The dysadherin/FAK axis promotes individual cell migration in colon cancer.

Dysregulation of cancer cell motility is a key driver of invasion and metastasis. High dysadherin expression in cancer cells is correlated with invasion and metastasis. Here, we found the molecular mechanism by which dysadherin regulates the migration and invasion of colon cancer (CC). Comprehensive analysis using single-cell RNA sequencing data from CC patients revealed that high dysadherin expression in cells is linked to cell migration-related gene signatures. We confirmed that the deletion of dysadherin in tumor cells hindered local invasion and distant migration using in vivo tumor models. In this context, by performing cell morphological analysis, we found that aberrant cell migration resulted from impaired actin dynamics, focal adhesion turnover and protrusive structure formation upon dysadherin expression. Mechanistically, the activation of focal adhesion kinase (FAK) was observed in dysadherin-enriched cells. The dysadherin/FAK axis enhanced cell migration and invasion by activating the FAK downstream cascade, which includes the Rho family of small GTPases. Overall, this study illuminates the role of dysadherin in modulating cancer cell migration by forcing actin dynamics and protrusive structure formation via FAK signaling, indicating that targeting dysadherin may be a potential therapeutic strategy for CC patients.

SEC22B inhibition attenuates colorectal cancer aggressiveness and autophagic flux under unfavorable environment.

Autophagy has bidirectional functions in cancer by facilitating cell survival and death in a context-dependent manner. Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are a large family of proteins essential for numerous biological processes, including autophagy; nevertheless, their potential function in cancer malignancy remains unclear. Here, we explored the gene expression patterns of SNAREs in tissues of patients with colorectal cancer (CRC) and discovered that SEC22B expression, a vesicle SNARE, was higher in tumor tissues than in normal tissues, with a more significant increase in metastatic tissues. Interestingly, SEC22B knockdown dramatically decreased CRC cell survival and growth, especially under stressful conditions, such as hypoxia and serum starvation, and decreased the number of stress-induced autophagic vacuoles. Moreover, SEC22B knockdown successfully attenuated liver metastasis in a CRC cell xenograft mouse model, with histological signs of decreased autophagic flux and proliferation within cancer cells. Together, this study posits that SEC22B plays a crucial role in enhancing the aggressiveness of CRC cells, suggesting that SEC22B might be an attractive therapeutic target for CRC.

Machine learning with in silico analysis markedly improves survival prediction modeling in colon cancer patients.

BACKGROUND: Predicting the survival of cancer patients provides prognostic information and therapeutic guidance. However, improved prediction models are needed for use in diagnosis and treatment. OBJECTIVE: This study aimed to identify genomic prognostic biomarkers related to colon cancer (CC) based on computational data and to develop survival prediction models. METHODS: We performed machine-learning (ML) analysis to screen pathogenic survival-related driver genes related to patient prognosis by integrating copy number variation and gene expression data. Moreover, in silico system analysis was performed to clinically assess data from ML analysis, and we identified RABGAP1L, MYH9, and DRD4 as candidate genes. These three genes and tumor stages were used to generate survival prediction models. Moreover, the genes were validated by experimental and clinical analyses, and the theranostic application of the survival prediction models was assessed. RESULTS: RABGAP1L, MYH9, and DRD4 were identified as survival-related candidate genes by ML and in silico system analysis. The survival prediction model using the expression of the three genes showed higher predictive performance when applied to predict the prognosis of CC patients. A series of functional analyses revealed that each knockdown of three genes reduced the protumor activity of CC cells. In particular, validation with an independent cohort of CC patients confirmed that the coexpression of MYH9 and DRD4 gene expression reflected poorer clinical outcomes in terms of overall survival and disease-free survival. CONCLUSIONS: Our survival prediction approach will contribute to providing information on patients and developing a therapeutic strategy for CC patients.

DCLK1 promotes colorectal cancer stemness and aggressiveness via the XRCC5/COX2 axis.

