\t\t\t[70, 131, 132] | \n\t\t\t\t\t\t
Morin | \n\t\t\t\t\t\t\tInhibits IL-8 production in antigen-stimulated hCBMCs (100 μM). | \n\t\t\t\t\t\t\t[75] | \n\t\t\t\t\t\t
Myricetin | \n\t\t\t\t\t\t\tInhibits IL-8 production in antigen-stimulated hCBMCs (100 μM). | \n\t\t\t\t\t\t\t[75] | \n\t\t\t\t\t\t
Naringenin | \n\t\t\t\t\t\t\tDecreases secretion of PMA-induced IL-8 in HL-60 cells (20 μM). Suppresses LPS-induced IL-8 production by macrophages and human whole-blood samples (25 & 50 μg/mL). Inhibits expression of RANTES and eotaxin-1 in BALF and lungs in asthmatic mouse model (50 & 100 mg/kg body wt.). | \n\t\t\t\t\t\t\t[78, 79, 133] | \n\t\t\t\t\t\t
Quercetin | \n\t\t\t\t\t\t\tDecreases production of IL-8 (3 & 30 μM) and MCP-1 (10-4, 10-5 and 10-6 M) in activated HMC-1 and IL-8 in human bronchial epithelial cells (0.1, 10 & 25 μM). | \n\t\t\t\t\t\t\t[134-136] | \n\t\t\t\t\t\t
Resveratrol | \n\t\t\t\t\t\t\tDecreases production of MIP-1α in lung tissue of mice with LPS-induced acute lung injury (10 mg/kg body wt.). Reduces TNF-induced IL-8 release in HASMCs in COPD. Inhibits IFNγ-induced production of IP-10 and MIG in macrophages and HMC-1 cells. Inhibits IL-8 production in THP-1 cells (0.1, 1, 10 & 100 μg/mL). Attenuates C5a-induced MIP-1α production in mouse model (1 mg/kg body wt.). | \n\t\t\t\t\t\t\t[68, 82, 83, 85, 86, 137] | \n\t\t\t\t\t\t
Tectorigenin | \n\t\t\t\t\t\t\tInhibits MCP-1 expression in endothelial cells. | \n\t\t\t\t\t\t\t[138] | \n\t\t\t\t\t\t
Wogonin | \n\t\t\t\t\t\t\tSuppresses mite antigen-induced TARC expression in human keratinocytes (250 ng/mL). | \n\t\t\t\t\t\t\t[139] | \n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t |
Caffeic acid | \n\t\t\t\t\t\t\tDecreases IL-8 release in chitinase-activated human airway epithelial cells (1 μM). Inhibits production of eotaxin in human lung fibroblast cells (1, 10 & 100 μM). Inhibits IP-10 expression in allergic patients’ DCs (10 μM). Decreases expression of CXCR4 receptor on CD4 T cells (20 μg/mL). Suppresses IL-8 levels in asthmatic patients (13% soln.). | \n\t\t\t\t\t\t\t[89, 90, 140-143] | \n\t\t\t\t\t\t
Curcumin | \n\t\t\t\t\t\t\tInhibits tryptase-induced IL-8 release in eosinophils (25 μM). | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t |
EGCG | \n\t\t\t\t\t\t\tInhibits IL-8 release in TNF-stimulated human keratinocytes (0.5, 1, 5 & 10 μM). Reduces airway inflammation in asthmatic mouse model by binding to chemokines CXCL9, CXCL10 and CXCL11 (10 & 100 μM). Decreases MCP-1 and CCR2 expression on THP-1 cells (100 μM). Attenuates production of MIP-2 in lungs of mice with LPS-induced acute lung injury. Reduces expression of MCP-1 and IL-8 in HMC-1 cells (100 μM). Inhibits neutrophil migration by suppression of CINC-1 production (15, 50 & 150 μg/mL). Downregulates cigarette smoke-induced IL-8 release from bronchial epithelial cells. | \n\t\t\t\t\t\t\t[97, 99, 125, 144-147] | \n\t\t\t\t\t\t
Gallic acid | \n\t\t\t\t\t\t\tInhibits production of IL-8 and TARC (5 & 10 μg/mL) in neutrophils and keratinocytes respectively. Inhibits eotaxin and RANTES in pleural lavage fluid of allergen-challenged mouse model (100 mg/kg body wt.). Inhibits IL-8 release in HMC-1 cells (10 μM). | \n\t\t\t\t\t\t\t[148-150] | \n\t\t\t\t\t\t
Rosmarinic acid | \n\t\t\t\t\t\t\tInhibits LPS-induced production of MCP-1 and MIP-1α in bone-marrow derived DCs (100 μM). Reduces diesel exhaust particles-induced MIP-1α, MCP-1 and KC expression in mice lung (4.6 μg/kg body wt.). Inhibits expression of eotaxin in lungs of mite antigen-sensitized mice (1.5 mg/kg body wt. PO). Inhibits expression of CCL11 and CCR3 genes induced by TNF in human dermal fibroblast cells. | \n\t\t\t\t\t\t\t[102, 107, 110, 151] | \n\t\t\t\t\t\t
Helenalin | \n\t\t\t\t\t\t\tInhibits eotaxin and RANTES secretion in ASMCs (1 μM). | \n\t\t\t\t\t\t\t[113] | \n\t\t\t\t\t\t
Phytochemical inhibitors of chemokines
The activation of mast cells involves the cross-linking of IgE bound to the FCεRI surface receptor. Activation is measured in the laboratory by the release of the Beta-hexosaminidase enzyme (β-hex) from cytosolic granules into the interstitial fluid. The following compounds (Table 7) have been found to be inhibitors of β-Hex release in vitro and have to potential to be inhibitor of IgE-antigen activation.
\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t |
Vitamin A/carotenoid | \n\t\t\t\t\t\t\t\t? | \n\t\t\t\t\t\t\t\t[152] | \n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t |
Apigenin | \n\t\t\t\t\t\t\t\t4.5 μM | \n\t\t\t\t\t\t\t\t[153] | \n\t\t\t\t\t\t\t
Baicalein | \n\t\t\t\t\t\t\t\t17 μM | \n\t\t\t\t\t\t\t\t[153] | \n\t\t\t\t\t\t\t
Chrysin | \n\t\t\t\t\t\t\t\t? | \n\t\t\t\t\t\t\t\t[62] | \n\t\t\t\t\t\t\t
Daidzein | \n\t\t\t\t\t\t\t\t? | \n\t\t\t\t\t\t\t\t[83] | \n\t\t\t\t\t\t\t
Fisetin | \n\t\t\t\t\t\t\t\t3 μM | \n\t\t\t\t\t\t\t\t[73] | \n\t\t\t\t\t\t\t
Genistein | \n\t\t\t\t\t\t\t\t28.5 μg/mL | \n\t\t\t\t\t\t\t\t[83] | \n\t\t\t\t\t\t\t
Ginkgetin | \n\t\t\t\t\t\t\t\t6.52 μM | \n\t\t\t\t\t\t\t\t[154] | \n\t\t\t\t\t\t\t
Glycitein | \n\t\t\t\t\t\t\t\t28.5 μg/ml | \n\t\t\t\t\t\t\t\t[83] | \n\t\t\t\t\t\t\t
Isoliquiritigenin | \n\t\t\t\t\t\t\t\t24 μM | \n\t\t\t\t\t\t\t\t[155] | \n\t\t\t\t\t\t\t
Kaempferol | \n\t\t\t\t\t\t\t\t7.5 μM | \n\t\t\t\t\t\t\t\t[62] | \n\t\t\t\t\t\t\t
Luteolin | \n\t\t\t\t\t\t\t\t3 μM | \n\t\t\t\t\t\t\t\t[73] | \n\t\t\t\t\t\t\t
Morin | \n\t\t\t\t\t\t\t\t51 μM | \n\t\t\t\t\t\t\t\t[153] | \n\t\t\t\t\t\t\t
Myricetin | \n\t\t\t\t\t\t\t\t6.7 μM | \n\t\t\t\t\t\t\t\t[153] | \n\t\t\t\t\t\t\t
Naringenin | \n\t\t\t\t\t\t\t\t29 μM | \n\t\t\t\t\t\t\t\t[156] | \n\t\t\t\t\t\t\t
Quercetin | \n\t\t\t\t\t\t\t\t3 μM | \n\t\t\t\t\t\t\t\t[73] | \n\t\t\t\t\t\t\t
Resveratrol | \n\t\t\t\t\t\t\t\t14 μM | \n\t\t\t\t\t\t\t\t[157] | \n\t\t\t\t\t\t\t
Sophoflavanone G | \n\t\t\t\t\t\t\t\t20 μM | \n\t\t\t\t\t\t\t\t[158] | \n\t\t\t\t\t\t\t
Tectorigenin | \n\t\t\t\t\t\t\t\t0.193 mM | \n\t\t\t\t\t\t\t\t[159] | \n\t\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t |
Caffeic acid | \n\t\t\t\t\t\t\t\t? | \n\t\t\t\t\t\t\t\t[160] | \n\t\t\t\t\t\t\t
Curcumin | \n\t\t\t\t\t\t\t\t5.3 μM | \n\t\t\t\t\t\t\t\t[161] | \n\t\t\t\t\t\t\t
EGCG | \n\t\t\t\t\t\t\t\t? | \n\t\t\t\t\t\t\t\t[162] | \n\t\t\t\t\t\t\t
Ginkgetin | \n\t\t\t\t\t\t\t\t? | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t |
Medicarpin | \n\t\t\t\t\t\t\t\t>100 μM | \n\t\t\t\t\t\t\t[155] | \n\t\t\t\t\t\t
Rosmarinic acid | \n\t\t\t\t\t\t\t? | \n\t\t\t\t\t\t\t[160] | \n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t |
Celastrol | \n\t\t\t\t\t\t\t? | \n\t\t\t\t\t\t\t[163] | \n\t\t\t\t\t\t
Costunolide | \n\t\t\t\t\t\t\t34 μM | \n\t\t\t\t\t\t\t[164] | \n\t\t\t\t\t\t
Phytochemical inhibitors of beta-hexosaminidase enzyme
The previous section focused on compounds that affected the function of extracellular, cell surface/receptor and cell to cell interactions. The following group of compounds affect the intercellular functions of the cells particular the components of cell signalling pathways.
\n\t\t\tProtein kinases have a key role in the expression and activation of inflammatory mediators implicated in airway inflammation. Enhanced activation of p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), spleen tyrosine kinase (Syk), and phosphoinositol 3-kinase (PI3K) signaling pathways have all been proposed to have a role in the pathogenesis of asthma.
p38 MAPK is involved in the airway inflammation and remodeling. A selective synthetic p38 MAPK inhibitor SB2439063 reduces synthesis of Th2 cytokines [54] and thus has a potential application in asthma treatment. Inhaled p38 MAPK antisense oligonucleotide attenuates asthma in OVA-sensitized and –challenged mice [165]. The natural product limonene inhibits eosinophil migration in p38 MAPK dependent manner and was investigation in an
JNK activity is increased in corticosteroid-resistant asthma and SP600125, a JNK inhibitor, reduces cytokines expression and inflammatory cells accumulation in BALF of asthmatic animal models. Celastrol, a natural compound, modulates the expression of JNK in asthma [167]. It supresses allergen-induced mouse asthma by decreasing expression of MAP kinases, ERK and JNK [168].
Syk is a protein kinase involved in signal transduction in many inflammatory cells, and its aberrant regulation is associated with asthma, thus is considered an interesting target for asthma therapies. BAY 61-3606, a synthetic Syk inhibitor, inhibits inflammatory mediator release from mast cells, basophils, eosinophils, and monocytes, and reduces allergic asthma in rats [169]. Eupatilin, a biological extract, inhibits Syk and blocks downstream signaling pathways in mast cell from guinea pig lung tissues, leading to inhibition of mediator release [170]. Thus, Syk inhibitors may have use clinically as a treatment for asthma.
The PI3K pathway plays a major role in the pathogenesis of asthma by promoting eosinophil and neutrophil recruitment and degranulation [171]. Sorbus commixta water extract, an anti-inflammatory medicinal plant, remarkably blocks PI3K activity in antigen-activated macrophages, suggesting the usefulness of PI3K inhibitors in asthma [172].
