Anti-allergy Drug Research Articles

Impact of Weight Loss on Olfaction in Patients Undergoing Bariatric Surgery.

Olfaction plays a vital role in regulating nutrition, avoiding potentially dangerous situations, and modulating behavior along with interpersonal relationships. Many common disorders can have a negative impact on olfaction; one of these is obesity. Bariatric surgery induces weight loss, and current evidence suggests that it can cause improvement in olfaction. However, more information is needed regarding this topic. One hundred eighty-five patients who underwent bariatric surgery and 184 age- and gender-matched control group who did not undergo any surgery have completed a questionnaire including items from the validated Self-Reported Mini Olfactory Questionnaire. Final analysis was based on 369 patients. There was a statistically significant difference between patients before and after surgery (p < 0.05). However, there was a statistically significant difference between people who underwent surgery with < 50% excess body weight loss and the control group but none with those > 50% excess body weight loss. No significant differences were found when comparing people with and without chronic illnesses, head and neck surgery, anti-allergy drug use, and COVID-19. Before surgery, there were statistically significant differences between patients with allergic rhinitis and polyps and those without, but no significant differences were observed after surgery. Patients had significantly improved olfactory scores post-surgery compared to before surgery. Patients who had > 50% excess body weight loss after surgery showed olfactory function as good as the general population represented by the control group. However, those with < 50% excess body weight loss had significantly worse olfactory scores compared to the general population.

Phosphorylated p38 MAP kinase expression by leucocytes is increased in allergic humans and associated with IgE responses.

Mitogen-activated protein kinases (MAPK) activate cascades that regulate cell proliferation, differentiation and death. Phosphorylated (phos-)p38 MAPK is a cell-signalling pathway associated with Th2 cytokine responses, which is required for immunoglobulin (Ig)E production. It is unknown whether MAPK are associated with IgE production. We examine the evidence linking p38 MAPK to inflammatory responses. Phos-p38, extracellular signal-related kinase (ERK) and c-JUN-n terminal (JNK) MAPK expression by blood leucocyte subsets and levels of serum Igs were measured in blood from adults with asthma and/or rhinoconjunctivitis (N = 28) and non-asthma (N = 10) (flow cytometry, microfluorenzymeimmunoassay). Peripheral blood mononuclear cells (PBMC) from allergic subjects were cultured for 10 days ± anti-CD40/recombinant IL-4 ± inhibitor of phos-P38. Culture supernatants were assayed for IgE (ELISA). Phos-p38 MAPK expression by all leucocyte subsets of allergic subjects was associated with serum IgE levels (p ≤ 0.01), after adjusting for cell counts, age, sex, race and smoking status (p ≤ 0.04). Leucocyte expression of phos-ERK and JNK did not correlate with IgE (p = 0.09-0.99). Instead, phos-ERK expression was associated with serum IgG. When PBMC from atopic subjects were cultured for 10 days with anti-CD40/rhIL-4, IgE levels were 26.2 ± 18 ng/mL. Inclusion of SB202190 (5-20 μg/mL), a specific inhibitor of phos-p38 MAPK, in culture suppressed IgE production in dose-dependent manner, with peak suppression obtained with SB202190 at 20 μg/mL (82.1% ± 11.8) (p = 0.0001), with virtually no cytotoxicity (<5%). Different MAPK pathways may be associated with IgE (p38) and IgG (ERK) responses. Phos-p38 MAPK can be a potential anti-allergy drug target.

House dust mite-induced endoplasmic reticulum stress mediates MUC5AC hypersecretion via TBK1 in airway epithelium