Rationale: Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase that selectively marks cancer stem-like cells (CSCs) and promotes malignant progression in colorectal cancer (CRC). However, the exact molecular mechanism by which DCLK1 drives the aggressive phenotype of cancer cells is incompletely determined. Methods: Here, we performed comprehensive genomics and proteomics analyses to identify binding proteins of DCLK1 and discovered X-ray repair cross-complementing 5 (XRCC5). Thus, we explored the biological role and downstream events of the DCLK1/XRCC5 axis in human CRC cells and CRC mouse models. Results: The results of comprehensive bioinformatics analyses suggested that DCLK1-driven CRC aggressiveness is linked to inflammation. Mechanistically, DCLK1 bound and phosphorylated XRCC5, which in turn transcriptionally activated cyclooxygenase-2 expression and enhanced prostaglandin E2 production; these events collectively generated the inflammatory tumor microenvironment and enhanced the aggressive behavior of CRC cells. Consistent with the discovered mechanism, inhibition of DCLK1 kinase activity strongly impaired the tumor seeding and growth capabilities in CRC mouse models. Conclusion: Our study illuminates a novel mechanism that mediates the pro-inflammatory function of CSCs in driving the aggressive phenotype of CRC, broadening the biological function of DCLK1 in CRC.

Dysadherin awakens mechanical forces and promotes colorectal cancer progression.

Rationale: Dysadherin is a tumor-associated, membrane-embedded antigen found in multiple types of cancer cells, and associated with malignant behavior of cancer cells; however, the fundamental molecular mechanism by which dysadherin drives aggressive phenotypes of cancer is not yet fully determined. Methods: To get a mechanistic insight, we explored the physiological relevance of dysadherin on intestinal tumorigenesis using dysadherin knockout mice and investigated its impact on clinicopathological features in patients with advanced colorectal cancer (CRC). Next, to discover the downstream signaling pathways of dysadherin, we applied bioinformatic analysis using gene expression data of CRC patient tumors and dysadherin knockout cancer cells. Additionally, comprehensive proteomic and molecular analyses were performed to identify dysadherin-interacting proteins and their functions. Results: Dysadherin deficiency suppressed intestinal tumorigenesis in both genetic and chemical mouse models. Moreover, increased dysadherin expression in cancer cells accounted for shorter survival in CRC patients. Comprehensive bioinformatics analyses suggested that the effect of dysadherin deletion is linked to a reduction in the extracellular matrix receptor signaling pathway. Mechanistically, the extracellular domain of dysadherin bound fibronectin and enhanced cancer cell adhesion to fibronectin, facilitating the activation of integrin-mediated mechanotransduction and leading to yes-associated protein 1 activation. Dysadherin-fibronectin interaction promoted cancer cell growth, survival, migration, and invasion, effects collectively mediated the protumor activity of dysadherin. Conclusion: Our results highlight a novel function of dysadherin as a driver of mechanotransduction that stimulates CRC progression, providing a potential therapy strategy for CRC.

The Small-Molecule Wnt Inhibitor ICG-001 Efficiently Inhibits Colorectal Cancer Stemness and Metastasis by Suppressing MEIS1 Expression.

Recurrence and metastasis remain major obstacles in colorectal cancer (CRC) treatment. Recent studies suggest that a small subpopulation of cells with a self-renewal ability, called cancer stem-like cells (CSCs), promotes recurrence and metastasis in CRC. Unfortunately, no CSC inhibitor has been demonstrated to be more effective than existing chemotherapeutic drugs, resulting in a significant unmet need for effective CRC therapies. In this study, transcriptomic profiling of metastatic tumors from CRC patients revealed significant upregulation in the Wnt pathway and stemness genes. Thus, we examined the therapeutic effect of the small-molecule Wnt inhibitor ICG-001 on cancer stemness and metastasis. The ICG-001 treatment efficiently attenuated self-renewal activity and metastatic potential. Mechanistically, myeloid ecotropic viral insertion site 1 (MEIS1) was identified as a target gene of ICG-001 that is transcriptionally regulated by Wnt signaling. A series of functional analyses revealed that MEIS1 enhanced the CSC behavior and metastatic potential of the CRC cells. Collectively, our findings suggest that ICG-001 efficiently inhibits CRC stemness and metastasis by suppressing MEIS1 expression. These results provide a basis for the further clinical investigation of ICG-001 as a targeted therapy for CSCs, opening a new avenue for the development of novel Wnt inhibitors for the treatment of CRC metastasis.