\n\t\t\tThe increased expression of various inflammatory proteins seen in asthma is the result of enhanced gene transcription, since many of the genes are not expressed in normal cells but are selectively induced during inflammation. Changes in gene transcription are under the control of transcription factors which therefore play a key role in the pathogenesis of asthma.
Transcription factors such as nuclear factor-κB (NF-κB), GATA-3, signal transducers and activators of transcription protein (STAT)s, nuclear factor of activated T cells (NFAT), and peroxisome proliferator-activated receptors (PPAR) have been implicated in asthma and therefore represent therapeutic targets.
NF-κB is induced by many factors involved in asthmatic inflammation and is implicated in glucocorticoid-resistant asthma. Inhibition of IκB (inhibitor of NF-κB) by small molecule inhibitors suppresses inflammatory responses in mast cell [173], OVA-induced rat model of airway inflammation [174], and macrophages from BALF of asthmatic patients. A number of herbal preparations (i.e. andrographolide and narigenin) have been demonstrated to inhibit airway inflammation and AHR by inhibiting NF-κB activity in OVA-induced murine asthma [78, 175]. Many inhibitors of NF-κB have been identified belonging to the Flavonoids, Polyphenols and Terpenoids classes of compounds as well as n-3 PUFA (see Table 8).
\n\t\t\t\t\n\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t
Apigenin Capsaicin Fisetin Kuraridin Kurarinone Luteolin Myrecitin Naringenin Quercetin Resveratrol | \n\t\t\t\t\t\t\tCAPE Curcumin Epigallocatechin-3-gallate Gallic acid Gingerol Rosmarinic acid | \n\t\t\t\t\t\t\tParthenolide Costunolide Helenalin Celastrol Celaphanol A Kamebanin Kamebacetal A Excisanin A Orbiculin | \n\t\t\t\t\t\t\tn-3 PUFA | \n\t\t\t\t\t\t
Naturally occurring NF-κB inhibitors
GATA-3 is a critical transcription factor that is specifically expressed by Th2 cells and is involved in their differentiation [176]. GATA-3 has been indicated in the development of airway eosinophilia and expression is increased in atopic asthma [177] and therefore is an obvious target for inhibition. Direct inhibition by using a specific antisense oligonucleotide or interference RNA promises a novel approach for asthma treatment [178]. Polyphenols, such as apigenin and quercetin, ameliorate asthma symptoms, and suppress the translocation of GATA-3 in the cytosol of lung tissue of OVA-sensitized and -challenged mice [179].
NFAT transcription factor is mostly involved in the production of Th2 cytokines through its interaction with GATA-3 and activator protein-1 (AP-1) [180]. Immunosupressive drugs cyclosporin A and FK506 block NFAT activation [181]. The use of peptides known as inhibitors of NFAT-calcineurin association (INCA) represents an alternative asthma treatment strategy [182].
PPARs are transcription factors belonging to the nuclear receptor superfamily activated by PUFA derivatives, oxidized fatty acids and phospholipids. PPARγ activation might exhibit anti-inflammatory properties in different inflammatory processes. In a murine model of asthma, treatment with PPARγ ligand ciglitazone significantly reduces AHR and lung inflammation [183]. PPARα and PPARγ ligands also decreases allergen-induced AHR, lung inflammation as well as serum IgE levels in different asthma models [184]. Popular anti-asthmatic Traditional Chinese Medicine San-ao Decoction (SAD), comprising
Oxidative stress plays a critical role in the development of asthmatic conditions. Oxidative stress and its by-products drive a Th2-dependent immune response. A number of antioxidants have been explored for their anti-inflammatory and anti-asthmatic properties, and a number of natural products have emerged as promising candidates. Resveratrol, a component of red wine, possesses anti-inflammatory and antioxidant properties. It inhibits inflammatory cytokines release in patients with chronic obstructive pulmonary diseases (COPD) [186] and may be beneficial in asthma. Several other biological compounds such as
\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\n\t\t\t\t\t\t | \n\t\t\t\t\t |
Apigenin | \n\t\t\t\t\t\tSuppresses LPS-induced NO production in RAW264.7 macrophages | \n\t\t\t\t\t\t[191] | \n\t\t\t\t\t
Baicalein | \n\t\t\t\t\t\tInhibits LPS-induced NO production and iNOS expression in RAW264.7 macrophages | \n\t\t\t\t\t\t[192] | \n\t\t\t\t\t
Chrysin | \n\t\t\t\t\t\tInhibits NO production (IC50 7.50±1.84 μM) in LPS-activated RAW264.7 macrophages | \n\t\t\t\t\t\t[74] | \n\t\t\t\t\t
Fisetin | \n\t\t\t\t\t\tInhibits TNF-induced ROS production in HEK cells | \n\t\t\t\t\t\t[123] | \n\t\t\t\t\t
Kaempferol | \n\t\t\t\t\t\tInhibits NO production (IC50 9.83±1.55 μM) in LPS-activated RAW264.7 macrophages | \n\t\t\t\t\t\t[74] | \n\t\t\t\t\t
Kuraridin | \n\t\t\t\t\t\tInhibits ROS, NO production (20 & 40 μM) and iNOS gene expression (40 μM) in LPS-activated RAW264.7 macrophages. | \n\t\t\t\t\t\t[66] | \n\t\t\t\t\t
Kurarinone | \n\t\t\t\t\t\tInhibits ROS, NO production (40 μM) and iNOS gene expression (40 μM) in LPS-activated RAW264.7 macrophages. | \n\t\t\t\t\t\t[66] | \n\t\t\t\t\t
Luteolin | \n\t\t\t\t\t\tInhibits NO production (4, 8 & 16 μM) in LPS-activated RAW264.7 macrophages. | \n\t\t\t\t\t\t[67] | \n\t\t\t\t\t
Morin | \n\t\t\t\t\t\tInhibits NO production (IC50 44.86±1.05 μM) in LPS-activated RAW264.7 macrophages | \n\t\t\t\t\t\t[74] | \n\t\t\t\t\t
Naringenin | \n\t\t\t\t\t\tInhibits lung iNOS expression in allergen-induced mouse asthma model | \n\t\t\t\t\t\t[78] | \n\t\t\t\t\t
Quercetin | \n\t\t\t\t\t\tInhibits NO production (IC50 36.9±1.24 μM) in LPS-activated RAW264.7 macrophages | \n\t\t\t\t\t\t[74] | \n\t\t\t\t\t
Resveratrol | \n\t\t\t\t\t\tInhibits NO production in mice with acute lung injury (1 mg/kg body wt.). | \n\t\t\t\t\t\t[85] | \n\t\t\t\t\t
\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\n\t\t\t\t\t\t | \n\t\t\t\t\t |
Caffeic acid | \n\t\t\t\t\t\tReduces ROS levels in BALF of OVA-sensitized and –challenged mice (10 mg/kg body wt. IP). | \n\t\t\t\t\t\t[88] | \n\t\t\t\t\t
Curcumin | \n\t\t\t\t\t\tReduces iNOS expression in lung tissue of OVA-sensitized asthmatic mice. | \n\t\t\t\t\t\t[91] | \n\t\t\t\t\t
EGCG | \n\t\t\t\t\t\tReduces NOS activity in lungs of OVA-sensitized asthmatic guinea pigs. | \n\t\t\t\t\t\t[96] | \n\t\t\t\t\t
Hydroxytyrosol | \n\t\t\t\t\t\tInhibits NO2 production as well as iNOS expression in THP-1 cells (50 & 100 μM) | \n\t\t\t\t\t\t[104] | \n\t\t\t\t\t
Rosmarinic acid | \n\t\t\t\t\t\tInhibits formation of ROS and RNS in activates macrophages | \n\t\t\t\t\t\t[193] | \n\t\t\t\t\t
Helenalin | \n\t\t\t\t\t\tInhibits iNOS expression in LPS-stimulated macrophages (10 μM) | \n\t\t\t\t\t\t[137] | \n\t\t\t\t\t
n-3 PUFA | \n\t\t\t\t\t\tDecreases exhaled NO from asthma patients challenged with mite allergen | \n\t\t\t\t\t\t[194] | \n\t\t\t\t\t
Phytochemical inhibitors of oxidative stress
Understanding respiratory sensitization mechanisms is the first step to designing therapeutic agents that may relieve patients of their asthma symptoms. A number of
\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\t | \n\t\t\t\t\t
OVA-induced allergic asthma | \n\t\t\t\t\tIntranasal or aerosol challenge, intrathoracic inoculation, intradermal challenge | \n\t\t\t\t\tIncreased serum IgE levels, histological changes in airways including cellular infiltration, mediator release, AHR, and remodeling. | \n\t\t\t\t
LPS lung inflammation model | \n\t\t\t\t\tIntranasal | \n\t\t\t\t\tLeukocytes (mainly neutrophils) recruitment to lung within 4 hr of LPS treatment. | \n\t\t\t\t
House dust mite exposure | \n\t\t\t\t\tIntraperitoneal sensitization followed by inhalational challenge | \n\t\t\t\t\tIncreased serum IgE levels, histological changes in airways including cellular infiltration, mediator release, AHR, and remodeling. | \n\t\t\t\t
Infection by Aspergillus fumigatus | \n\t\t\t\t\tIntraperitoneal sensitization followed by inhalational challenge | \n\t\t\t\t\tIncreased serum IgE levels, histological changes in airways including cellular infiltration, mediator release, AHR, and remodeling. | \n\t\t\t\t
Ragweed allergen exposure | \n\t\t\t\t\tIntraperitoneal sensitization followed by inhalational challenge | \n\t\t\t\t\tAirway inflammation and AHR. | \n\t\t\t\t
Infection with Ascaris suum | \n\t\t\t\t\tSubcutaneous and intratracheal sensitization, aerosol challenge | \n\t\t\t\t\tBronchoconstriction, AHR and cellular infiltration. | \n\t\t\t\t
\n\t\t\t\t\t\t | \n\t\t\t\t\t\n\t\t\t\t\t\t | \n\t\t\t\t\t\n\t\t\t\t\t\t | \n\t\t\t\t
Mast cells: | \n\t\t\t\t||
Human mast cells | \n\t\t\t\t\tCD34+-derived primary mast cells, cord blood mast cells, skin mast cells, lung mast cells, LAD2, LUVA , HMC-1, RBL-2H3 | \n\t\t\t\t\tRelease of proinflammatory mediators such as histamine, tryptase, chymase, cytokines, chemokines, leukotrienes, and prostaglandins. | \n\t\t\t\t
Rodent mast cells | \n\t\t\t\t\tBone marrow-derived mast cells, peritoneal mast cells | \n\t\t\t\t\tRelease of proinflammatory mediators such as histamine, tryptase, chymase, cytokines, chemokines, leukotrienes, and prostaglandins. | \n\t\t\t\t
Eosinophils | \n\t\t\t\t\tPrimary cells, EoL-1, AML14.3D10 | \n\t\t\t\t\tRelease of proinflammatory mediators such as ECP, EPO, EDN, MBP, cytokines, and chemokines. | \n\t\t\t\t
Bronchial epithelial cells | \n\t\t\t\t\tPrimary cells, NHBE, BEAS-2B | \n\t\t\t\t\tRelease of proinflammatory mediators such as cytokines and chemokines. Morphological changes. | \n\t\t\t\t
Alveolar epithelial cells | \n\t\t\t\t\tPrimary cells, A549 | \n\t\t\t\t\tRelease of proinflammatory mediators such as cytokines and chemokines. Morphological changes. | \n\t\t\t\t
Monocytes/ Macrophages | \n\t\t\t\t\tPrimary cells, Mono-Mac-6, THP-1, RAW 264.7 | \n\t\t\t\t\tRelease of proinflammatory mediators such as cytokines, chemokines, leukotrienes, prostaglandins, ROS, and RNS. | \n\t\t\t\t
Dendritic cells | \n\t\t\t\t\tPrimary cells, U-937, CD34-DC, Mo-DC, KG-1, MUTZ-3 | \n\t\t\t\t\tRelease of proinflammatory mediators such as cytokines and chemokines. | \n\t\t\t\t
\n\t\t\t\t\t
The airways are continuously exposed to oxidants, either generated endogenously by various metabolic reactions (e.g. from mitochondrial respiration or released from phagocytes) or derived from exogenous sources (e.g. air pollutants and cigarette smoke). Allergen-activated inflammatory cells from asthmatic patients produce more ROS than from healthy individuals. In addition, several inflammatory mediators including histamine, lipid mediators, cytokines, chemokines, ECP, and EPO are potential stimuli for ROS production in the airways, leading to asthma exacerbation.