Purpose: Endoplasmic reticulum (ER) stress regulates mucus hypersecretion, and may activate downstream factors via TBK1 signaling to induce gene expression. However, it remains unclear whether ER stress promotes airway mucus secretion through the TBK1 pathway. We aimed to investigate the role of the TBK1 pathway in the regulation of MUC5AC expression in a mouse model of house dust mite (HDM)-induced allergic asthma. Materials and Methods: Mice with HDM-induced asthma and human bronchial epithelial BEAS-2B cells were treated with amlexanox, an anti-allergy drug (25 μM), or 4-PBA (10 mM). Tissue and cell samples were collected. Tissue samples were stained with hematoxylin and eosin (H&E) or periodic acid Schiff (PAS) to evaluate pathology. Protein expression was analyzed by western blotting and immunofluorescence. Results: Mice exposed to HDM presented ER stress and hypersecretion of mucus Muc5ac from airway epithelial cells (p < 0.001). Similar results were observed in BEAS-2B cells following exposure to HDM. Both in vivo and in vitro studies revealed that HDM-induced ER stress induced MUC5AC overexpression via TBK1 signaling. Amlexanox and 4-PBA markedly reduced mucus production and weakened the TBK1 signal, which mediates MUC5AC hypersecretion. Conclusion: TBK1 plays a pivotal role in HDM-induced ER stress, leading to overproduction of MUC5AC in the asthmatic airway epithelium. The overproduction of MUC5AC can be significantly decreased by inhibiting TBK1 or ER stress using 4-PBA. These findings highlight potential target-specific therapies for patients with chronic allergic asthma.

Cromolyn Sodium differentially regulates human mast cell and mouse leukocyte responses to control allergic inflammation

BackgroundCromolyn Sodium (CS) has been used in the past as an anti-allergy drug owing to its mast cell (MC) stabilizing properties that impair histamine release. However, additional mechanisms for its clinical actions are likely and might help to identify new roles for MCs and leukocytes in regulating inflammation. Here, using human cord blood-derived MCs (CBMCs), mouse bone marrow-derived MCs (BMMCs) and eosinophils (BMEos), and in vivo mouse models of allergic inflammation (AI), additional actions of CS on MCs were determined. MethodsThe in vitro effects of CS on IgE-activated human and mouse MCs were assessed by measuring the levels of pro-inflammatory (tryptase, LTC4, IL-8, CD48) and pro-resolution effectors (IL-10, CD300a, Annexin A1) before and after CS treatment. The in vivo effects of daily CS injections on parameters of inflammation were assessed using mouse models of allergic peritonitis (AP) (Ovalbumin/Alum- or Ovalbumin/S. aureus enterotoxin B) and allergic airways inflammation (AAI) (house dust mite (HDM)). ResultsIn vitro, CS did not affect pro-inflammatory effectors but significantly increased the anti-inflammatory/pro-resolution CD300a levels and IL-10 release from IgE-activated CBMCs. BMMCs were not affected by CS. In vivo, CS injections decreased total cell and Eos numbers in the peritoneal cavity in the AP models and bronchoalveolar lavage and lungs in the AAI model. CS reduced EPX release from PAF-activated BMEos in vitro, possibly explaining the in vivo findings. ConclusionTogether, these results demonstrate immunomodulatory actions for CS in AI that are broader than only MC stabilization.

Abstract 2794: Blocking histamine receptor H1 on macrophages with anti-allergy drugs restores T-cell anti-tumor immunity

Abstract CD8+ T lymphocytes in tumors often become dysfunctional, prompting cancer immune escape and immunotherapy resistance. Restoring T-cell anti-tumor immunity remains an unmet challenge. Here, we show that histamine receptor H1 (HRH1) is highly expressed and tightly associated with T-cell dysfunction in human cancers. Histamine, the HRH1 ligand, is also increased in human and mouse tumors. HRH1 is predominantly expressed on tumor-associated macrophages (TAMs) and is activated by cancer cell-secreted histamine. The histamine/HRH1 axis in TAMs confers CD8+ T-cell dysfunction via increasing membrane localization of V-domain Ig suppressor of T cell activation (VISTA), an inhibitory immune checkpoint that promotes immunotherapy resistance. Blocking HRH1, genetically, or by anti-allergy drugs, reversed immunosuppressive TAMs, activated T-cells, and inhibited tumor growth in vivo. HRH1-targeting anti-allergy drugs more efficaciously enhanced immunotherapy response than anti-VISTA antibodies. Markedly, allergy-induced histamine also activates HRH1 on macrophages to induce T-cell dysfunction and immunotherapy resistance, which were reversed by the over-the-counter anti-allergy drug. Taken together, tumor cell-derived and allergy-released histamines activate HRH1 on TAMs to concede immunosuppression, pro-tumor function, and immunotherapy resistance, which can be negated by inexpensive and safer anti-allergy drugs. Citation Format: Hongzhong Li, Yi Xiao, Jun Yao, Xiangliang Yuan, Xuedong Yin, Yuan Zhang, Yohei Saito, Hideo Yagita, Don Gibbons, Dihua Yu. Blocking histamine receptor H1 on macrophages with anti-allergy drugs restores T-cell anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2794.