Optic nerve changes in chronic sinusitis patients: Correlation with disease severity and relevant sinus location.

PURPOSE: This study was to evaluate whether optic nerve damage occurs in eyes with adjacent chronic sinusitis. METHODS: Data were collected from eighty-eight eyes of 46 chronic sinusitis patients and 93 eyes of 57 normal controls. Visual sensitivity using standard automated perimetry (SAP) and inner retinal thickness using optical coherence tomography (OCT) were measured. The Lund-Mackay system was used to quantify radiographic findings on the ostiomeatal unit CT scan with a numerical score representing the severity of sinusitis. RESULTS: There was a significant positive correlation between the pattern standard deviation (dB) and Lund-Mackay score (P = 0.031). Nasal retinal nerve fiber layer (RNFL) thickness, average, minimum, superotemporal, superior, superonasal, and inferonasal ganglion cell-inner plexiform layer (GCIPL) thickness were negatively correlated significantly with Lund-Mackay score (all, P < 0.05). Eyes with grade 2 opacification of the posterior ethmoid sinus showed a significantly lower mean deviation (dB) and higher pattern standard deviation (dB) than those with clear respective sinuses (P = 0.007 and <0.001, respectively). Eyes with grades 1,2 and 3 opacification of the sphenoid sinus had a significantly less average RNFL thickness (P = 0.004, <0.001, and <0.001, respectively) and a significantly less average GCIPL thickness (P = 0.004, 0.003, and 0.003, respectively) than those with a clear sphenoid sinus. CONCLUSIONS: Structural and functional optic nerve changes were correlated with the severity of chronic sinusitis. Inflammation of the posterior ethmoid and sphenoid sinuses was associated with optic nerve changes to a greater extent than that of the other paranasal sinuses.

Hypergravity enhances the therapeutic effect of dexamethasone in allergic asthma and rhinitis animal model.

We investigated whether the therapeutic effects of dexamethasone for allergic asthma and rhinitis were enhanced in mice when exposed to hypergravity. Forty mice were divided into 5 groups (n = 8/group): Control group received saline intraperitoneally (i.p.) and intranasally (i.n.); Asthma group received i.p./i.n. ovalbumin (OVA) for inducing allergic asthma/rhinitis; Dexa group received i.n. dexamethasone (0.75 mg/kg) 30 minutes before each OVA challenge; Hypergravity group was subjected to allergic asthma/rhinitis as well as exposed to 5 G hypergravity for 30 days; Finally in Dexa/Hypergravity group, hypergravity and dexamethasone were used simultaneously during induction of allergic asthma/rhinitis. Dexa group and Hypergravity group showed a significant decrease in serum total IgE levels compared to the Asthma group (p<0.05). Dexa/Hypergravity group showed greater IgE decrease compared with Dexa group (p = 0.040). Compared with the monotherapy groups, Dexa/Hypergravity group showed significantly fewer eosinophils in BAL fluid (p<0.05). Dexa/Hypergravity group showed significantly decreased eosinophilic infiltration into the lungs and nasal cavity (p<0.05). EC-SOD (extracellular superoxide dismutase) expression was significantly upregulated in the Hypergravity group and Dexa/Hypergravity group, compared with the Dexa group (p<0.05). In conclusion, hypergravity enhanced the therapeutic effect of dexamethasone in a murine model of allergic asthma and rhinitis. Therefore, combination could be a promising strategy, and one of its mechanisms could be up-regulation of EC-SOD expression.