Deficiency of endogenous antioxidant defenses has been reported in asthma [195]. Since a diet rich in vitamin A or carotenoids, vitamin C vitamin E, and flavonoids, has been associated with a decreased prevalence of asthma, understanding the relationship between dietary antioxidants and asthma-associated inflammatory responses has been a recent focus.
\n\t\t\tA systemic review and meta-analysis by Allen
All-trans retinoic acid (ARTA), a derivative of vitamin A, inhibits airway inflammation in asthmatic rats. ARTA inhibits total cell counts and the proportion of inflammatory cells in BALF, suppresses the expression of NF-κB and intercellular adhering molecule-1 (ICAM-1), and increases the expression of iκB [199]. Retinoid acid also downregulates the expression of Th1 and Th2 chemokines in monocytes, including macrophage-derived chemokine and IP-10, which are all important in the inflammatory process [200]. Airway smooth muscle cell migration, which contributes to the airway remodeling in chronic asthma is also inhibited by ARTA [201]. However, excessive intake of vitamin A exacerbates pulmonary hyperresponsiveness in murine asthma model, suggesting that excessive vitamin A may increase the risk and severity of asthma [202].
Mechanistically, vitamin A may regulate bronchial hyperreactivity by altering the function and abundance of the muscarinic M(2) receptors in bronchial tissue [203]. Moreover, carotenoids may regulate activation of a variety of transcription factors. Treatment of cells exposed to oxidative stress with β-carotene suppresses oxidative stress-induced activation of NF-κB and production of IL-6, TNF, and inflammatory cytokines. Carotenoids may influence the process of apoptosis in healthy cells. While the pro-apoptotic protein Bax is downregulated after induction of external stimuli, β-carotene is able to increase expression of the anti-apoptotic protein Bcl-2 in normal cells. In addition, β-carotene exhibits a pro-apoptotic effect in colon and leukemic cancer cells, and this effect occurs by a redox-dependent mechanism linked with NF-κB activity. These dual roles of vitamin A, including carotenoids, on apoptosis provide the capability of carotenoids as an effective anti-inflammatory agent in various diseases.
\n\t\t\tMany observational studies have reported associations between reduced dietary/blood vitamin C levels and reduced lung functions. Asthmatic children undergoing an exacerbation have significant lower serum levels of vitamin C [204]. There is a positive correlation between serum vitamin C levels and asthma development in children (OR=0.72 per mg/dl, 95% CI=0.55, 0.95) [10]. Furthermore, asthma patients have significantly lower vitamin C level in both the cellular and fluid-phase fraction in induced sputum [205]. Higher maternal intake of citrus fruits rich in vitamin C during pregnancy is significantly associated with a reduced risk of allergic inflammation in the offspring [206]. Administration of vitamin C in OVA-challenged mice decreases AHR, influx of inflammatory cells in BALF and attenuates lung inflammation [207]. Similarly, high dose vitamin C supplementation significantly reduces eosinophilic infiltration in BALF and increases the Th1/Th2 cytokine secretion ratio; thus, skewing the Th1/Th2 balance toward non-allergic Th1 immune response in asthmatic mice [208].
A randomized, placebo controlled, double-blinded crossover trial has shown that vitamin C supplementation (1500 mg/day) attenuates asthma symptoms. Moreover, exhaled nitric oxide, urinary leukotriene C4, D4, E4 and 9α, 1β-prostaglandin F2 after exercise are downregulated [209]. On the contrary, there are also studies showing no significant effect of vitamin C supplementation on asthma symptoms. For example, in a randomized, placebo-controlled, double-blind parallel group trial three hundred asthma patients provided with 1 g/day vitamin C or placebo for 6 weeks do not show any improvements of asthma symptoms [210], therefore, there is insufficient evidence from randomised-controlled trials to support the use of vitamin C for asthma treatment [211].
As its mechanism of action, vitamin C may regulate factors that can influence gene expression, apoptosis, and other cellular functions indicated in inflammation. In fact, vitamin C protects against cell death triggered by various stimuli, and major proportion of this protection is associated with its antioxidant ability [212]. Vitamin C inhibits the AP-1 activation by regulating MAPK-ERK pathway [213]. Treatment of cells exposed to UV-B irradiation with vitamin C results in a 50% decrease in JNK phosphorylation, which activates AP-1, therewith inhibiting the JNK/AP-1 signaling pathways [214]. At present, however, evidence from randomized controlled trials is insufficient to recommend a specific role for vitamin C in the treatment of asthma due to variable study design and generally poor reporting system.
\n\t\t\tThe body of evidence from multiple studies suggests that a positive association between asthma outcomes and vitamin E intake or serum vitamin E levels. Asthmatic children have significantly lower serum levels of vitamin E than non-asthmatic children [204, 215]. A longitudinal birth cohort study has explored association between maternal plasma vitamin E, fetus and fetal lungs growth, and childhood asthma. The findings have shown that maternal vitamin E status has a positive effect on the growth of fetus and fetal lungs during early pregnancy and better asthma outcomes during childhood [216]. Moreover, high maternal vitamin E intake during pregnancy also reduces the risk of infantile wheeze [206]. Vitamin E intake is higher in control subjects than in asthma patients [217]. However there is no relationship found between serum vitamin E level and asthma [4, 218]. On the other hand, administration of vitamin E for 6 weeks does not have an effect on asthma features and serum immunoglobulin levels in adults [219].
Role of Vitamin E has been investigated in animal models of allergic asthma. Administration of Vitamin E to allergen-challenged mice reduces mitochondrial dysfunction, Th2 cytokines production, allergen-specific IgE, and expression of lipid mediators in lung leading to alleviation of asthmatic features [220]. Expression of IL-5 mRNA and protein in lung, and plasma IgE level are reduced after OVA sensitization and challenge compared to wild type mice in vitamin E transfer protein knockout mice [221]. Moreover, dietary supplementation with vitamin E affords variable degree of protection against ozone-induced enhanced airway response in allergen-sensitized guinea pigs [222]. However, oral α-tocopherol has no protective effect on lung response in rat model of allergic asthma. There is no improvement in OVA-induced AHR, the inflammatory cell infiltrate and histological changes [223]. The observed opposite effects of vitamin E could be associated with the study design in an animal model of asthma. The effect of vitamin E deserves further evaluation.
Vitamin E may induce immunological effects via modulation of the functional activity of T cells and enhancing the phagocytic activity of peripheral granulocytes [224]. A derivative γ-tocopherol appears to be a more potent anti-inflammatory agent than α-tocopherol. It decreases systemic oxidative stress, cytokine release from monocytes in asthmatic patients, and inhibits monocyte response to LPS and LPS-induced degradation of IκB and JNK activation [225]. There is a contradictory study demonstrating that γ-tocopherol elevates inflammation and ablates the anti-inflammatory benefit of the α-tocopherol by regulation of endothelial cell signals during leukocyte recruitment in experimental asthma [226]. Dietary tocopherols are taken up from the intestine and transported via the lymph to the blood and then to the liver. In the liver, α-tocopherol is transferred to plasma lipoproteins, resulting in retention of γ-tocopherol in tissues at 10% that of α-tocopherol. On interpreting these two contradictory results, one should consider their serum levels with caution since low plasma level of γ-tocopherol (1.2–7.0 μM) may act as prooxidant, while higher level of γ-tocopherol (19.5 μM at 8 days) exerts antioxidative and anti-inflammatory effects.
\n\t\t\tOver the past several years, the role of vitamin D in immunomodulation has been studied and shown to have a significant impact on innate and adaptive immunity to infections, including the pathophysiology of allergic asthma. It has been proposed that the increase in allergy and asthma is a consequence of widespread vitamin D insufficiency which appears to be frequent in industrialized countries, reflecting the insufficient intake of diet-sourced vitamin D.
The serum vitamin D level is associated with asthma in children as well as adults. A randomized, placebo controlled clinical study with 1024 children suffering from mild-to-moderate persistent asthma has shown that Vitamin D deficiency ias associated with a higher rate of severe asthma [227]. There is a significant positive correlation between forced vital capacity percent predicted and serum vitamin D level children with asthma. Moreover, 91.6% of these asthmatic children are not sufficient in serum vitamin D level [228]. Low level of vitamin D in serum are also associated with increased hyperresponsiveness and reduced glucocorticoid response in adults with asthma [229]. These studies have indicated that the low serum vitamin D level is related to reduced lung function and higher risk of asthma. Reduced the risk of asthma exacerbation triggered by acute respiratory tract infection is observed in a vitamin D supplementation [230]. Higher consumption of vitamin D during pregnancy may reduce the risk of childhood wheeze and asthma.
One possible mechanism of vitamin D’s protective effect against asthma can be that it inhibits the maturation process of dendritic cells by suppressing the expression of costimulatory molecules HLA-DR, CD86, CD80, the maturation marker CD83, and IL-12 which are important for the recruitment of Th1 cells [231]. Vitamin D also upregulates the expression of IL-10 receptor in dendritic cells, which is an anti-inflammatory cytokine. In addition, it can promote the production of FoxP3 positive and IL-10 positive regulatory T cells, and induce the release of IL-10, TGF-β and CTLA-4 [232]. Furthermore, it may reverse steroid-resistance in asthmatic patients through induction of IL-10 secreting T-regulatory cells [233], and vitamin D has been shown to regulate expression of many genes in ASM cells, including genes previously implicated in asthma predisposition and pathogenesis [234].
\n\t\t\tFlavonoids interfere with oxidation of lipids and other molecules and this strong antioxidative property makes them protective against airway diseases linked to oxidative stress. In fact, several epidemiologic studies suggest the beneficial effects of flavonoids on asthma. A population-based case-control study has shown that apple consumption and red wine intake are inversely associated with asthma prevalence or severity, perhaps due to a protective effect of flavonoids [18]. Moreover, a 30-year longitudinal epidemiological study has reported that the incidence of asthma is lower in populations with higher intake of flavonoids [235].
\n\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
Anthocyanidins | \n\t\t\t\t\t\tCyanidin, Delphinidin, Malvidin, Pelargonidin, Peonidin, Petunidin | \n\t\t\t\t\t\tRed, blue, and purple berries; red and purple grapes; red wine | \n\t\t\t\t\t
Flavanols | \n\t\t\t\t\t\tMonomers (Catechins): Catechin, Epicatechin, Epigallocatechin Epicatechin gallate, Epigallocatechin gallate Dimers and Polymers: Theaflavins, Thearubigins, Proanthocyanidins | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\t \n\t\t\t\t\t\t\t \n\t\t\t\t\t\t\t | \n\t\t\t\t\t
Flavanones | \n\t\t\t\t\t\tHesperetin, Naringenin, Eriodictyol | \n\t\t\t\t\t\tCitrus fruits and juices, e.g., oranges, grapefruits, lemons | \n\t\t\t\t\t
Flavonols | \n\t\t\t\t\t\tQuercetin, Kaempferol, Myricetin, Isorhamnetin | \n\t\t\t\t\t\tWidely distributed: yellow onions, scallions, kale, broccoli, apples, berries, teas | \n\t\t\t\t\t
Flavones | \n\t\t\t\t\t\tApigenin, Luteolin | \n\t\t\t\t\t\tParsley, thyme, celery, hot peppers | \n\t\t\t\t\t
Isoflavones | \n\t\t\t\t\t\tDaidzein, Genistein, Glycitein | \n\t\t\t\t\t\tSoybeans, soy foods, legumes | \n\t\t\t\t\t
Common dietary flavanoids.
Beyond antioxidative effects, flavonoids inhibit the release of histamine and other preformed granule associated mediators by inhibiting the activation of basophils and mast cells [66]. Flavonoids inhibit synthesis of IL-4, IL-13, and CD40 ligand but initiate generation of new phospholipid-derived mediators. One of the well-characterized flavonoids, quercetin, inhibits eosinophilic secretion of Charcot-Leyden crystal protein and ECP in a concentration-dependent manner. Very recently, Li
Vascular changes are one of the major components of asthmatic pathogenesis. These changes include an increase in vascular permeability, vascular dilation/engorgement, and vasculogenesis/angiogenesis. Flavonoids and their related compounds have been shown to modulate expression of HIF-1, VEGF, matrix metalloproteinases (MMPs), and epidermal growth factor receptor but also inhibit NF-κB, PI3K/Akt, and ERK1/2 signaling pathways [236]. These observations suggest that flavonoids as well as their related compounds inhibit certain steps of angiogenesis including cell migration, microcapillary tube formation, and MMP expression.
