Allergic Inflammatory Disorders Research Articles

Effect of bisphenol A on formation and process of alergic reaction - review

One of the possible immunomodulatory effects of BPA is alterating the allergy process and asthma. The growth in the prevalence of asthma around the world roughly corresponds with the rise in the widespread usage of certain chemicals. Despite the fact that asthma is a complicated and varied condition brought on by exposure to a variety of environmental factors and genetic predispositions, many classes of chemicals that are frequently present in the surrounding environment and are linked to endocrine disruption have recently been linked to the disease's pathogenesis. BPA is endocrine disrupting chemical compound made up of two phenol rings joined by a methyl bridge and two methyl functional groups adhered to the bridge. BPA is ingested by humans, inhaled via home dust, and exposed through the skin. An allergy is an aberrant immunological reaction to an antigen, such as a protein or allergen. An ingested or breathed allergen encounters the epithelium as its initial barrier. The inflammatory condition and increased permeability of the epithelial barrier are associated with allergic inflammatory disorders, and this suggests that the epithelium barrier is more sensitive to allergen sensitization. The existing literature and scientific publications do not adequately address the direct influence of bisphenols on the development and influence of the allergic process. Multiple authors discuss how bisphenol affects specific allergic response components. We may conclude that exposure to bisphenol A alters the allergic response based on the findings of the studies and the analysis of the literature.

Comorbidities in childhood atopic dermatitis: A population-based study.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that is associated with allergic comorbidities. However, studies examining comorbidities in childhood AD are incomplete, which may contribute to suboptimal care. The objective was to compare the risk of developing different allergic and non-allergic comorbidities among children with AD to that of a matched non-AD reference cohort in Sweden. This was a nationwide population-based cohort study using longitudinal data from primary and specialist care registers. Patients with AD were identified by confirmed diagnosis in primary or specialist care. The non-AD reference cohort was randomly drawn from the general population and matched 1:1 with the AD patients. The risk of developing the following conditions was evaluated: hypersensitivity and allergic disorders, neurological disorders, psychiatric disorders, infections, immunological and inflammatory disorders, Type 1 diabetes (T1D), endocrine and metabolic disorders, skeletal disorders, ocular disorders and malignancies. This study included 165,145 patients with AD (mild-to-moderate [n = 126,681] and severe [n = 38,464]) and an equally sized reference cohort. Patients with AD displayed a higher risk of developing comorbid conditions for all investigated categories, except for T1D and skeletal disorders, compared with the reference cohort. The highest risk compared with the reference cohort was observed for hypersensitivity and allergic disorders (hazard ratio [HR]: 3.87), followed by malignancies (HR: 2.53) and immunological and inflammatory disorders (HR: 2.36). Patients with AD also had higher risk of developing multiple comorbidities (≥2). The risk of comorbidity onset increased alongside AD severity and patients with active AD were associated with increased risk of comorbidity onset compared with patients in remission. The clinical burden of AD is substantial for children with AD and patients are at an increased risk of developing several comorbid conditions extending beyond the atopic march. Our results also showed a positive association between worsening severity of AD and an increased risk of comorbidity onset.

Carnosic acid inhibits secretion of allergic inflammatory mediators in IgE-activated mast cells via direct regulation of Syk activation

Mast cells are essential regulators of inflammation most recognized for their central role in allergic inflammatory disorders. Signaling via the high-affinity immunoglobulin E (IgE) receptor, FcεRI, leads to rapid degranulation of preformed granules and the sustained release of newly synthesized proinflammatory mediators. Our group recently established rosemary extract as a potent regulator of mast cell functions, attenuating MAPK and NF-κB signaling. Carnosic acid (CA)-a major polyphenolic constituent of rosemary extract-has been shown to exhibit anti-inflammatory effects in other immune cell models, but its role as a potential modulator of mast cell activation is undefined. Therefore, we sought here to determine the modulatory effects of CA in a mast cell model of allergic inflammation. We sensitized bone marrow-derived mast cells with anti-trinitrophenyl IgE and activated with allergen (TNP-BSA) under stem cell factor potentiation, in addition to treatment with CA. Our results indicate that CA significantly inhibits allergen-induced early phase responses including Ca2+ mobilization, ROS production, and subsequent degranulation. We also show CA treatment reduced late phase responses, including the release of all cytokines and chemokines examined following IgE stimulation and corresponding gene expression excepting that of CCL2. Importantly, we determined that CA mediates its inhibitory effects through modulation of tyrosine kinase Syk and downstream effectors TAK1 (Ser412) and Akt (Ser473) as well as NFκB signaling, while phosphorylation of FcεRI (γ chain) and MAPK proteins remained unaltered. These novel findings establish CA as a potent modulator of mast cell activation, warranting further investigation as a putative anti-allergy therapeutic.