Correlation of Nasal Eosinophilia and Response after Nasal Provocation Test in Patients with Nonallergic Rhinitis.

Objectives We aimed to evaluate the relationship between nasal eosinophilia and nasal hyperresponsiveness to allergen extract. Study Design Retrospective chart review. Setting Academic tertiary rhinologic practice. Subjects and Methods We performed allergy tests (skin prick test and multiple allergosorbent test) and nasal cytology for 194 patients with rhinitis symptoms (76 males and 118 females; age, 11-69 years). According to the results, they were classified into 4 groups: group A (allergic rhinitis with eosinophilia, n = 26), group B (allergic rhinitis without eosinophilia, n = 77), group C (nonallergic rhinitis with eosinophilia syndrome, n = 20), and group D (nonallergic rhinitis without eosinophilia, n = 71). We performed a nasal provocation test (NPT) using house dust mite extract and assessed the changes in symptoms and the decrease in acoustic parameters (total nasal volume and minimal cross-sectional area [MCA]). Results Patients in group C were more likely to have severe rhinorrhea and sneezing than those in group D ( P < .001). After NPT, group C had greater aggravation of nasal obstruction than group D ( P < .001). Group C also showed markedly greater MCA changes as compared with group D 15 minutes after the antigen challenge ( P = .002). There was significant correlation between the number of eosinophils and an increase in nasal obstruction ( r = 0.319, P = .0009), rhinorrhea ( r = 0.302, P = .0017), sneezing ( r = 0.219, P = .0241), change in the total nasal volume 15 minutes after NPT ( r = 0.287, P = .0028), and change in the MCA 15 minutes ( r = 0.322, P = .0008) and 30 minutes ( r = 0.250, P = .0098) after NPT. Conclusion In patients with NAR, nasal eosinophilia is associated with provocative response after NPT. Further research should be performed to elucidate the mechanisms that underlie this phenomenon.

Anti-allergic effect of luteolin in mice with allergic asthma and rhinitis.

AIM OF THE STUDY: We aimed to evaluate the anti-allergic effect of luteolin treatment in mice with allergic asthma and rhinitis. MATERIAL AND METHODS: Thirty-two BALB/c mice (n = 8 for each group) were used. Mice in group A (nonallergic group) were exposed to saline, while those in Group B (allergic group) were exposed to ovalbumin (OVA) intraperitoneal (i.p.) injection and intranasal (i.n.) challenge. Null treatment group (Group C) received sterile saline (150 µl) i.p. injection, 30 minutes before each i.n. challenge. Finally, the treatment group (Group D) received luteolin (0.1 mg/kg) by i.p. injection, 30 minutes before each i.n. challenge. We evaluated the number of inflammatory cells including eosinophils, neutrophils and lymphocytes in bronchoalveolar lavage (BAL) fluid, the titers of IL-4, IL-5 and IL-13 in lung homogenate, and we also evaluated histopathologic findings, including infiltration of inflammatory cells into the pulmonary parenchyma and nasal mucosa. RESULTS: After the OVA challenge, the number of eosinophils, neutrophils and lymphocytes in BAL fluid was significantly increased in group B, compared to group A (p < 0.001). Mice in group C had no significant difference (p > 0.05). On the other hand, group D showed a significant decrease in all inflammatory cells compared to group B (p < 0.05). Also, group D showed a significant decrease in IL-4, IL-5 and IL-13 in their lung homogenate compared to groups B and C (p < 0.05). Group D also showed a significant decrease in inflammatory cell infiltration after luteolin treatment (p < 0.05). CONCLUSION: Luteolin had an anti-allergic effect in a murine model of allergic asthma and rhinitis.

Usefulness of Allerkin House Dust Mite Extract for Nasal Provocation Testing.