Tranilast prevents doxorubicin-induced myocardial hypertrophy and angiotensin II synthesis in rats

An increase in oxidative stress is an important pathological mechanism of heart injury induced by doxorubicin (DOX). Tranilast is an anti-allergy drug that has been shown to possess good antioxidant activity in previous studies. The overexpression and secretion of chymase by mast cells (MCs) increase the pathological overexpression of angiotensin II (Ang II), which plays a crucial role in myocardial hypertrophy and the deterioration of heart disease. The MC stabilizer tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid; tran) prevents mast cells from degranulating, which may reduce DOX-induced Ang II synthesis. Therefore, in the present study, we hypothesized that tranilast will protect rats from DOX-induced myocardial damage via its antioxidant activity, thereby inhibiting Ang II expression. Thirty male Wistar rats were divided into three groups (n = 10 in each group) that received DOX, a combination of DOX and tranilast or saline (the control group) to test this hypothesis. Tranilast suppressed chymase expression, reduced Ang II levels and prevented the myocardial hypertrophy and the deterioration of heart function induced by DOX. Based on the findings of the present study, the suppression of chymase-dependent Ang-II production and the direct effect of tranilast on the inhibition of apoptosis and fibrosis because of its antioxidant stress capacity may contribute to the protective effect of tranilast against DOX-induced myocardial hypertrophy.

&lt;p&gt;Tranilast Inhibits Pulmonary Fibrosis by Suppressing TGFβ/SMAD2 Pathway&lt;/p&gt;

PurposeIdiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix (ECM) protein in the lungs. Transforming growth factor (TGF) β-induced ECM protein synthesis contributes to the development of IPF. Tranilast, an anti-allergy drug, suppresses TGFβ expression and inhibits interstitial renal fibrosis in animal models. However, the beneficial effects of tranilast or its mechanism as a therapy for pulmonary fibrosis have not been clarified.MethodsWe investigated the in vitro effect of tranilast on ECM production and TGFβ/SMAD2 pathway in TGFβ2-stimulated A549 human alveolar epithelial cells, using quantitative polymerase chain reaction, Western blotting, and immunofluorescence. In vitro observations were validated in the lungs of a murine pulmonary fibrosis model, which we developed by intravenous injection of bleomycin.ResultsTreatment with tranilast suppressed the expression of ECM proteins, such as fibronectin and type IV collagen, and attenuated SMAD2 phosphorylation in TGFβ2-stimulated A549 cells. In addition, based on a wound healing assay in these cells, tranilast significantly inhibited cell motility, with foci formation that comprised of ECM proteins. Histological analyses revealed that the administration of tranilast significantly attenuated lung fibrosis in mice. Furthermore, tranilast treatment significantly reduced levels of TGFβ, collagen, fibronectin, and phosphorylated SMAD2 in pulmonary fibrotic tissues in mice.ConclusionThese findings suggest that tranilast inhibits pulmonary fibrosis by suppressing TGFβ/SMAD2-mediated ECM protein production, presenting tranilast as a promising and novel anti-fibrotic agent for the treatment of IPF.

Homoharringtonine Inhibits Allergic Inflammations by Regulating NF-κB-miR-183-5p-BTG1 Axis.