Highly potent and selective 5-lipoxygenase inhibition by new, simple heteroaryl-substituted catechols for treatment of inflammation

5-Lipoxygenase (LO) catalyzes the first steps in the formation of pro-inflammatory leukotrienes (LT) that are pivotal lipid mediators contributing to allergic reactions and inflammatory disorders. Based on its key role in LT biosynthesis, 5-LO is an attractive drug target, demanding for effective and selective inhibitors with efficacy in vivo, which however, are still rare. Encouraged by the recent identification of the catechol 4-(3,4-dihydroxyphenyl)dibenzofuran 1 as 5-LO inhibitor, simple structural modifications were made to yield even more effective and selective catechol derivatives. Within this new series, the two most potent compounds 3,4-dihydroxy-3′-phenoxybiphenyl (6b) and 2-(3,4-dihydroxyphenyl)benzo[b]thiophene (6d) potently inhibited human 5-LO in cell-free (IC506b and 6d = 20 nM) and cell-based assays (IC506b = 70 nM, 6d = 60 nM). Inhibition of 5-LO was reversible, unaffected by exogenously added substrate arachidonic acid, and not primarily mediated via radical scavenging and antioxidant activities. Functional 5-LO mutants expressed in HEK293 cells were still prone to inhibition by 6b and 6d, and docking simulations revealed distinct binding of the catechol moiety to 5-LO at an allosteric site. Analysis of 5-LO nuclear membrane translocation and intracellular Ca2+ mobilization revealed that these 5-LO-activating events are hardly affected by the catechols. Importantly, the high inhibitory potency of 6b and 6d was confirmed in human blood and in a murine zymosan-induced peritonitis model in vivo. Our results enclose these novel catechol derivatives as highly potent, novel type inhibitors of 5-LO with high selectivity and with marked effectiveness under pathophysiological conditions.

A Case Report on Multiple Adverse Events Associated with Systemic Usage of Dexamethasone

Dexamethasone is a corticosteroid used in the management of various allergic conditions, inflammatory and autoimmune disorders such as rheumatoid arthritis, nausea and vomiting associated with cancer chemotherapy, multiple sclerosis, cerebral edema. ADRs associated usage of corticosteroids includes steroid-induced hyperglycemia, osteoporosis, dyslipidemia, steroid-induced Cushing syndrome, cataracts, increased risk of infections, and thinning of the skin. Cushing's syndrome is a hormonal disorder triggered due to chronic exposure of body tissues to high levels of cortisol. As corticosteroids are widely used by physicians for the management of various inflammatory disorders, patients must be warned about the possible ADRs associated with chronic use. In summary, this is a case of a patient who developed multiple adverse events after usage of dexamethasone that is evident by clinical features and laboratory investigations for which the patient was successfully provided with symptomatic and supportive care.
 Keywords: Adverse Drug Reaction (ADR), Buffalo hump, Hyperglycaemia, Osteoporosis.