OBJECTIVES: We evaluated the clinical usefulness of Allerkin (Lofarma) for nasal provocation testing (NPT) in patients with rhinitis symptoms, by examining changes in nasal symptoms and acoustic parameters after exposure to house dust mite (HDM) extract. METHODS: Twenty patients (16 males and 4 females, mean age: 29.6±14.6 years) were enrolled. We performed skin prick test (SPT) before and 15 and 30 minutes after intranasal challenge with Allerkin HDM extract, and we evaluated symptom changes (nasal obstruction, rhinorrhea, sneezing, and itching) using a visual analogue scale. We also evaluated changes in acoustic parameters such as total nasal volume (TNV) and minimal cross-sectional area (MCA) before and after challenge. RESULTS: Group A (the nonallergic group, n=8) showed negative results for all tested aeroallergens in SPT and nonprovocative results (<25% decrease of TNV and MCA from the baseline value) in NPT. Group B (the allergic group, n=7) exhibited strongly positive results (wheal size larger than that of histamine) for HDM allergens on SPT. Group C (the local allergic group, n=5) showed negative results on SPT, but a provocative response on NPT (>29% decrease in TNV/MCA from the baseline value). Patients in group C showed significant aggravation of nasal obstruction compared to those in group A (P<0.05). Thirty minutes after HDM challenge, patients in groups B and C showed significantly greater decreases in MCA compared to those in group A (P<0.01). CONCLUSION: Allerkin HDM extract can be a useful provocative agent in NPT for diagnosing allergic rhinitis and local allergic rhinitis.

Low Concentration PM10 Had No Effect on Nasal Symptoms and Flow in Allergic Rhinitis Patients.

OBJECTIVES: Since Korea is geographically close to China (the origin site for Asian sand dust [ASD]) the health influence of ASD event will be still greater in Korea. We aimed to evaluate the effect of PM10 (particulate matter with aerodynamic diameter <10 µm, below 150 µg/m3) on the clinical course of allergic rhinitis (AR). METHODS: We enrolled 47 healthy volunteers (group A) and 108 AR patients sensitized to house dust mites (group B). For 120 consecutive days (from February 1st to May 30th, 2012), all subjects reported their daily nasal symptoms and performed 2 peak flowmeter readings to measure peak nasal inspiratory flow (PNIF). We evaluated the correlation between the daily concentration of PM10, symptoms, and PNIF of patients. We also investigated changes in symptoms and PNIF 2 days before and after 'dusty' days (daily concentration of PM10 >100 µg/m3). RESULTS: There was no significant difference between group A and B in nasal symptoms and PNIF during the 120-day period. Changes in nasal symptoms and PNIF were not statistically significant before or after a PM10 concentration rise above 100 µg/m3. CONCLUSION: Low concentration PM10 does not have significant effect on nasal symptoms and PNIF in AR patients.

Recent Updates on the Systemic and Local Safety of Intranasal Steroids.

BACKGROUND: Allergic rhinitis is a global health problem, and its prevalence rate and socioeconomic burden continue to increase. Intranasal steroid (INS) is the first treatment choice in the majority of patients, because of its ability to effectively control allergic symptoms. However, patients and clinicians are concerned about the potential adverse effects of prolonged INS use. METHODS: We performed to review for evaluating systemic and local safety of INS use, by searching MEDLINE, EMBASE, and Cochrane Library database for identification of relevant articles. RESULTS: In the present study, the systemic bioavailabilities of several commercially available INSs were researched, and then systemic safeties were reviewed with focus on suppression of the hypothalamus-pituitary-adrenal axis and their effects on pediatric growth. In addition, local adverse effects, such as, epistaxis and nasal septal perforation, were investigated. Finally, the authors proposed some techniques in order to avoid these complications. CONCLUSION: INSs offer a safe, effective means of treating allergic rhinitis in the short- and long-term with no or minimal adverse systemic and local effects.

Hormetic Effect of Chronic Hypergravity in a Mouse Model of Allergic Asthma and Rhinitis.