Homoharringtonine (HHT) is a drug for treatment of chronic myeloid leukemia. However, the role of HHT in allergic inflammations remains unknown. Mouse model of atopic dermatitis (AD) induced by 2, 4,-dinitroflurobenzene (DNFB) and anaphylaxis employing 2,4-dinitropheny-human serum albumin (DNP-HSA) were used to examine the role of HHT in allergic inflammations. HHT inhibited in vitro allergic reactions and attenuated clinical symptoms associated with AD. DNFB induced features of allergic reactions in rat basophilic leukemia (RBL2H3) cells. HHT suppressed effect of AD on the expression of Th1/Th2 cytokines. HHT inhibited passive cutaneous anaphylaxis and passive systemic anaphylaxis. MiR-183-5p, increased by antigen stimulation, was downregulated by HHT in RBL2H3 cells. MiR-183-5p inhibitor suppressed anaphylaxis and AD. B cell translocation gene 1 (BTG1) was shown to be a direct target of miR-183-5p. BTG1 prevented antigen from inducing molecular features of in vitro allergic reactions. AD increased the expression of NF-κB, and NF-κB showed binding to the promoter sequences of miR-183-5p. NF-κB and miR-183 formed positive feedback to mediate in vitro allergic reactions. Thus, HHT can be an anti-allergy drug. We present evidence that NF-κB-miR-183-5p-BTG1 axis can serve as target for development of anti-allergy drug.

Drug interaction between shoseiryuto extract or catechins and fexofenadine through organic-anion-transporting polypeptide 1A2 In vitro

Objective: Fexofenadine is an anti-allergy drug frequently used to treat rhinitis, which is absorbed through organic-anion-transporting polypeptide (OATP) 1A2 in the intestine. Clinical studies have revealed that grapefruit juice inhibits OATP1A2 to reduce the absorption of fexofenadine. In Japanese traditional Kampo medicine, shoseiryuto, a formula composed of eight crude drugs, is frequently used to treat allergic rhinitis, especially cases of pollinosis. The objective of this study is to present the drug information regarding the interaction between shoseiryuto and fexofenadine through OATP1A2. Materials and Methods: We established human embryonic kidney 293 cells stably expressing OATP1A2 and evaluated the inhibitory effects of the extracts of shoseiryuto and its herbal components on the uptake of fexofenadine into the cells. Results: Shoseiryuto extract inhibited fexofenadine uptake in a concentration-dependent manner with an IC50 value of 238 μg/ml. The inhibitory titer of shoseiryuto was much lower than that of grapefruit juice, and it is predicted that shoseiryuto could not pharmacokinetically interact interaction with fexofenadine through OATP1A2. Among the eight herbal components of shoseiryuto, the extracts of the terrestrial stem of Ephedra sinica and the root and stolon of Glycyrrhiza uralensis inhibited fexofenadine uptake with IC50 values of 102 and 89 μg/ml, respectively. We isolated catechin as the active ingredient from the extract of the terrestrial stem of E. sinica. Catechins inhibited the uptake of fexofenadine in a concentration-dependent manner, and the IC50 values of epicatechin (EC) gallate, epigallocatechin (EGC) gallate, EGC, catechin, and EC were 11, 26, 41, 52, and 96 μM, respectively. Conclusion: These results would contribute to the safe and effective use of shoseiryuto in clinics. Abbreviations used: CYP: Cytochrome P450; JPXVII: The 17th Edition of the Japanese Pharmacopoeia; EC: Epicatechin; ECG: Epicatechin gallate; EGC: Epigallocatechin; EGCG: Epigallocatechin gallate; HBSS: Hanks' balanced salt solution; HEK: Human embryonic kidney; OATP: Organic-anion-transporting polypeptide; PBS: Phosphate-buffered saline; PHB: p-hydroxybenzoic acid butyl ester.