Short-Chain Fatty Acids Augment Differentiation and Function of Human Induced Regulatory T Cells

Regulatory T cells (Tregs) control immune system activity and inhibit inflammation. While, in mice, short-chain fatty acids (SCFAs) are known to be essential regulators of naturally occurring and in vitro induced Tregs (iTregs), data on their contribution to the development of human iTregs are sparse, with no reports of the successful SCFAs-augmented in vitro generation of fully functional human iTregs. Likewise, markers undoubtedly defining human iTregs are missing. Here, we aimed to generate fully functional human iTregs in vitro using protocols involving SCFAs and to characterize the underlying mechanism. Our target was to identify the potential phenotypic markers best characterizing human iTregs. Naïve non-Treg CD4+ cells were isolated from the peripheral blood of 13 healthy adults and cord blood of 12 healthy term newborns. Cells were subjected to differentiation toward iTregs using a transforming growth factor β (TGF-β)-based protocol, with or without SCFAs (acetate, butyrate, or propionate). Thereafter, they were subjected to flow cytometric phenotyping or a suppression assay. During differentiation, cells were collected for chromatin-immunoprecipitation (ChIP)-based analysis of histone acetylation. The enrichment of the TGF-β-based protocol with butyrate or propionate potentiated the in vitro differentiation of human naïve CD4+ non-Tregs towards iTregs and augmented the suppressive capacity of the latter. These seemed to be at least partly underlain by the effects of SCFAs on the histone acetylation levels in differentiating cells. GITR, ICOS, CD39, PD-1, and PD-L1 were proven to be potential markers of human iTregs. Our results might boost the further development of Treg-based therapies against autoimmune, allergic and other chronic inflammatory disorders.

Psychosocial impact of ocular surface allergic inflammatory disorders.

Allergic rhinoconjunctivitis is one of the most common ocular surface allergic inflammatory conditions seen in primary care that impacts patient's quality of life. Allergic conjunctivitis is increasingly being recognized as its own symptom complex that negatively impacts patient's quality of life separate from allergic rhinitis. This article reviews the psychosocial impact of ocular surface allergic inflammatory disorders (namely seasonal allergic conjunctivitis, ocular allergy, perennial allergic conjunctivitis, and atopic keratoconjunctivitis) on adult and pediatric populations. Despite the perception that allergic conjunctivitis is a trivial condition, it imposes a burden on numerous psychosocial aspects of life for adolescents and adults. Several questionnaires specific to rhinoconjunctivitis have been found to be effective tools at gauging quality of life (QoL) and communicating impairments in specific behavioral domains for adult and pediatric populations. An emerging focus on the role of hormone fluctuations and age on ocular surface allergic inflammation underscores the importance of nuancing the physiologic effects on ocular allergy and QoL at every decade of life. Further exploration and research of symptoms by age would greatly improve our understanding of age's impact on QoL in these patients and contribute to improved management of allergic conjunctivitis.

Paeoniflorin attenuates the allergic contact dermatitis response via inhibiting the IFN-γ production and the NF-κB/IκBα signaling pathway in T lymphocytes

Paeoniflorin (PF) has been demonstrated to have an anti-allergic and anti-inflammatory effect in the treatment of allergic contact dermatitis (ACD). However, its clinical application is hampered by the lacking of comprehensive mechanical explanation. This research aimed to study the effect of PF on the proliferation, apoptosis and cytokines secretion as well as the expression of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways of T lymphocytes activation in vitro and in vivo. We found that PF depressed human T lymphocytes activation via inhibition ofinterferon-gamma (IFN-γ) production and NF-κB/IκBα and p38 MAPK signaling pathway in vitro, also PF could attenuate such ACD responses by inhibiting the production of IFN-γ and NF-κB/IκBα pathway in T lymphocytes of ACD mouse model, suggesting that PF might be useful for the treatment of T cell-mediated allergic inflammatory disorders such as ACD. This would make PF a promising T cell-targeted drug candidate for further study because of its immunosuppressive and anti-inflammatory effects.

Molecular Modeling of Histamine Receptors-Recent Advances in Drug Discovery.

The recent developments of fast reliable docking, virtual screening and other algorithms gave rise to discovery of many novel ligands of histamine receptors that could be used for treatment of allergic inflammatory disorders, central nervous system pathologies, pain, cancer and obesity. Furthermore, the pharmacological profiles of ligands clearly indicate that these receptors may be considered as targets not only for selective but also for multi-target drugs that could be used for treatment of complex disorders such as Alzheimer’s disease. Therefore, analysis of protein-ligand recognition in the binding site of histamine receptors and also other molecular targets has become a valuable tool in drug design toolkit. This review covers the period 2014–2020 in the field of theoretical investigations of histamine receptors mostly based on molecular modeling as well as the experimental characterization of novel ligands of these receptors.