We aimed to evaluate the effect of chronic hypergravity in a mouse model of allergic asthma and rhinitis. Forty BALB/c mice were divided as: group A (n = 10, control) sensitized and challenged with saline, group B (n = 10, asthma) challenged by intraperitoneal and intranasal ovalbumin (OVA) to induce allergic asthma and rhinitis, and groups C (n = 10, asthma/rotatory control) and D (n = 10, asthma/hypergravity) exposed to 4 weeks of rotation with normogravity (1G) or hypergravity (5G) during induction of asthma/rhinitis. Group D showed significantly decreased eosinophils, neutrophils, and lymphocytes in their BAL fluid compared with groups B and C (p < 0.05). In real-time polymerase chain reaction using lung homogenate, the expression of IL-1ß was significantly upregulated (p < 0.001) and IL-4 and IL-10 significantly downregulated (p < 0.05) in group D. Infiltration of inflammatory cells into lung parenchyma and turbinate, and the thickness of respiratory epithelium was significantly reduced in group D (p < 0.05). The expression of Bcl-2 and heme oxygenase-1 were significantly downregulated, Bax and extracellular dismutase significantly upregulated in Group D. Therefore, chronic hypergravity could have a hormetic effect for allergic asthma and rhinitis via regulation of genes involved in antioxidative and proapoptotic pathways. It is possible that we could use hypergravity machinery for treating allergic respiratory disorders.

Effect of Long-Term Antiorthostatic Suspension in a Murine Model of Acute Lung Injury.

OBJECTIVES: Antiorthostatic suspension (AOS) is ground-based model of simulated microgravity. There is still no study about the effect of long-term microgravity on the clinical course of acute lung injury. We evaluated the effect of simulated microgravity using AOS in a murine model of acute lung injury by lipopolysaccharide (LPS). METHODS: Thirty BALB/c mice were used. During 4 weeks, mice were equally allocated to control (free movement), restraint (tail suspended, but hindlimbs not unloaded), and AOS group (hindlimb unloaded). After then, mice got intranasal challenge with LPS (20 mg/kg, 50 µL). We measured: weight gain before and after AOS, the number of inflammatory cells and titers of cytokines (interleukin [IL]-1ß, IL-6, IL-10, tumor necrosis factor-α, and interferon-γ) in bronchoalveolar lavage (BAL) fluid, titer of myeloperoxidase (MPO) in serum and lung homogenate, and histopathologic examination of lung tissue. RESULTS: AOS group had significant weight loss compared to control and restraint group (P<0.001). AOS group also showed significantly decreased lymphocytes (P=0.023) compared to control group. In AOS group, titer for IL-1ß in BAL fluid was significantly lower than restraint group (P=0.049). Titer for serum MPO was significantly decreased in AOS group compared to restraint group (P=0.004). However, there was no significant difference of MPO titers in lung tissue between groups. Histopathologic examination of lung tissue revealed no significant difference in the degree of pulmonary infiltration between restraint and AOS group. CONCLUSION: In spite of modest anti-inflammatory effect, prolonged AOS caused no significant change in LPS-induced pulmonary inflammation.

Hypergravity Effects on the Retina and Intraocular Pressure in Mice.

BACKGROUND: We investigated the effect of exposure to +10.0 G for 4 h on the intraocular pressure and the retina of mice. METHODS: We exposed 10 mice to +10.0 Gz for 4 h by using a centrifugal acceleration test facility for animals. Intraocular changes were compared before and after hypergravity exposure. The eyeballs of the mice were enucleated after measuring the intraocular pressure. Tissue slides of the retina were prepared with hematoxylin and eosin (H&E) for histological examination and immunohistochemical analyses for vascular endothelial growth factor-A (VEGF-A), VEGF receptor 1 (VEGF-R1), VEGF-R2, glial fibrillary acidic protein (GFAP), and glutamine synthetase (GS). RESULTS: The average intraocular pressure was 7.7 ± 0.86 mmHg before the hypergravity exposure and 6.65 ± 0.67 mmHg after the exposure. No histological difference was observed between the retinas in the two groups. The levels of VEGF-A, VEGF-R1, VEGF-R2, GFAP, and GS as assessed by immunohistochemistry were increased in the group exposed to hypergravity compared to the control group. DISCUSSION: Repeated exposure to a high level of hypergravity could cause elevation of intraocular pressure and hypoxic damage to the retina.