Many flavonoids have been tested for their anti-asthma effect. Quercetin decreases the eosinophil recruitment, reduces IL-5 and IL-4 levels, and inhibits NF-κB activation in BALF in OVA-induced mouse model [237]. It also regulates Th1/Th2 balance by enhancing IFN-γ and decreasing IL-4 levels in mouse asthma model [179]. Naringenin alleviates airway inflammation and reactivity by decreasing serum total IgE level and IL-4, IL-13 level in BALF and inhibiting NF-κB activity [78]. Licorice is a Traditional Chinese Medicine, which contain many flavonoids. Flavonoids extracted from licorice attenuates LPS-induced acute pulmonary inflammation by inhibiting inflammatory cells infiltration and inflammatory mediator release [238]. Neutrophils, macrophages and lymphocytes accumulation in BALF, lung TNF and IL-1β mRNA expression and lung myeloperoxidase activity are reduced; whereas BALF superoxide dismutase activity is increased [238]. Flavonoids from red algae decrease eosinophil infiltration, levels of TNF, IL-4 and IL-5 in BALF, airway luminal narrowing, AHR and level of allergen-specific IgE in the serum [239]. A complex mixture of bioflavonoids derived from purple passion fruit peel extract supplemented to asthma patients in a randomized, placebo-controlled, double-blinded trial alleviates asthma clinical symptoms, including FVC and FEV1 [240].
\n\t\tResveratrol scavenges intracellular ROS by inducing and stabilizing antioxidant enzymes such as catalase, SOD, and glutathione peroxidase hemoxygenase. In addition to its reducing properties, resveratrol has been shown to attenuate inflammation via inhibition of prostaglandin production [241] and to decrease the phosphorylation of ERK1/2, COX-2 activity, and activity of various transcription factors including NF-κB, STAT3, HIF-1α, and β-catenin [236]. Resveratrol also inhibits protein kinases (e.g. src, PI3K, JNK, and Akt) and the production of inflammatory mediators (e.g. IFN-γ, TNF, COX-2, iNOS, CRP and various interleukins). Recent studies have reported that resveratrol activates sirtuin1 (SIRT1) which is modulates apoptosis and has been shown to increase longevity in some experimental systems [242]. SIRT1 modulates poly (ADP-ribose) polymerase-1 (PARP-1) activity upon DNA damage. Activation of SIRT1 by resveratrol leads to a decrease in PARP-1 activity and promotes cell survival, which can attenuate the inflammatory reaction. We investigated the effects of resveratrol on human mast cell activation in comparison to the anti-allergic drug tranilast. The results show that resveratrol inhibits mast cell degranulation, cytokine, chemokine and leukotriene release, and is more efficacious than tranilast [316].
Resveratrol is able to modulate innate immune response by inhibiting expression of costimulatory molecules (CD80 and CD86) and major histocompatibility complex classes I and II in bone marrow-derived dendritic cells and inhibit angiogenesis pathway that is mediated through expression of MMPs, VEGF, cathepsin D, ICAM-1, and E-selectin [236]. These findings suggest that resveratrol can be a very attractive compound for preventing/treating asthma since this compound displays multiple therapeutic effects, showing antioxidative, anti-inflammatory, immune modulating, and vascular protective property.
Resveratrol has been shown to inhibit the airway inflammation and hyperresponsiveness in OVA-induced mouse asthma by reducing eosinophil/neutrophils infiltration, the levels of IL-4 and IL-5 in plasma and BALF [81]. It can modulate Th1/Th2 balance, polarization of naive CD4+ T cells to the Th2 phenotype, and the expression of Th2 regulatory transcription factor, GATA-3 [81]. It also inhibits cytokine release in vitro by alveolar macrophages from patients with COPD, including IL-8 and GM-CSF [186].
\n\t\tSelenium is an important molecule in both innate and adaptive immune responses. It stabilizes activated platelets by inhibiting platelet aggregation and secretion of adenine nucleotide, thus possibly blocking the release of acrachidonic acid from platelet membrane [243]. In asthma, platelets participate by acting as inflammatory cells, by releasing mediators, spasmogens and/or by interacting with other inflammatory cell types [168]. Selenium affects the expression of endothelial cell adhesion molecules, E-selectin, P-selectin, ICAM-1, VCAM-1, and ELAM-1, which are crucial in the inflammatory process for recruitment of inflammatory cells into the target tissue [244].
Some studies have reported that asthma patients have lower selenium level in platelets and serum compared to healthy controls [245, 246]. While others studies have found no relationship between serum selenium level and asthma in Japanese and Europe populations [247, 248]. Selenium supplementation studies in mouse OVA-induced asthma models have shown that selenium has some protective effects on asthma-associated inflammation. Mice with decreased and increased levels of selenium intake show lower cytokine levels, airway inflammatory cell infiltration, serum anti-OVA IgE, airway hyperreactivity, and phosphorylated STAT-6 levels in the lung compared to medium selenium intake [249]. Selenium supplementation does not show any clinical benefit in adult asthma patients [250].
Despite the data showing positive effects of selenium on some of the pathologies associated with asthma, there are still some conflicting findings of selenium supplementation in animal and human studies. Thus the issue regarding selenium is not conclusive.
\n\t\tAvenanthramides (Avns) are extracted from oats and those synthetically prepared exhibit potent antioxidant properties
In addition to demonstrating antioxidant activity, Avn compounds may also interact with cellular components, through their interactions with the molecular and signaling pathways that govern cellular responses during inflammation. Using the human aortic endothelial cell (HAEC) culture system, the potentially beneficial health effects of oat Avns was found to be mediated via modulation of the cellular and molecular processes that are known to play an important role in the inflammation of arteries and the development of atherosclerosis [251]. They have been shown to inhibit vascular endothelial cell expression of adhesion molecules, including ICAM-1, VCAM-1, and E-selectin. Suppression of these adhesion molecules resulted in inhibition of monocyte adhesion to HAEC monolayers and reduced production of several inflammatory cytokines and chemokines, including IL-6, IL-8, and MCP-1, the inflammatory components involved in fatty streak formation in arteries. The production of proinflammatory cytokines, chemokines, and adhesion molecules by endothelial cells has been shown to be regulated by redox-sensitive signal transduction involving nuclear transcription factor NF-κB. The above-observed effects of Avns on HAEC and other cells are reported to be mediated through inhibition of NF-κB. More recently, dihydroavenanthramide (DHAv), a synthetic analog of Avn, has been shown to protect pancreatic β-cells from damage via inhibition of NF-κB. In a series of experiments, Guo
Herbs have been used to treat airway diseases including asthma for thousands years in many nations, especially in Asian and African countries. In recent decades, some Chinese, Japanese, Indian, and African herbs have been tested for their anti-asthmatic effects.
\n\t\t\tBoswellia serrata, Indian frankincense, is commonly found in many regions of the world, such as South Asia, Northern Africa, and Middle East. Traditional medicine using extract made from sap, has long been used to treat inflammatory diseases [204]. These extracts contain resin, amino acids, phenols, terpenes, polysaccharides [205] and β-boswellic acid the major active anti-inflammatory component [206].
Extract of Boswellia Serrata or β-boswellic acid has been reported to inhibit hypersensitivity reactions by regulating both the humoral and cellular immune systems They decrease primary antibody synthesis, inhibit polymorphonuclear leukocyte proliferation and infiltration, enhance the phagocytotic function of macrophages, and suppress the classical and alternate complement pathways [254, 255] and suppress the inflammation process, one of the critical pathological features in asthma. It has been shown that β-boswellic acid inhibits the production of proinflammatory cytokines, including TNF, IL-1, IL-2, IL-6, IL-12 and IFN-γ by suppressing the activation of NF-κB [256]. It also inhibits histamine release from mast cells challenged with G protein stimulator c48/80 in a dose-dependent manner [257]. β-boswellic acid can down-regulate the synthesis of prostaglandins by inhibiting COX-1 in intact human platelets [258]. The synthesis of 5-hydroxyeicosatetraenoic acid (5-HETE) and leukotriene B4 from rat peritoneal polymorphonuclear leukocytes, which contribute to bronchoconstriction, and increased vascular permeability, are reduced by Boswellia Serrata extract as a result of 5-LO inhibition [259]. These results suggest that Boswellia Serrata might be effective in controlling the inflammation process and contraction of airway smooth muscle in asthmatic condition by inhibiting enzymes required for production of proinflammatory mediators and bronchoconstrictor.
\n\t\t\t\tBoswellia serrata
Preliminary clinical investigation has shown Boswellia Serrata’s potential therapeutic effect on asthma. In a double-blind, placebo-controlled clinical study [260], 40 patients took 300 mg of extract daily for six weeks, while a control group received a lactose placebo for the same period of time. Lung and immune functions were recorded, including dyspnoea, rhonchi, frequency of attacks, FEV1, FVC, peak expiratory flow rate (PEFR), eosinophil count and erythrocyte sedimentation rate. In the treatment group 70% of patients and 27% in the control group showed improvement in terms of recorded physical symptoms and signs. These results suggest that Boswellia Serrata extract has potential benefit for asthma patients, although the age for control and treatment group was not perfectly matched. However, there is not enough evidence to draw a conclusion on the potential use of Boswellia Serrata for treating asthma in human.
\n\t\t\tBromelain is an extract from the pineapple stem, Ananas comosus, containing a mixture of cysteine proteases, peroxidase, acid phosphatase, protease inhibitors, and calcium, with cysteine proteases being the main functional components [214].
Bromelain modulates immune responses both
Bromelain administration via intraperitoneal injection alleviates some of the features of airway inflammation in the OVA-induced murine asthma model. It reduces the total numbers of leukocytes, eosinophils, CD4+ and CD8+ T cells in BALF, and decreases IL-13 concentration, which is a critical mediator for AHR in asthma [266]. In separate study, oral supplementation has been shown to suppress airway methacholine sensitivity, decrease IL-13 level, and eosinophils, CD19+ B cells and CD8+ T cells counts in BAL [267]. These results suggest that Bromelain modulates airway reactivity by altering the presence of leukocytes in airway, which is consistent with the
Butterbur is a member of the perennial sunflower family found in Europe and northern Asia. The ancient Greeks used butterbur roots to treat airway diseases and alleviate bronchial spasms [268].
\n\t\t\t\tFukinolic acid
Petasin
Extract from the flower bud, leaves and root have been shown to inhibit β-hexosaminidase release, leukotriene C4/D4/E4 synthesis, and TNF production from IgE-sensitized RBL-2H3 cell [223]. A group of Japanese researchers reported that Japanese butterbur contains multiple active compounds including two eremophilane-type sesquiterpenes, six polyphenolic compounds, and two triterpene glycosides [223], and based on its inhibitory activity on mast cell degranulation, fukinolic acid is believed to be the most active component [269]. Another active component petasin, can reduce leukotriene and ECP production from eosinophils activated by platelet-activating factor (PAF) or C5a via suppression of cytosolic phospholipase A2 (cPLA2) activity, decreasing intracellular calcium concentration and inhibiting 5-LO translocation from the cytosol to nuclear membrane [270]. Pepsin inhibits leukotriene production from macrophages [271] and suppresses bronchial constriction induced by histamine, carbachol, KCl and leukotriene D4 in isolated guinea pig trachea [272]. In the OVA murine model, butterbur extract given intranasally together with antigen challenge has been shown to inhibit airway inflammation induced by OVA and hyperresponsiveness to aerosolized methacholine, reduce eosinophil count and decrease Th2 cytokine production including IL-4, IL-5 and RANTES in BALF [227]. These results suggest that Butterbur may have inhibitory effects on proinflammatory mediator release from a broad range of immune cells.
In 2003, a prescription-based Butterbur extract was approved in Switzerland for the treatment of seasonal allergic rhinitis and in response some researchers have tested Butterbur extract for the treatment of asthma. Ziolo
Curcumin is a yellow polyphenol compound, extracted from the rhizomes of
Curcumin
Many pharmacological effects of curcumin have been reported, including antioxidative, anti-inflammatory and antimicrobial activities [276]. In terms of its antioxidative effects, curcumin is thought to be more potent than vitamin E [277] with the mechanism including downregulation of NO production, scavenging free radicals, and inducing heme oxygenase-1 to repair the oxidative damage caused by free radicals [278-280]. Curcumin can inhibit the production of proinflammatory cytokines such as IL-1β and IL-8, suppress inducible iNOS and NO production, and modulate steroid activity. It’s effect on steroid activity may be the result of inhibition of NF-κB through blocking IKK activity [281-284].