Gross ways to live long: Parasitic worms as an anti-inflammaging therapy?

Evolutionary medicine argues that disease can arise because modern conditions do not match those in which we evolved. For example, a decline in exposure to commensal microbes and gastrointestinal helminths in developed countries has been linked to increased prevalence of allergic and autoimmune inflammatory disorders (the hygiene hypothesis). Accordingly, probiotic therapies that restore ‘old friend’ microbes and helminths have been explored as Darwinian treatments for these disorders. A further possibility is that loss of old friend commensals also increases the sterile, aging-associated inflammation known as inflammaging, which contributes to a range of age-related diseases, including cardiovascular disease, dementia, and cancer. Interestingly, Crowe et al., 2020 recently reported that treatment with a secreted glycoprotein from a parasitic nematode can protect against murine aging by induction of anti-inflammatory mechanisms. Here, we explore the hypothesis that restorative helminth therapy would have anti-inflammaging effects. Could worm infections provide broad-spectrum protection against age-related disease?

Allergies and Asthma in a Warming World: A Threat to Public Health

The prevalence of allergic diseases has risen in industrialized countries over the past 50 years.(Arbes, Gergen, Elliott, & Zeldin, 2005; Meng, Nagarajan, Son, Koutsoupias, & Bielory, 2016) Likewise, pollen counts have risen over the same period of time and are predicted to continue rising.(Zhang, Bielory, Cai, Mi, & Georgopoulos, 2015; Zhang, Bielory, Mi, et al., 2015) This is not only problematic for the millions of people who suffer from seasonal allergies affecting the eyes and upper airways (nose, sinuses, and eustachian tubes) but also for those who suffer from lower inflammatory respiratory disorders (e.g. asthma). A significant factor contributing to this observation has been climate change. Sensitivity to seasonal aeroallergens (i.e. pollen) has frequently been used to study the relationship between pollution, climate change, and allergic inflammatory respiratory disorders (e.g. rhinitis and asthma) (D'Amato et al., 2015).

HMGB1-mediated chromatin remodeling attenuates Il24 gene expression for the protection from allergic contact dermatitis

Significance High-mobility group box 1 protein (HMGB1) protein gained attention for its proinflammatory function in a number of pathological conditions, such as skin inflammation. In this study, a Cre/loxP-engineered mouse strain allowed for HMGB1 conditionally ablated in keratinocytes. When allergic contact dermatitis was induced in the HMGB1 mutant mice, skin inflammation was exacerbated in the mutant mice. Expression of interleukin-24 (IL-24), a proinflammatory cytokine associated to skin inflammatory disorders, was elevated in skin lesions of these mice. We also adduced evidence that that HMGB1 represses the binding of histone H3 (lys4) (H3K4me3) to the Il24 gene promoter in keratinocytes. Therefore, our study revealed a facet of nuclear HMGB1 that represses the Il24 gene for the suppression of allergic inflammatory skin disorders.

Oleanolic acid protects against mast cell-mediated allergic responses by suppressing Akt/NF-κB and STAT1 activation

BackgroundOleanolic acid (OA) is an active compound found in a variety of medicinal herbs and plants. Though OA has been widely attributed with a variety of biological activities, studies focused on its anti-allergic inflammation properties are insufficient. PurposeGiven the rapid increase in allergic diseases and the lack of fundamental treatment options, this study aimed to find a safe and effective therapy for allergic disorders. MethodsWe evaluated the inhibitory effect of OA on allergic inflammatory response and the possible mechanisms underlying the effect using phorbol-12-myristate 13-acetate plus calcium ionophore A23187 (PMACI)-stimulated human mast cell (HMC)-1, and a mouse model of compound 48/80-induced anaphylactic shock. ResultsOA suppressed pro-inflammatory cytokine expressions in PMACI-induced HMC-1 cells by inhibiting activation of the Akt, p38 mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), and signal transducer and activator of transcription (STAT) 1 signaling pathways. Moreover, OA showed a protective effect against compound 48/80-induced anaphylactic shock through inhibition of histamine release and immunoglobulin E level via regulation of NF-κB and STAT1 activation. ConclusionThe results showed that OA suppressed mast cell-mediated allergic response by transcriptional regulation. We suggest that OA has potential effect against allergic inflammatory disorders, including anaphylaxis, and might be a useful therapeutic agent for allergic disease.