Antiallergic effects of anti-interleukin-33 are associated with suppression of immunoglobulin light chain and inducible nitric oxide synthase.

OBJECTIVE: We aimed to find novel genes that are significantly induced in allergic mice and that are significantly downregulated with anti-interleukin (IL) 33 treatment. METHODS: Thirty-six mice were allocated into each of group A (intraperitoneal [i.p.]) sensitized and intranasally challenged to saline solution), group B (sensitized and challenged to ovalbumin), group C (sensitized and challenged with ovalbumin, and null treatment with i.p. saline solution), and group D (sensitized and challenged with ovalbumin, and treatment with anti-IL-33 i.p. injection). We counted the number of nose-scratching in 10 minutes, serum ovalbumin-specific immunoglobulin E (IgE), and titers of cytokines (IL-1, IL-4, IL-5, IL-10, IL-13) in bronchoalveolar lavage fluid. By using one whole lung from each mouse, we performed microarray analysis and real-time polymerase chain reaction. RESULTS: group D showed a significantly reduced nose-scratching events and lower serum ovalbumin-specific IgE compared with groups B and C. All the cytokines in the bronchoalveolar lavage fluid were significantly decreased after anti-IL-33 treatment. Microarray analysis revealed that group B (immunoglobulin free light chain [IgFLC], 89.1 times; nitric oxide synthase [NOS] 2, 11.5 times) and group C (IgFLC, 141.6 times; NOS2, 11.7 times) had significantly increased expression of IgFLC and NOS2 genes compared with group A. After anti-IL-33 treatment, group D showed significantly decreased expression of both IgFLC (49.3 times) and NOS2 (6.5 times). In real-time polymerase chain reaction, groups B and C had significantly increased expression of these genes (IgFLC, 10.4 times and 29 times, respectively; NOS2, 3.8 times and 4.5 times, respectively). After treatment, group D showed significantly decreased expression of IgFLC (5.0 times) and NOS2 (2.5 times). CONCLUSION: The antiallergic effect of anti-IL-33 can be explained by suppression of IgFLC and NOS2 in a murine model of allergic rhinitis.

Interleukin-33 and Mast Cells Bridge Innate and Adaptive Immunity: From the Allergologist's Perspective.

Interleukin (IL) 33, a member of the IL-1 superfamily, is an "alarmin" protein and is secreted in its active form from damaged cells undergoing necrotic cell death. Mast cells are one of the main effector cell types in allergic disorders. They secrete a variety of mediators, including T helper 2 cytokines. As mast cells have high-affinity IgE receptors (FcεRI) on their surface, they can capture circulating IgE. IgE-bound mast cells degranulate large amounts of histamine, heparin, and proteases when they encounter antigens. As IL-33 is an important mediator of innate immunity and mast cells play an important role in adaptive immune responses, interactions between the two could link innate and adaptive immunity. IL-33 promotes the adhesion of mast cells to laminin, fibronectin, and vitronectin. IL-33 increases the expression of adhesion molecules, such as intracellular adhesion molecule-1 and vascular cell adhesion molecule-1, in endothelial cells, thus enhancing mast cell adhesion to blood vessel walls. IL-33 stimulates mast cell proliferation by activating the ST2/Myd88 pathway; increases mast cell survival by the activation of survival proteins such as Bcl-XL; and promotes the growth, development, and maturation of mast cell progenitors. IL-33 is also involved in the activation of mature mast cells and production of different proinflammatory cytokines. The interaction of IL-33 and mast cells could have important clinical implications in the field of clinical urology. Epithelial dysfunction and mast cells could play an important role in the pathogenesis of interstitial cystitis. Urinary levels of IL-33 significantly increase in patients with interstitial cystitis. In addition, the number of mast cells significantly increase in the urinary bladders of patients with interstitial cystitis. Therefore, inhibition of mast cell activation and degranulation in response to increase in IL-33 is a potential therapeutic target in the treatment of interstitial cystitis.