During allergic inflammation, curcumin may modulate both early and late phase responses by altering Th2 responses. In a murine latex-induced allergy model, characterized by an increased serum total IgE and latex specific IgG1, elevated peripheral blood eosinophils count, and enhanced lung tissue IL-4, IL-5 and IL-13, intragastric curcumin administration reduces lung inflammation. Protein expression of costimulatory molecules CD80, CD86, and OX40-Ligand, and RNA expression of MMP-9, ornithine aminotransferase (OAT), and thymic stromal lymphopoietin (TSLP) in antigen-presenting cells are all decreased. These results suggest that curcumin may disrupt antigen presentation, so that has potential therapeutic value on allergen triggered airway inflammation [285].
Curcumin has been shown to have anti-asthmatic effects in both
Licorice root has been widely used around the world to treat cough since ancient time [247]. It contains the active compounds including glycyrrhizin, glycyrrhetinic acid, flavonoids, isoflavonoids, and chalcones [248]. Glycyrrhizin and glycyrrhetinic acid are considered to be the main active components [249] and are potent inhibitors of cortisol metabolism, due to their steroid like structures inhibiting the key steroid metabolic enzymes, delta 4-5-reductase, 11 beta-hydroxysteroid dehydrogenase and 20-hydroxysteroid dehydrogenase [250, 251]. Therefore, the benefits and side effects of steroid are both expected to be enhanced in the presence of glycyrrhetinic acid and glycyrrhizin.
\n\t\t\t\tGlycyrrhetinic acid
Glycyrrhizin
Liquiritige
The anti-inflammatory effect of glycyrrhizin during virus infection has been well documented [288-290] and may alleviate allergic inflammation as well. In a contact skin hypersensitivity mouse model, glycyrrhizin and its metabolite 18 β-glycyrrhetinic acid-3-O-β-D-glucuronide show protective effects in terms of reduced passive cutaneous anaphylaxis and inflammation, with glycyrrhizin being more potent than 18 β-glycyrrhetinic acid-3-O-β-D-glucuronide [291]. In an OVA-induced murine asthma model, glycyrrhizin provided orally alleviates airway constriction and hyperreactivity, pulmonary inflammation. In BAL, IFNγ level is increased, while IL-4, IL-5 levels and eosinophil count are decreased. It also reduces OVA-specific IgE levels and upregulates total IgG2a in serum as well [292]. These results indicate that glycyrrhizin interfere the production of IgE by decreasing the IgE-stimulating cytokines.
The effects of glycyrrhetinic acid and liquiritigenin (a flavonoid of licorice root) on asthma have been tested both
Mai-Men-Dong-Tang is an old Chinese herb formula commonly used for treating lung diseases, which contains Ophiopogon, Ginseng, Pinellia, Licorice, Jujube, and Oryza [260]. It is reported to increase the cough threshold to inhaled capsaicin in asthmatic patients. Also, the eosinophil count in peripheral blood, sputum eosinophil ratio, and serum eosinophil cationic protein level are significantly decreased, especially in patients with severe airway inflammation [261], which suggests that Mai-Men-Dong-Tang may alleviate asthma-related cough by inhibiting eosinophil function.
Modified Mai-Men-Dong-Tang (mMMDT) contains five herbs, Ophiopogon, American ginseng, Pinellia, Licorice root, and Lantern tridax [262]. The efficacy and safety of this formula to persistent, mild to moderate asthma has been evaluated in a double-blind, randomized clinical study of 100 patients with mild to moderate asthma. After 4 months, improvements in FEV1 and symptom scores has been reported in mMMDT treatment groups with decreased serum IgE and no drug-related adverse effects seen in terms of blood test, and liver, kidney functions [295]. Modified Mai-Men-Dong-Tang is a potential effective herb formula in treatment of childhood asthma for long time use. However, recommendation cannot be made because of small sample size used in the study.
\n\t\t\tDing-Chuan-Tang (DCT) is a traditional Chinese herb formula used for the treatment of cough, wheezing, and chest tightness, developed about four hundred years ago during the Ming dynasty. This formula contains nine herbs including
Randomized double-blind, placebo-controlled study to assess the effect of DCT on airway hyperreactivity in children with mild to moderate persistent asthma has shown that the FEV1 is significantly increased in DCT group (196%, p=0.034), but not in placebo control group. Compared to placebo control group, total clinical/medication score shows improvement in the DCT group (p=0.004). No side effects have been reported [296]. These results suggest that DCT might be effective in treating asthma in children. Larger sample size and wider population are required in further investigations.
\n\t\t\tSTA is a combination of mMMDT and another Chinese herb formula Liu-Wei-Di-Huang-Wan (LWDHW), which is also used by Chinese as an anti-cough agent. LWDHW contains six herbs including
ASHMI is a relatively new formula developed by a group of Chinese researchers and physicians, which is an extract from three herbs:
In clinical trial, ASHMI has been shown to improve lung function indicated by increased FEV1 and peak expiratory flow. Clinical symptom scores, use of β2-bronchodilators, serum IgE level, serum IL-5, IL-13 concentrations are all reduced, and some effects are even better than prednisone. During the study no adverse effect were recorded [298]. These results indicate the effectiveness of ASHMI on treating asthma in both young and old adult patients. More adequately powered investigations are needed to evaluate ASHMI’s effect on asthma.
\n\t\t\tPUFA are a group of fatty acids with more than two carbon-carbon double bonds. There are three types of PUFA, n-3, n-6 and n-9, with their names based on the position of first double band from methyl end in their chemical structures. Currently, many studies have focused on n-3 and n-6 PUFA because EPA (20:4 n-3), Dihomo-γ-Linolenic acid (DGLA, 20:3 n-6) and Arachidonic acid (AA, 20:4 n-6) in cell membrane can be metabolized and become eicosanoid precursors, which are important modulatory autocrine molecules. Eicosanoids include prostaglandins, leukotrienes, thromboxanes, resolvins, lipoxins, are signal molecules that exert complex effects on health. They can modulate inflammation, fever, blood pressure, the immune system, etc. Eicosanoids can be made by oxidation of twenty carbon n-3 (EPA) and n-6 (DGLA, AA) PUFA. Eicosanoids from AA are proinflammatory, while those from EPA and DGLA are less so. There is competition between n-3 PUFA and n-6 PUFA in oxidation in terms of cyclooxygenase and lipoxygenase, which are critical enzymes for eicosanoid generation. AA is the predominant n-6 PUFA in body. In general, n-3 and n-6 are hypothesized to be beneficial and detrimental respectively [299, 300]. Fish, fish oil, krill, mussel and seal oil are natural sources of n-3 PUFA.
The major n-3 PUFA are listed in Table 12. In mammals, including humans, n-3 PUFA cannot be synthesized
\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t\t\n\t\t\t\t\t\t\t\t | \n\t\t\t\t\t\t
(HTA) | \n\t\t\t\t\t\tC16:3 ( | \n\t\t\t\t\t\tall-cis-7,10,13-hexadecatrienoic acid | \n\t\t\t\t\t\tC16H26O2/250.376 | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\t | \n\t\t\t\t\t
α-Linolenic acid (ALA) | \n\t\t\t\t\t\tC18:3 ( | \n\t\t\t\t\t\tall-cis-9,12,15-octadecatrienoic acid | \n\t\t\t\t\t\tC18H30O2/278.430 | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\t | \n\t\t\t\t\t
α -Parinaric acid | \n\t\t\t\t\t\tC18:4 ( | \n\t\t\t\t\t\tall-cis-9,11,13,15-octadecatetraenoic acid | \n\t\t\t\t\t\tC18H28O2/276.414 | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\t | \n\t\t\t\t\t
Stearidonic acid (SDA) | \n\t\t\t\t\t\tC18:4 ( | \n\t\t\t\t\t\tall-cis-6,9,12,15-octadecatetraenoic acid | \n\t\t\t\t\t\tC18H28O2/276.414 | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\t | \n\t\t\t\t\t
(ETE) | \n\t\t\t\t\t\tC20:3 ( | \n\t\t\t\t\t\tall-cis-11,14,17-eicosatrienoic acid | \n\t\t\t\t\t\tC20H34O2/306.483 | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\t | \n\t\t\t\t\t
(ETA) | \n\t\t\t\t\t\tC20:4 ( | \n\t\t\t\t\t\tall-cis-8,11,14,17-eicosatetraenoic acid | \n\t\t\t\t\t\tC20H32O2/304.467 | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\t | \n\t\t\t\t\t
(EPA) | \n\t\t\t\t\t\tC20:5 ( | \n\t\t\t\t\t\tall-cis-5,8,11,14,17-eicosapentaenoic acid | \n\t\t\t\t\t\tC20H30O2/302.451 | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\t | \n\t\t\t\t\t
(DPA) | \n\t\t\t\t\t\tC22:5 ( | \n\t\t\t\t\t\tall-cis-7,10,13,16,19-docosapentaenoic acid | \n\t\t\t\t\t\tC22H34O2/330.504 | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\t | \n\t\t\t\t\t
(DHA) | \n\t\t\t\t\t\tC22:6 ( | \n\t\t\t\t\t\tall-cis-4,7,10,13,16,19-docosahexaenoic acid | \n\t\t\t\t\t\tC22H32O2/328.488 | \n\t\t\t\t\t\t\n\t\t\t\t\t\t\t | \n\t\t\t\t\t
The common name, lipid name and chemical name of major n-3 PUFA
In recent decade, the relationship between n-3 PUFA and inflammatory diseases has been investigated in many studies. In a study conducted in rheumatoid arthritis patients, significant improvement in symptoms have been reported after 3 month fish oil supplementation in terms of tender joint count and duration of morning stiffness [307]. Besides reduction in the production of proinflammatory eicosanoids by competition with n-6 PUFA, n-3 PUFA has been found to be effective in inhibiting the synthesis of proinflammatory cytokines. In
There have been a number of clinical studies that have shown n-3 PUFA’s potentially protective effects on asthma, especially on childhood patients. There is a positive association between the n-6:n-3 PUFA in diet and risk for asthma [313]. A randomized, double-blind, placebo-controlled 3-year study on effect of n-3 PUFA supplementation on asthma has found that high n-3 PUFA diet intervention significantly reducesd the prevalence of cough in atopic children, suggesting that n-3 PUFA may be effective in preventing the development of asthma in early childhood [314]. In a cohort study on the relations between fish/cod oil intake and asthma, results have shown that adults with low fish intake frequency (less than weekly) have increased risk to have asthma [315]. Another randomized double-blind study with 5-weeks n-3 PUFA supplementation has reported a significant decrease in exhaled NO from asthma patients challenged with mite allergen. Serum eosinophils count and ECP, and the production of CysLTs from isolated leukocyte stimulated with mite antigen are also reduced [194]. Overall, n-3 PUFA might be a promising remedy agents for allergic diseases like asthma but the mechanism remains to be elucidated.
\n\t\tThe prevalence of asthma is becoming the mortality and morbidity pandemic of the 21st century. The cost of in quality of patient’s lives and economic burden of treatment is continuing to grow at pace unmatched in our current health system. It is impossible to enter public classroom now without seeing a young sufferer of this condition and any trip to the emergency department will show how dangerous this disease can be. As the incidence and severity of the disease continues to rise, medical research is continuing to search new treatment strategies. While many treatments currently exists those reserve for the severest of conditions carry their own inherent risk which may match the severity of disease itself. It is for these reasons alone that health care professionals are now examining the traits of our ancestors in time when this epidemic was less severe to determine if their medicines and practices hold the answer for the next treatment strategy. By combining the scientific knowledge at the molecular and clinical level and the resources of past it might hold the answer to breathless pandemic of the 21st century.
\n\tThe authors are thankful to Dr. Clayton Macdonald for his assiatance with the manuscript preparation. This work is supported by the National Research Council Canada. Priyanka Pundir is the recipient of Innovation PEI Graduate Student Fellowship.