Host–microbiota interactions in immune-mediated diseases

Host-microbiota interactions are fundamental for the development of the immune system. Drastic changes in modern environments and lifestyles have led to an imbalance of this evolutionarily ancient process, coinciding with a steep rise in immune-mediated diseases such as autoimmune, allergic and chronic inflammatory disorders. There is an urgent need to better understand these diseases in the context of mucosal and skin microbiota. This Review discusses the mechanisms of how the microbiota contributes to the predisposition, initiation and perpetuation of immune-mediated diseases in the context of a genetically prone host. It is timely owing to the wealth of new studies that recently contributed to this field, ranging from metagenomic studies in humans and mechanistic studies of host-microorganism interactions in gnotobiotic models and in vitro systems, to molecular mechanisms with broader implications across immune-mediated diseases. We focus on the general principles, such as breaches in immune tolerance and barriers, leading to the promotion of immune-mediated diseases by gut, oral and skin microbiota. Lastly, the therapeutic avenues that either target the microbiota, the barrier surfaces or the host immune system to restore tolerance and homeostasis will be explored.

SG-SP1 suppresses mast cell-mediated allergic inflammation via inhibition of FcɛRI signaling

Abstract As the number of allergic disease cases increases, studies to identify new treatments take on new urgency. In previous study, gallic acid (GA), a part of EGCG, a major component of green tea, has shown anti-allergic inflammatory effect. However, GA has low metabolic stability and structure-activity relationship. Therefore, we designed SG-SP1 based on GA. We aimed to assess the effects of SG-SP1 on mast cell-mediated allergic inflammation using various animal and in vitro models. For in vitro experiments, IgE-mediated various mast cells (RBL-2H3 and primary cultured peritoneal and bone marrow-derived mast cells) were used to determine the role of SG-SP1 (0.1–1 nM). Immunoglobulin (Ig) E-induced passive cutaneous anaphylaxis and Ovalbumin-induced systemic anaphylaxis are standard animal models for immediate-type hypersensitivity. For in vitro, SG-SP1 reduced degranulation of mast cells by down-regulating intracellular calcium levels in a concentration-dependent manner. In addition, SG-SP1 decreased expression and secretion of inflammatory cytokines in activated mast cells. This suppressive effect was associated to inhibition of the phosphorylation of Lyn, Syk and Akt, and the nuclear translocation of nuclear factor-κB. Due to the strong inhibitory effect of SG-SP1 on Lyn, the known upstream signaling of FcɛRI-dependent pathway, we confirmed the direct binding of SG-SP1 to FcɛRI, a high affinity IgE receptor by surface plasmon resonance experiment. We determined that SG-SP1 directly interacts with FcɛRI and propose SG-SP1 as a therapeutic candidate for mast cell-mediated allergic inflammatory disorders via inhibition of FcɛRI signaling.

TAK1ng aim at mechanisms of allergic inflammation: contribution of TAK1 activity in allergen‐mediated mast cell activation