Prolonged Anti-Orthostatic Hind Limb Unloading and Murine Allergic Asthma.

BACKGROUND: Hind limb unloading (HU) is one of the ground-based models of simulated microgravity. As bacterial and viral infections could affect the immune system, the immunologic effect of HU should be studied in a specific-pathogen-free (SPF) laboratory. However, a review of the literature did not reveal any studies on the immunologic effects of prolonged HU in a murine model of allergic disease. Accordingly, the present study was undertaken to evaluate the effect of HU in a murine model of allergic asthma in a SPF laboratory. METHODS: Twenty BALB/c mice were allocated equally to Group A (control group), Group B (HU group), Group C (allergic group), or Group D (allergic + HU group). Weight gains, serum total and ovalbumin (OVA)-specific IgE, titers of IL-1, IL-5, IL-10, and IFN-γ in bronchoalveolar lavage (BAL) fluid, and histopathologic findings of the lungs were compared. RESULTS: After 2 wk of HU, Group D showed significantly more weight loss (-2.0±0.2 g) than Group C (-1.1±0.4 g). Groups B and D showed significant increases in serum OVA-specific IgE as compared with Groups A and C. Group D had significantly lower titers of IL-5 (Group C: 53.0±15.2 pg·ml(-1), Group D: 21.9±13.9 pg·ml(-1)), IL-10 (Group C: 430.8±138.3 pg·ml(-1), Group D: 217.6±51.2 pg·ml(-1)), and IFN-γ (Group C: 104.3±37.5 pg·ml(-1), Group D: 36.7±12.8 pg·ml(-1)) in BAL fluid than Group C. Peri-bronchiolar and pulmonary infiltrations of inflammatory cells were significantly greater in Group D than in Group C. CONCLUSIONS: Prolonged HU may cause significant weight loss and aggravate disease courses.

Nasal provocation test is useful for discriminating allergic, nonallergic, and local allergic rhinitis.

BACKGROUND: No standard study protocol or diagnostic criteria based on nasal provocation test (NPT) and acoustic rhinometry (AR) results are available for allergic rhinitis. OBJECTIVE: We aimed to evaluate the usefulness of NPT plus AR for the differential diagnosis of local allergic rhinitis (LAR), allergic, and nonallergic rhinitis. METHODS: The medical records and skin-prick test (SPT) and NPT results of 262 patients with symptoms of chronic rhinitis were reviewed. Patients were allocated to one of three groups, that is, group A [n = 110, negative SPT result for Dermatophagoides pteronyssinus (DP)], group B (n = 53, weakly positive result), or group C (n = 99, strongly positive result). RESULTS: Twelve patients had a negative SPT result and provoked response in NPT [≥29% decrease of minimal cross-sectional area (MCA) after DP challenge] were diagnosed to have LAR. After DP challenge, group C showed significant aggravation of nasal symptoms and a greater decrease in acoustic parameters than groups A and B (p < 0.01). In patients with a more than or equal to 2 visual analog scale (VAS) increase in nasal obstruction (NO) after DP challenge, the criterion "a change of total nasal symptom score (TNSS) of more than or equal to 6.5" had 90.6% sensitivity and 77.4% specificity for the diagnosis of allergic rhinitis, whereas the diagnostic criterion "a total nasal volume (TNV) change at 30 minutes after DP challenge of more than or equal to 27.6%" had 73.4% sensitivity and 58.1% specificity. CONCLUSION: NPT with AR could be a useful tool for the differential diagnosis of allergic, nonallergic, and local allergic rhinitis.