\n\tSince 2020, we have faced drastic changes in our lives due to the pandemic. This caused a big paradigm shift in working styles. Parallel careers or multiple jobs are getting more common, and people are ascertaining their own competencies. The utilization of personal knowledge will continue to accelerate and this study sheds light on its societal value.
Aoki [1] revealed that participation in knowledge sharing has a significant positive impact on contributors’ well-being. Those findings are more pertinent as utilization of personal knowledge increases under the ongoing paradigm shift in work style, and the expansion of C-to-C business. However, the reason for the correlation between knowledge sharing and well-being has not been identified. This research aims to reveal the relationship between knowledge sharing and well-being.
Due to the growing sharing economy and the large ongoing paradigm shift in work styles caused by the pandemic, people have more opportunities to utilize their personal knowledge than ever before. However, vast amounts of personal knowledge are untapped. For instance, one instantiation of personal knowledge is user innovation, and user innovation research has pointed out the ‘market failure’ in its diffusion due to a lack of incentives for the innovators [2, 3]. This study contributes to increase knowledge sharing and filling the gap between personal knowledge and society.
Since von Hippel [4] pointed out that not only manufacturers but also ‘users’ innovate, user innovation has been studied by various researchers throughout the world. In early research, the term ‘users’ referred to firms that were supplied products by manufacturers; in other words, user innovation was carried out in the business-to-business community. Over the decades, the importance of individual consumers as user innovators has been articulated (e.g. [5]). In this digital era, the line between a firm and a consumer is becoming blurred, and co-creation between the two has become pervasive.
Some users innovate by themselves and whose innovations occasionally have been commercially successful. Previous studies showed that user innovations increased social welfare because user innovators created financial value from their leisure-time activities [6, 7]. Furthermore, user innovation is distinct from producer innovation in that the former provides benefits from participation, including the use or sale of the output to the innovators themselves [6, 8]. Consequently, user innovation which brings satisfaction to the innovators increases social welfare better than producer innovation.
Even if it has a high potential to enhance social welfare, user innovation tends to be restricted to innovators themselves and not diffused. User innovators are likely to choose free information diffusion, rather than paid diffusion, and avoid seeking commercialization on their own or through an existing firm, because it costs more than they would gain. Earlier studies have shown ‘market failure’ in user innovation diffusion [2, 3]. When valuable innovation remains underground, it is society’s loss.
Each user innovation is based on personal needs, which, by nature, are self-centered. Thus, innovation communities play an important role in integrating these isolated individuals [5]. Baldwin et al. [9] revealed that user innovators who commercialized their innovations had participated in innovation communities at an earlier stage and improved their ideas. Earlier research has shown that user communities play an important role in diffusing user innovations and has examined the innovators’ motivations to participate in these communities.
People tend to join peer communities (e.g., open-source software communities) to fulfill personal needs. Then, their participation becomes a hobby, and they discover that they are helping other people [10]. In addition to personal needs, feedback from peers and enjoyment were found to be important motivations [11, 12, 13, 14]. Feedback in the user community also plays a key role in increasing entrepreneurship [10, 15].
Diffusion of user innovation is ultimate knowledge sharing and contributors enjoy financial and/or non-financial benefits from sharing. Aoki [1] focused on non-financial benefits and revealed that knowledge sharing increases contributors’ well-being.
In terms of psychology, Seligman [16] defined well-being as the ultimate objective of positive psychology. He argued that well-being is sustainable and separate from ‘happiness’ and suggested the importance of flourishing as a standard to measure well-being. Flourishing consists of five elements, positive emotion, engagement, relationship, meaning, accomplishment, or PERMA for short [16]. Each element represents the following.
Positive emotion: a subjective feeling of well-being itself
Engagement: a subjective feeling denoting the extent to which people are absorbed in something
Relationships with others
Meaning: the extent how lives are meaningful for themselves
Accomplishment, the extent how people accomplish something in their lives
Aoki [1] visualized non-financial benefits from knowledge sharing with the measurement of PERMA which was developed by Butler and Kern [17] and have been used to explain the relationship between well-being and a continuous process such as career [18], education [19, 20], and hobby [21]. Although this is an important finding, the cause has not yet been revealed. Thus, this research explores why knowledge sharing increases well-being. In line with Aoki [1], this research follows Seligman’s definition of well-being and adopts PERMA to examine the changes in well-being that knowledge sharing contributors’ experience.
To answer the research question, in-depth interviews with the knowledge-sharing contributors were conducted. The interviewees were sourced from LEGO users who share their original creations. The LEGO Group, one of the world’s largest toy manufacturers, was founded in 1932. The brick in its present form was launched in 1958 and has attracted people for over 60 years. LEGO has a lot of adult fans across the world who call themselves AFOL (Adult Fan of LEGO). The LEGO Group has collaborated with these users with novel ideas for decades and much research has revealed the competitive advantages of this collaboration (e.g. [22, 23, 24, 25, 26]). Antorini, Muñiz and Askildsen [11] pointed out that the relationship among community members is the strongest motivation for contributors to co-creation with LEGO.
Co-creation among LEGO and its users varies from new product development to programming. Furthermore, users frequently share ideas, some of which are quite new beyond the brand’s intention. This research examines how such knowledge sharing affects contributors themselves. This research distinguishes itself from previous research mainly in two aspects. First, this research observes changes in contributors not one specific point but over time. Second, this research shed light to not firms but contributors.
The interview respondents were selected using the following criteria: who share the idea related to LEGO with other people in some form. The interviews reached theoretical saturation with ten respondents. The primary respondent activity was sorted into three groups as follows.
Artistic photography of LEGO in scenic environments (n = 4).
Designing and creating original crafts with LEGO blocks (n = 4).
Programming original LEGO Mindstorms crafts (n = 2).
Their activities were user-generated beyond the firm’s original aim. Group A especially, as they go out of their homes with LEGO blocks and/or mini-figures, and enjoy sharing with other people through SNS. These activities were not expected by the firm; however, they have become worldwide trends among LEGO users.
The one-to-one semi-structured interviews covered the beginning of LEGO, current occasion to use, purchase situations, and the relationship with the user community and the firm. The interviews were conducted between September 2020 and February 2021, and each interview lasted 30–120 min (average 59 min).
To structurally understand chronological changes in the respondents, the data were analyzed using the Grounded theory approach (GTA) [27]. In line with other marketing research (e.g., [28, 29, 30]), this chapter follows the Strauss approach (e.g. [31]). All interviews were transcribed and applied the scheme of open, axial coding converging into theory as follows [32]:
breaking down data into manageable analytic pieces.
brainstorming with data to arrive at possible meanings and delineate the concepts (open coding).
elaborating concepts to form categories (axial coding).
integrating categories into a core category and other categories.
analyzing data for context.
The data were analyzed (first and second steps) after each interview, and data collecting and analysis were continued until reaching theoretical saturation. The concepts in open coding were based on the actual language respondents used. Then, the concepts were grouped into categories based on theoretical abstracts in axial coding. For analyst triangulation, the coding results were reviewed by the marketing researcher and two of the interview respondents; and the theory was constructed objectively via the reviewers’ feedback. Finally, the categories were referred to PERMA [16] to observe the relationship between knowledge sharing and well-being.
Through the process of coding, 22 first-order categories were distilled from 67 concepts and consequently converged into the seven second-order categories ending with the two core categories below (Table 1). The results are described below for each second-order category.
First-order categories | Seligman [16] | Second-order categories | |
---|---|---|---|
1 | Childhood experiences | A) Formative LEGO experience | |
2 | Superiority of LEGO blocks | Positive emotion | |
3 | Restart using LEGO | Positive emotion | B) Renewed LEGO experience |
4 | Exposed to new playing styles via the internet | Positive emotion | |
7 | Absorbed in creating | Engagement | C) Absorption in LEGO |
8 | Being an extension of oneself | Engagement | |
9 | Huge expenditure | ||
5 | Self-recognition of developing creativity | Engagement | D) Satisfaction of intellectual curiosities |
6 | Knowledge transformation | Meaning | |
10 | Goal representative of ideals | Meaning | E) Goal setting and hardships to reach the achievement |
11 | Hurdles to reach achievement | ||
12 | Collaboration with peers | Relationship | F) Deepening of knowledge and experiences via competitive co-creation (core category) |
13 | Deep communication | Relationship | |
14 | Opportunities for feedback | Accomplishment | |
15 | Existence of more experienced people | ||
16 | Objective judgment of one’s own works | Meaning | |
17 | Recognition from third parties | Accomplishment | |
18 | Collaborative relations with LEGO | Relationship | |
19 | Interests and comprehension of brand mission | Meaning | |
20 | Social engagement via LEGO | Meaning | G) Passing on knowledge and experience to the next generation (core category) |
21 | Awareness of salient issues | Meaning | |
22 | Altruism | Meaning |
GTA results.
They found themselves spending a lot of time and money as the product lines fired up their enthusiasm for collecting.
Moreover, the restrictive regulations of colors and shapes promoted their creativity. The author found that AFOLs usually purchase sets to collect parts necessary for their creations. In other words, they do not follow the official instructions but made original creations using blocks collected from various sources. Furthermore, each respondent is a specialist in a field of their LEGO creations, for example, graphic design or photography. Their LEGO creations inspired them with their specialties, and they recognized this synergy.
Though they aim to entertain others in addition to their own enjoyment, they face some hardships. First, realizing their ideas is not only fun but quite challenging. Furthermore, all respondents mentioned the high cost of LEGO. Some respondents do not purchase official sets, but individual authentic blocks from overseas through unofficial channels, which needs know-how.
Experiencing success in contests or recognizing well-known people in their community enthused the respondents to further create.
Importantly, the LEGO group assists those collaborative relationships. The firm officially recognizes such user communities worldwide as LEGO User Group (LUG). While LUGs contribute to diffusing LEGO, the firm supports its activities. Some respondents belong to LUGs and have indirect collaborative relationships with the firm, whereas some are more directly related to the firm such as by collaborating in new product development.
In summary, AFOLs compete with each other in creating, and such competition increases their motivation. Thus their relationships are co-creative overall. The balance between competition and co-creation enriches the respondents’ knowledge and experiences. Furthermore, it broadens their opportunities beyond LEGO creations.
As a hobby or as a source of income, the respondents commonly expanded their fields through LEGO activities and expanded their connection to society.
Moreover, some respondents eagerly passed on their experiences, which was deeply satisfying. Particularly, they were passionate about developing children’s creativities and tried to do so by holding events, establishing websites, and so on.
Referring to their beliefs, they tended to be unsatisfied with current product lines and contemporary trends in society which spoils children’s creativity.
The author finally matched the first-order categories to the PERMA model [16], where appropriate, to observe undergoing changes in the respondents (Table 1). The respondents started their experience with a ‘positive emotion,’ such as fun, then fell into absorption (‘engagement’). Then, they recognized the meaning of investing their cultivated knowledge into their creations and their ideals (‘meaning’). In the process of achieving their goals, they shared their knowledge with their peers (‘relationship’) and felt a sense of ‘accomplishment’ via competition and recognition. Finally, most were motivated to be altruistic (higher level of ‘meaning’) in the form of knowledge flow to the next generation. Four of the categories do not match PERMA elements but influenced the PERMA outcome. For example, experience in childhood includes unsatisfied feelings but it increases the respondents’ absorption in adulthood.
As a result, it was proven that the flow of knowledge sharing is circular while increasing contributors well-being (Figure 1). The respondents had accumulated knowledge and experience with LEGO since their childhood (A). They then found a renewed attraction to LEGO and became reabsorbed in it in their adulthood (B&C). They enjoyed applying their non-LEGO knowledge to their LEGO creations and realizing that it was developing their creativity (D). Sooner after, they each set their own goal which represented their ideal, but there were obstacles (E). To overcome those obstacles, they developed their skills and ideas by collaborating with other users, sometimes competing with them, which resulted in a deepening of their knowledge and experience (F). After reaching their achievements, most respondents were motivated to pass on their experiences to the next generation.
The flow of knowledge sharing.
This study concludes that the reason for knowledge sharing increases contributors well-being is that it further deepens their knowledge and experience. The respondents could further deepen their previously accumulated knowledge and experience with LEGO creation through competitive co-creation with others. Moreover, regardless of their initial goals, they converged into the broader goal of knowledge flow to the next generation which, importantly, contributes to the realization of sustainability in knowledge development.