Allergic inflammatory disorders are at epidemic levels worldwide. Mast cells drive this inappropriate immune response via release of a variety of pro‐inflammatory mediators in response to environmental cues detected by the IgE‐FcɛRI complex, but the contributing molecular mechanisms are not fully understood. Transforming growth factor β‐activated kinase 1 (TAK1) is a known participant in related signaling through both the MAPK and NFκB pathways; however, the role of TAK1 in IgE‐FcɛRI mediated signaling and resultant allergic inflammation remains unknown. This study was carried out to assess the role of TAK1 in IgE‐mediated mast cell activation and to determine the effect its inhibition would have on the severity of an allergic inflammatory response. Assessment of the role of TAK1 was conducted by exploiting the characterized inhibitory function of 5Z‐7‐oxozeaenol (OZ), a resorcylic acid lactone established to be an ATP‐competitive selective inhibitor of TAK1. Bone marrow‐derived mast cells were sensitized with allergen‐specific IgE and treated with the corresponding allergen for various times in the presence or absence of OZ. Mast cell signaling was measured by western blotting, induced gene expression by qPCR, pro‐inflammatory mediator release by ELISA, mast cell degranulation by β‐hexosaminidase release assay, and calcium mobilization alterations via Indo‐1 based spectrofluorometry. We detect novel activation of TAK1 at Ser412 in response to IgE‐mediated activation under SCF‐c‐kit potentiation in a mast cell‐driven response characteristic of allergic inflammation, which is potently blocked by TAK1 inhibitor OZ. We therefore interrogated the role of TAK1 in a series of mast cell mediator responses using IgE‐sensitized murine bone marrow‐derived mast cells, stimulated with allergen under several TAK1 inhibition strategies. TAK1 inhibition resulted in significant impairment in the phosphorylation of MAPKs p38, ERK, and JNK; and mediation of the NFκB pathway via IκBα. Impaired gene expression and near abrogation in release of pro‐inflammatory cytokines TNF (p<0.0001), IL‐6 (p<0.0001), IL‐13 (p<0.0001), and chemokines CCL1 (p=0.0002), and CCL2 (p<0.0001) was detected. Finally, a significant inhibition of mast cell degranulation (p<0.0001), accompanied by an impairment in calcium mobilization, was observed in the TAK1‐inhibited cells. These results suggest that TAK1 acts as a signaling node, not only linking the MAPK and NFκB pathways in driving the late‐phase response, but also initiation of the degranulation mechanism of the mast cell early‐phase response following allergen recognition and may warrant consideration in future therapeutic development.Support or Funding InformationFunding: This work was supported by the Natural Sciences and Engineering Research Council (NSERC), the Canada Foundation for Innovation (CFI), the Ontario Research Fund (ORF), and Ontario Graduate Scholarships.

TAK1 signaling activity links the mast cell cytokine response and degranulation in allergic inflammation.

Mast cells drive the inappropriate immune response characteristic of allergic inflammatory disorders via release of pro-inflammatory mediators in response to environmental cues detected by the IgE-FcεRI complex. The role of TGF-β-activated kinase 1 (TAK1), a participant in related signaling in other contexts, remains unknown in allergy. We detect novel activation of TAK1 at Ser412 in response to IgE-mediated activation under SCF-c-kit potentiation in a mast cell-driven response characteristic of allergic inflammation, which is potently blocked by TAK1 inhibitor 5Z-7-oxozeaenol (OZ). We, therefore, interrogated the role of TAK1 in a series of mast cell-mediated responses using IgE-sensitized murine bone marrow-derived mast cells, stimulated with allergen under several TAK1 inhibition strategies. TAK1 inhibition by OZ resulted in significant impairment in the phosphorylation of MAPKs p38, ERK, and JNK; and mediation of the NF-κB pathway via IκBα. Impaired gene expression and near abrogation in release of pro-inflammatory cytokines TNF, IL-6, IL-13, and chemokines CCL1, and CCL2 was detected. Finally, a significant inhibition of mast cell degranulation, accompanied by an impairment in calcium mobilization, was observed in TAK1-inhibited cells. These results suggest that TAK1 acts as a signaling node, not only linking the MAPK and NF-κB pathways in driving the late-phase response, but also initiation of the degranulation mechanism of the mast cell early-phase response following allergen recognition and may warrant consideration in future therapeutic development.

Anti-Allergic and Anti-Inflammatory Effects and Molecular Mechanisms of Thioredoxin on Respiratory System Diseases.