This study demonstrates the importance of competitive co-creation with individuals utilizing personal knowledge. This personal knowledge is not necessarily related to their work or major, but rather their outside interests which were accumulated over a longer span. A marriage of diversified ideas could be the resource for innovative ideas.
The COVID-19 pandemic has restricted the flow of people and goods, but owing to the internet, not knowledge. Activation of knowledge sharing increases people’s well-being and social welfare.
This work was supported by JSPS Grants-in-Aid for Scientific Research (Grant Number 20K13631).
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The analysis of periods of research scarce, research abundance and research trends provides a dynamic view of the strategies used in this field in the last 20 years and suggests future lines of research.",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Jorge Fernández-Herrero, Gonzalo Lorenzo-Lledó and Asunción\nLledó Carreres",authors:[{id:"187920",title:"Prof.",name:"Gonzalo",middleName:null,surname:"Lorenzo",slug:"gonzalo-lorenzo",fullName:"Gonzalo Lorenzo"},{id:"189580",title:"Prof.",name:"Asunción",middleName:null,surname:"Lledó",slug:"asuncion-lledo",fullName:"Asunción Lledó"},{id:"213024",title:"Mr.",name:"Jorge",middleName:null,surname:"Fernandez-Herrero",slug:"jorge-fernandez-herrero",fullName:"Jorge Fernandez-Herrero"}]},{id:"57391",doi:"10.5772/intechopen.71287",title:"Influence of Parental Divorce on Anxiety Level of Adolescents",slug:"influence-of-parental-divorce-on-anxiety-level-of-adolescents",totalDownloads:1897,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Family divorce might have an effect on some aspects of child development. Adolescence as a transitional stage is marked by process of seeking identity, the need for intimate relationship, as well as the struggle for psychological independence from family. Anxiety is defined as a state of extreme worry, fear, and uncertainty which results from the expectation of a threatening event or situation. The aims of study are: to explore the differences in anxiety levels among adolescents from divorced and intact families; to explore the level of anxiety of adolescents from divorced and intact families with respect to their genders. A demographic questionnaire was created and The Beck Anxiety Inventory was applied to measure anxiety. The scale was applied with 162 participants who were chosen randomly from 5 different high schools in Istanbul province. The study found out that there are statistically significant differences in anxiety level of adolescents between children from divorced and intact families. Descriptive measures are in range as follows: (17.67 ± 9.645). The adolescents from divorced families had a higher level of anxiety (t = 17.322; p < .05). The result related to the second study aim shows that there are no statistically significant differences in anxiety between male and female adolescents from divorced and intact families (p > .05).",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Senija Tahirović and Gokce Demir",authors:[{id:"214445",title:"Dr.",name:"Senija",middleName:null,surname:"Tahirovic",slug:"senija-tahirovic",fullName:"Senija Tahirovic"},{id:"214465",title:"MSc.",name:"Gokce",middleName:null,surname:"Demir",slug:"gokce-demir",fullName:"Gokce Demir"}]},{id:"57269",doi:"10.5772/intechopen.71265",title:"Enhancing Young Children’s Access to Early Childhood Education and Care in Tanzania",slug:"enhancing-young-children-s-access-to-early-childhood-education-and-care-in-tanzania",totalDownloads:1494,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"This chapter draws on the current situation of limited access of young children to early childhood education and care (ECEC) settings in Tanzania. It offers information and evidence on early childhood education and care (ECEC) from an international perspective to those who are, directly or indirectly, involved with young children and their families. Basically, early childhood education and care in Tanzania is still unsatisfactory. Many children have no access to early childhood settings for various reasons including: lack of parents’ awareness on the importance of early investment in education, lack of support from the government, low socio-economic status of parents, gender discrimination, and traditional norms and cultural values. To improve the situation, there is need for a forging of partnership between the government, parents, and the community. Government policy-makers have to set clear policies regarding how quality early childhood education and care can be equitably funded and conducted throughout the country.",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Ignasia Mligo",authors:[{id:"212055",title:"Dr.",name:"Ignasia",middleName:null,surname:"Mligo",slug:"ignasia-mligo",fullName:"Ignasia Mligo"}]},{id:"57686",doi:"10.5772/intechopen.71672",title:"Children and Young People’s Vulnerabilities to Grooming",slug:"children-and-young-people-s-vulnerabilities-to-grooming",totalDownloads:2238,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Child abuse is evolving, pervasive and complex and children are vulnerable to its widespread reach in many aspects of their lives, from face-to-face interactions to those they have online. This chapter aims to review contemporary literature which outlines the vulnerabilities of children to face-to-face and online grooming as part of a process leading to child abuse and exploitation. The chapter will undertake a review of literature on two aspects of grooming: child sexual exploitation (CSE) and radicalisation. It will draw on contemporary case examples to illustrate grooming drawn from UK Serious Case Reviews (SCR) on CSE and, on radicalisation, the case of the three girls from Bethnal Green who were groomed for travel to Syria. It will then reflect on the push and pull factors of grooming to highlight the similarities between CSE and radicalisation. Moving on, the chapter will then consider how and if interactive social media simulations, linked to an innovative, preventative educational approach and designed with reference to Vygotsky’s social construction theory, have the potential to educate young people to help protect them from being groomed. The chapter will then make reference to the findings of a small pilot study which evaluated the use of this approach with young people.",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Jane Reeves, Emma Soutar, Sally Green and Tracy Crowther",authors:[{id:"211328",title:"Prof.",name:"Jane",middleName:null,surname:"Reeves",slug:"jane-reeves",fullName:"Jane Reeves"},{id:"211838",title:"Dr.",name:"Tracy",middleName:null,surname:"Crowther",slug:"tracy-crowther",fullName:"Tracy Crowther"},{id:"211839",title:"Mrs.",name:"Emma",middleName:null,surname:"Soutar",slug:"emma-soutar",fullName:"Emma Soutar"},{id:"211840",title:"Mrs.",name:"Sally",middleName:null,surname:"Green",slug:"sally-green",fullName:"Sally Green"}]},{id:"57167",doi:"10.5772/intechopen.70998",title:"The Early Childhood Educators’ Attitudes Towards Innovative Instructional Applications about Digital Learning Activities for Young Children",slug:"the-early-childhood-educators-attitudes-towards-innovative-instructional-applications-about-digital-",totalDownloads:1204,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The innovative value and practices of digital learning activities assist early childhood educators in employing effective instruction to improve young children’s performance as well as advance their own professional autonomy to implement digital learning activities for young children. This study examined the factors and relationships about early childhood educators’ attitudes towards the integration and behavioral intention of digital learning tools into young children’s innovative pedagogical activities using a questionnaire survey. The questionnaire consisted of five factors, including digital innovative value (DIV), digital innovative practices (DIP), perception of instructional use (PIU), instructional professional autonomy (IPA), and behavioral intention to use (BIU). The researcher used structural equation modeling to analyze the survey data. The results showed that early childhood educators’ perceptions about innovative value and applications of digital learning activities play a key role in the success of young children’s performance and competence in preschool. The early childhood educators with positive attitudes towards the innovative consideration and practical instructional applications of digital learning activities had more behavioral intention to plan and design instructional activities with innovative applications of digital learning tools.",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Ru-Si Chen",authors:[{id:"211677",title:"Prof.",name:"Ru-Si",middleName:null,surname:"Chen",slug:"ru-si-chen",fullName:"Ru-Si Chen"}]}],mostDownloadedChaptersLast30Days:[{id:"57686",title:"Children and Young People’s Vulnerabilities to Grooming",slug:"children-and-young-people-s-vulnerabilities-to-grooming",totalDownloads:2238,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"Child abuse is evolving, pervasive and complex and children are vulnerable to its widespread reach in many aspects of their lives, from face-to-face interactions to those they have online. This chapter aims to review contemporary literature which outlines the vulnerabilities of children to face-to-face and online grooming as part of a process leading to child abuse and exploitation. The chapter will undertake a review of literature on two aspects of grooming: child sexual exploitation (CSE) and radicalisation. It will draw on contemporary case examples to illustrate grooming drawn from UK Serious Case Reviews (SCR) on CSE and, on radicalisation, the case of the three girls from Bethnal Green who were groomed for travel to Syria. It will then reflect on the push and pull factors of grooming to highlight the similarities between CSE and radicalisation. Moving on, the chapter will then consider how and if interactive social media simulations, linked to an innovative, preventative educational approach and designed with reference to Vygotsky’s social construction theory, have the potential to educate young people to help protect them from being groomed. The chapter will then make reference to the findings of a small pilot study which evaluated the use of this approach with young people.",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Jane Reeves, Emma Soutar, Sally Green and Tracy Crowther",authors:[{id:"211328",title:"Prof.",name:"Jane",middleName:null,surname:"Reeves",slug:"jane-reeves",fullName:"Jane Reeves"},{id:"211838",title:"Dr.",name:"Tracy",middleName:null,surname:"Crowther",slug:"tracy-crowther",fullName:"Tracy Crowther"},{id:"211839",title:"Mrs.",name:"Emma",middleName:null,surname:"Soutar",slug:"emma-soutar",fullName:"Emma Soutar"},{id:"211840",title:"Mrs.",name:"Sally",middleName:null,surname:"Green",slug:"sally-green",fullName:"Sally Green"}]},{id:"57391",title:"Influence of Parental Divorce on Anxiety Level of Adolescents",slug:"influence-of-parental-divorce-on-anxiety-level-of-adolescents",totalDownloads:1897,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Family divorce might have an effect on some aspects of child development. Adolescence as a transitional stage is marked by process of seeking identity, the need for intimate relationship, as well as the struggle for psychological independence from family. Anxiety is defined as a state of extreme worry, fear, and uncertainty which results from the expectation of a threatening event or situation. The aims of study are: to explore the differences in anxiety levels among adolescents from divorced and intact families; to explore the level of anxiety of adolescents from divorced and intact families with respect to their genders. A demographic questionnaire was created and The Beck Anxiety Inventory was applied to measure anxiety. The scale was applied with 162 participants who were chosen randomly from 5 different high schools in Istanbul province. The study found out that there are statistically significant differences in anxiety level of adolescents between children from divorced and intact families. Descriptive measures are in range as follows: (17.67 ± 9.645). The adolescents from divorced families had a higher level of anxiety (t = 17.322; p < .05). The result related to the second study aim shows that there are no statistically significant differences in anxiety between male and female adolescents from divorced and intact families (p > .05).",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Senija Tahirović and Gokce Demir",authors:[{id:"214445",title:"Dr.",name:"Senija",middleName:null,surname:"Tahirovic",slug:"senija-tahirovic",fullName:"Senija Tahirovic"},{id:"214465",title:"MSc.",name:"Gokce",middleName:null,surname:"Demir",slug:"gokce-demir",fullName:"Gokce Demir"}]},{id:"57167",title:"The Early Childhood Educators’ Attitudes Towards Innovative Instructional Applications about Digital Learning Activities for Young Children",slug:"the-early-childhood-educators-attitudes-towards-innovative-instructional-applications-about-digital-",totalDownloads:1204,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"The innovative value and practices of digital learning activities assist early childhood educators in employing effective instruction to improve young children’s performance as well as advance their own professional autonomy to implement digital learning activities for young children. This study examined the factors and relationships about early childhood educators’ attitudes towards the integration and behavioral intention of digital learning tools into young children’s innovative pedagogical activities using a questionnaire survey. The questionnaire consisted of five factors, including digital innovative value (DIV), digital innovative practices (DIP), perception of instructional use (PIU), instructional professional autonomy (IPA), and behavioral intention to use (BIU). The researcher used structural equation modeling to analyze the survey data. The results showed that early childhood educators’ perceptions about innovative value and applications of digital learning activities play a key role in the success of young children’s performance and competence in preschool. The early childhood educators with positive attitudes towards the innovative consideration and practical instructional applications of digital learning activities had more behavioral intention to plan and design instructional activities with innovative applications of digital learning tools.",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Ru-Si Chen",authors:[{id:"211677",title:"Prof.",name:"Ru-Si",middleName:null,surname:"Chen",slug:"ru-si-chen",fullName:"Ru-Si Chen"}]},{id:"57680",title:"Thinking and Learning Demands in Contemporary Childhood",slug:"thinking-and-learning-demands-in-contemporary-childhood",totalDownloads:1480,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Is today’s childhood is the same as the past’s? Frankly speaking, we cannot answer this question as a clear yes. It is obvious that children today are more into tablet computers, social networks and online games than traditional child games. Besides, our communication styles have been changed significantly for the past years. We, no longer need to meet others face to face to ask for help or to chat. Artificial intelligence, machine learning and robots are another story of the contemporary world. Robots capable of perceiving their surroundings and making decisions have started to deprive many people of their jobs. But what kind of jobs will human beings perform? The increasing emphasis on innovation, cooperation, critical thinking, being creative, problem solving, communication skills and project management is an indicator of what kind of a business world will today’s children meet in the future. This on-going trend also includes clues about how should children be educated. This study is focusing on thinking and learning demands expected contemporary children to meet. Throughout the chapter, the changing world was depicted briefly and then demands of the contemporary age on critical thinking, creative thinking, problem solving and learning were explored respectively.",book:{id:"6327",slug:"contemporary-perspective-on-child-psychology-and-education",title:"Contemporary Perspective on Child Psychology and Education",fullTitle:"Contemporary Perspective on Child Psychology and Education"},signatures:"Cenk Akbiyik",authors:[{id:"212205",title:"Associate Prof.",name:"Cenk",middleName:null,surname:"Akbiyik",slug:"cenk-akbiyik",fullName:"Cenk Akbiyik"}]},{id:"57269",title:"Enhancing Young Children’s Access to Early Childhood Education and Care in Tanzania",slug:"enhancing-young-children-s-access-to-early-childhood-education-and-care-in-tanzania",totalDownloads:1494,totalCrossrefCites:2,totalDimensionsCites:2,abstract:"This chapter draws on the current situation of limited access of young children to early childhood education and care (ECEC) settings in Tanzania. 