Significance: The pathogenesis and progression of allergic inflammation in the respiratory system are closely linked to oxidative stress. Thioredoxin (TRX) is an essential redox balance regulator in organisms and is induced by various oxidative stress factors, including ultraviolet rays, radiation, oxidation, viral infections, ischemia reperfusion, and anticancer agents. Recent Advances: We demonstrated that systemic administration and transgenic overexpression of TRX is useful in a wide variety of in vivo inflammatory respiratory diseases models, such as viral pneumonia, interstitial lung disease, chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome, and obstructive sleep apnea syndrome, by removing reactive oxygen species, blocking production of inflammatory cytokines, inhibiting migration and activation of neutrophils and eosinophils, and regulating the cellular redox status. In addition, TRX's anti-inflammatory mechanism is different from the mechanisms associated with anti-inflammatory agents, such as glucocorticoids, which regulate the inflammatory reaction in association with suppressing immune responses. Critical Issues: Understanding the molecular mechanism of TRX is very helpful for understanding the role of TRX in respiratory diseases. In this review, we show the protective effect of TRX in various respiratory diseases. In addition, we discuss its anti-allergic and anti-inflammatory molecular mechanism in detail. Future Directions: The application of TRX may be useful for treating respiratory allergic inflammatory disorders. Antioxid. Redox Signal. 32, 785-801.

SG-SP1 Suppresses Mast Cell-Mediated Allergic Inflammation via Inhibition of FcεRI Signaling

Background: As the number of allergic disease increases, studies to identify new treatments take on new urgency. Epigallocatechin gallate (EGCG), a major component of green tea, has been shown to possess a wide range of pharmacological properties, including anti-inflammation and anti-viral infection. In previous study, gallic acid (GA), a part of EGCG, has shown anti-allergic inflammatory effect. To improve on preliminary evidence that GA has allergy mitigating effect, we designed SG-SP1 based on GA, and aimed to assess the effects of SG-SP1 on mast cell-mediated allergic inflammation using various animal and in vitro models.Methods: For in vitro experiments, various types of IgE-stimulated mast cells (RBL-2H3: mast cell-like basophilic leukemia cells, and primary cultured peritoneal and bone marrow-derived mast cells) were used to determine the role of SG-SP1 (0.1–1 nM). Immunoglobulin (Ig) E-induced passive cutaneous anaphylaxis and ovalbumin-induced systemic anaphylaxis, standard animal models for immediate-type hypersensitivity were also used.Results: For in vitro, SG-SP1 reduced degranulation of mast cells by down-regulating intracellular calcium levels in a concentration-dependent manner. SG-SP1 decreased expression and secretion of inflammatory cytokines in activated mast cells. This suppressive effect was associated with inhibition of the phosphorylation of Lyn, Syk and Akt, and the nuclear translocation of nuclear factor-κB. Due to the strong inhibitory effect of SG-SP1 on Lyn, the known upstream signaling to FcεRI-dependent pathway, we confirmed the direct binding of SG-SP1 to FcεRI, a high affinity IgE receptor by surface plasmon resonance experiment. Oral administration of SG-SP1 hindered allergic symptoms of both anaphylaxis models evidenced by reduction of hypothermia, serum IgE, ear thickness, and tissue pigmentation. This inhibition was mediated by the reductions in serum histamine and interleukin-4.Conclusions: We determined that SG-SP1 directly interacts with FcεRI and propose SG-SP1 as a therapeutic candidate for mast cell-mediated allergic inflammatory disorders via inhibition of FcεRI signaling.

Melatonin and Allergic Rhinitis

Atopy is a tendency to produce Ig-E antibodies in response to allergens and to develop allergic clinical symptoms such as allergic rhinitis, allergic bronchial asthma, and atopic dermatitis. Among them, allergic rhinitis AR is a chronic inflammatory disease of the intranasal mucosa, characterized by nasal symptoms reducing the quality of life. Management of AR maintains entirely symptomatic and is intended only to relieve the undesirable effects of mediators resulting from the allergic inflammatory reaction. The only disease-modifying treatment is immunotherapy, which can eliminate the pathophysiology of the disease. However, it is a long-lasting modality with several limitations and contraindications. In recent years, melatonin has been evaluated in various allergic inflammatory disorders due to its anti-inflammatory and antioxidant properties and has been suggested as a promising therapeutic. The role of melatonin has not been investigated in the treatment of AR, even though AR has a similar pathogenesis to those of atopic dermatitis and allergic bronchial asthma. This review is aimed to examine the pathophysiological mechanism of AR and illuminate the common pathways with atopic dermatitis and allergic bronchial asthma to discuss the potential hypothetical therapeutic role of the melatonin in AR, similar to the other two atopic diseases