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He is currently appointed as the Voigt Chair in Data Science in the Department of Industrial Engineering, with a joint appointment as Professor in the Computer Science Division, Stellenbosch University. Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). 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Travieso-González received his MSc degree in Telecommunication Engineering at Polytechnic University of Catalonia (UPC), Spain in 1997, and his Ph.D. degree in 2002 at the University of Las Palmas de Gran Canaria (ULPGC-Spain). He is a full professor of signal processing and pattern recognition and is head of the Signals and Communications Department at ULPGC, teaching from 2001 on subjects on signal processing and learning theory. His research lines are biometrics, biomedical signals and images, data mining, classification system, signal and image processing, machine learning, and environmental intelligence. He has researched in 52 international and Spanish research projects, some of them as head researcher. He is co-author of 4 books, co-editor of 27 proceedings books, guest editor for 8 JCR-ISI international journals, and up to 24 book chapters. He has over 450 papers published in international journals and conferences (81 of them indexed on JCR – ISI - Web of Science). He has published seven patents in the Spanish Patent and Trademark Office. He has been a supervisor on 8 Ph.D. theses (11 more are under supervision), and 130 master theses. He is the founder of The IEEE IWOBI conference series and the president of its Steering Committee, as well as the founder of both the InnoEducaTIC and APPIS conference series. He is an evaluator of project proposals for the European Union (H2020), Medical Research Council (MRC, UK), Spanish Government (ANECA, Spain), Research National Agency (ANR, France), DAAD (Germany), Argentinian Government, and the Colombian Institutions. He has been a reviewer in different indexed international journals (<70) and conferences (<250) since 2001. He has been a member of the IASTED Technical Committee on Image Processing from 2007 and a member of the IASTED Technical Committee on Artificial Intelligence and Expert Systems from 2011. \n\nHe has held the general chair position for the following: ACM-APPIS (2020, 2021), IEEE-IWOBI (2019, 2020 and 2020), A PPIS (2018, 2019), IEEE-IWOBI (2014, 2015, 2017, 2018), InnoEducaTIC (2014, 2017), IEEE-INES (2013), NoLISP (2011), JRBP (2012), and IEEE-ICCST (2005)\n\nHe is an associate editor of the Computational Intelligence and Neuroscience Journal (Hindawi – Q2 JCR-ISI). He was vice dean from 2004 to 2010 in the Higher Technical School of Telecommunication Engineers at ULPGC and the vice dean of Graduate and Postgraduate Studies from March 2013 to November 2017. He won the “Catedra Telefonica” Awards in Modality of Knowledge Transfer, 2017, 2018, and 2019 editions, and awards in Modality of COVID Research in 2020.\n\nPublic References:\nResearcher ID http://www.researcherid.com/rid/N-5967-2014\nORCID https://orcid.org/0000-0002-4621-2768 \nScopus Author ID https://www.scopus.com/authid/detail.uri?authorId=6602376272\nScholar Google https://scholar.google.es/citations?user=G1ks9nIAAAAJ&hl=en \nResearchGate https://www.researchgate.net/profile/Carlos_Travieso",institutionString:null,institution:{name:"University of Las Palmas de Gran Canaria",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"23",title:"Computational Neuroscience",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",isOpenForSubmission:!0,annualVolume:11419,editor:{id:"14004",title:"Dr.",name:"Magnus",middleName:null,surname:"Johnsson",slug:"magnus-johnsson",fullName:"Magnus Johnsson",profilePictureURL:"https://mts.intechopen.com/storage/users/14004/images/system/14004.png",biography:"Dr Magnus Johnsson is a cross-disciplinary scientist, lecturer, scientific editor and AI/machine learning consultant from Sweden. \n\nHe is currently at Malmö University in Sweden, but also held positions at Lund University in Sweden and at Moscow Engineering Physics Institute. \nHe holds editorial positions at several international scientific journals and has served as a scientific editor for books and special journal issues. \nHis research interests are wide and include, but are not limited to, autonomous systems, computer modeling, artificial neural networks, artificial intelligence, cognitive neuroscience, cognitive robotics, cognitive architectures, cognitive aids and the philosophy of mind. \n\nDr. Johnsson has experience from working in the industry and he has a keen interest in the application of neural networks and artificial intelligence to fields like industry, finance, and medicine. \n\nWeb page: www.magnusjohnsson.se",institutionString:null,institution:{name:"Malmö University",institutionURL:null,country:{name:"Sweden"}}},editorTwo:null,editorThree:null},{id:"24",title:"Computer Vision",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",isOpenForSubmission:!0,annualVolume:11420,editor:{id:"294154",title:"Prof.",name:"George",middleName:null,surname:"Papakostas",slug:"george-papakostas",fullName:"George Papakostas",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002hYaGbQAK/Profile_Picture_1624519712088",biography:"George A. Papakostas has received a diploma in Electrical and Computer Engineering in 1999 and the M.Sc. and Ph.D. degrees in Electrical and Computer Engineering in 2002 and 2007, respectively, from the Democritus University of Thrace (DUTH), Greece. Dr. Papakostas serves as a Tenured Full Professor at the Department of Computer Science, International Hellenic University, Greece. Dr. Papakostas has 10 years of experience in large-scale systems design as a senior software engineer and technical manager, and 20 years of research experience in the field of Artificial Intelligence. Currently, he is the Head of the “Visual Computing” division of HUman-MAchines INteraction Laboratory (HUMAIN-Lab) and the Director of the MPhil program “Advanced Technologies in Informatics and Computers” hosted by the Department of Computer Science, International Hellenic University. He has (co)authored more than 150 publications in indexed journals, international conferences and book chapters, 1 book (in Greek), 3 edited books, and 5 journal special issues. His publications have more than 2100 citations with h-index 27 (GoogleScholar). His research interests include computer/machine vision, machine learning, pattern recognition, computational intelligence. \nDr. Papakostas served as a reviewer in numerous journals, as a program\ncommittee member in international conferences and he is a member of the IAENG, MIR Labs, EUCogIII, INSTICC and the Technical Chamber of Greece (TEE).",institutionString:null,institution:{name:"International Hellenic University",institutionURL:null,country:{name:"Greece"}}},editorTwo:null,editorThree:null},{id:"25",title:"Evolutionary Computation",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",isOpenForSubmission:!0,annualVolume:11421,editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",slug:"sebastian-ventura-soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",biography:"Sebastian Ventura is a Spanish researcher, a full professor with the Department of Computer Science and Numerical Analysis, University of Córdoba. Dr Ventura also holds the positions of Affiliated Professor at Virginia Commonwealth University (Richmond, USA) and Distinguished Adjunct Professor at King Abdulaziz University (Jeddah, Saudi Arabia). Additionally, he is deputy director of the Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI) and heads the Knowledge Discovery and Intelligent Systems Research Laboratory. He has published more than ten books and over 300 articles in journals and scientific conferences. Currently, his work has received over 18,000 citations according to Google Scholar, including more than 2200 citations in 2020. In the last five years, he has published more than 60 papers in international journals indexed in the JCR (around 70% of them belonging to first quartile journals) and he has edited some Springer books “Supervised Descriptive Pattern Mining” (2018), “Multiple Instance Learning - Foundations and Algorithms” (2016), and “Pattern Mining with Evolutionary Algorithms” (2016). He has also been involved in more than 20 research projects supported by the Spanish and Andalusian governments and the European Union. He currently belongs to the editorial board of PeerJ Computer Science, Information Fusion and Engineering Applications of Artificial Intelligence journals, being also associate editor of Applied Computational Intelligence and Soft Computing and IEEE Transactions on Cybernetics. Finally, he is editor-in-chief of Progress in Artificial Intelligence. He is a Senior Member of the IEEE Computer, the IEEE Computational Intelligence, and the IEEE Systems, Man, and Cybernetics Societies, and the Association of Computing Machinery (ACM). Finally, his main research interests include data science, computational intelligence, and their applications.",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"26",title:"Machine Learning and Data Mining",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",isOpenForSubmission:!0,annualVolume:11422,editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. 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His research interests include swarm intelligence, parallel and distributed metaheuristics, machine learning, intelligent agents and multi-agent systems, resource planning, scheduling and optimization, combinatorial optimization. Dr. Aydin is currently a Fellow of Higher Education Academy, UK, a member of EPSRC College, a senior member of IEEE and a senior member of ACM. In addition to being a member of advisory committees of many international conferences, he is an Editorial Board Member of various peer-reviewed international journals. 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He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. 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Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 29th, 2022",hasOnlineFirst:!0,numberOfOpenTopics:4,numberOfPublishedChapters:318,numberOfPublishedBooks:32,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},subseries:[{id:"14",title:"Cell and Molecular Biology",keywords:"Omics (Transcriptomics; Proteomics; Metabolomics), Molecular Biology, Cell Biology, Signal Transduction and Regulation, Cell Growth and Differentiation, Apoptosis, Necroptosis, Ferroptosis, Autophagy, Cell Cycle, Macromolecules and Complexes, Gene Expression",scope:"The Cell and Molecular Biology topic within the IntechOpen Biochemistry Series aims to rapidly publish contributions on all aspects of cell and molecular biology, including aspects related to biochemical and genetic research (not only in humans but all living beings). We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics include, but are not limited to: Advanced techniques of cellular and molecular biology (Molecular methodologies, imaging techniques, and bioinformatics); Biological activities at the molecular level; Biological processes of cell functions, cell division, senescence, maintenance, and cell death; Biomolecules interactions; Cancer; Cell biology; Chemical biology; Computational biology; Cytochemistry; Developmental biology; Disease mechanisms and therapeutics; DNA, and RNA metabolism; Gene functions, genetics, and genomics; Genetics; Immunology; Medical microbiology; Molecular biology; Molecular genetics; Molecular processes of cell and organelle dynamics; Neuroscience; Protein biosynthesis, degradation, and functions; Regulation of molecular interactions in a cell; Signalling networks and system biology; Structural biology; Virology and microbiology.",annualVolume:11410,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"79367",title:"Dr.",name:"Ana Isabel",middleName:null,surname:"Flores",fullName:"Ana Isabel Flores",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRpIOQA0/Profile_Picture_1632418099564",institutionString:null,institution:{name:"Hospital Universitario 12 De Octubre",institutionURL:null,country:{name:"Spain"}}},{id:"328234",title:"Ph.D.",name:"Christian",middleName:null,surname:"Palavecino",fullName:"Christian Palavecino",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000030DhEhQAK/Profile_Picture_1628835318625",institutionString:null,institution:{name:"Central University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",fullName:"Francisco Javier Martin-Romero",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",institutionString:null,institution:{name:"University of Extremadura",institutionURL:null,country:{name:"Spain"}}}]},{id:"15",title:"Chemical Biology",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. 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Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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