Tranilast inhibits the expression of genes related to epithelial-mesenchymal transition and angiogenesis in neurofibromin-deficient cells

Neurofibromatosis type 1 (NF1) is caused by germline mutations in the NF1 gene and is characterized by café au lait spots and benign tumours known as neurofibromas. NF1 encodes the tumour suppressor protein neurofibromin, which negatively regulates the small GTPase Ras, with the constitutive activation of Ras signalling resulting from NF1 mutations being thought to underlie neurofibroma development. We previously showed that knockdown of neurofibromin triggers epithelial-mesenchymal transition (EMT) signalling and that such signalling is activated in NF1-associated neurofibromas. With the use of a cell-based drug screening assay, we have now identified the antiallergy drug tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid) as an inhibitor of EMT and found that it attenuated the expression of mesenchymal markers and angiogenesis-related genes in NF1-mutated sNF96.2 cells and in neurofibroma cells from NF1 patients. Tranilast also suppressed the proliferation of neurofibromin-deficient cells in vitro more effectively than it did that of intact cells. In addition, tranilast inhibited sNF96.2 cell migration and proliferation in vivo. Knockdown of type III collagen (COL3A1) also suppressed the proliferation of neurofibroma cells, whereas expression of COL3A1 and SOX2 was increased in tranilast-resistant cells, suggesting that COL3A1 and the transcription factor SOX2 might contribute to the development of tranilast resistance.

Repositioning of Solifenacin and Hydroxyzine as Antibiofilm Agents in Candida albicans

Biofilm growth and drug resistance by Candida albicans can cause serious health problems in immunocompromised patients. Therefore there is a necessity for developing novel drugs. One of the strategies is repositioning of drugs. Solifenacin is a muscarinic receptor antagonist used for overactive bladder treatment. While Hydroxyzine is an anti-allergy drug and also it has mild anti-muscarinic receptor effect. In this manuscript, the effect of Solifenacin and hydroxyzine against C. albicans virulence factors is reported. It is found that Solifenacin and Hydroxyzine inhibited biofilm formation, adhesion, growth and morphogenesis in C. albicans. C. albicans Rrp9, an essential protein is found to exhibit identity and similarity with muscarinic receptor M1. A docking study between Hydroxyzine and C. albicans Rrp9 revealed good binding energy. Molecular docking studies between human muscarinic M1 receptor and muscarinic receptor antagonists, Solifenacin and hydroxyzine were carried out. It was found that both Solifenacin and Hydroxyzine can bind with muscarinic M1 receptor. Based on this study, it is suggested that Solifenacin and Hydroxyzine could be repositioned as anti-biofilm as well as anti-virulence agents in the human pathogen, C. albicans.

Targeting histone-acetyltransferase Tat-interactive protein 60 inhibits intestinal allergy.

The overproduction of IgE plays a critical role in the pathogenesis of allergy; the mechanism is unclear. Histone-acetyltransferase (HAT) activities are required in gene transcription of a large number of molecules in the immune system of the body. This study tests a hypothesis that HAT Tat-interactive protein 60 (Tip60) plays an important role in the initiation of IgE-mediated allergy. The effects of Tip60 on regulating IgE expression were assessed with B cells. An intestinal allergy mouse model was developed to assess the role of Tip60 in the induction of IgE-mediated allergic inflammation. High levels of Tip60 were observed in the peripheral B cells of patients with FA. Tat-interactive protein 60 (Tip60) was required in the expression of IgE and IgG1 in B cells by inducing the chromatin remolding at the gene locus, in which histone acetylation, signal transducer and activator of transcription 6 (STAT6), and nuclear factor-κB at the locus of Iε promoter were markedly increased. Blocking Tip60 significantly attenuated the allergic inflammation in the mouse intestinal mucosa. Tat-interactive protein 60 (Tip60) plays an important role in the induction of IgE in B cells. Blocking Tip60 inhibits the allergic inflammation in the intestine, suggesting Tip60 inhibitor may be a potential anti-allergy drug.

Amlexanox Downregulates S100A6 to Sensitize KMT2A/AFF1-Positive Acute Lymphoblastic Leukemia to TNFα Treatment.

Acute lymphoblastic leukemias (ALL) positive for KMT2A/AFF1 (MLL/AF4) translocation, which constitute 60% of all infant ALL cases, have a poor prognosis even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This poor prognosis is due to one of two factors, either resistance to TNFα, which mediates a graft-versus-leukemia (GVL) response after allo-HSCT, or immune resistance due to upregulated expression of the immune escape factor S100A6. Here, we report an immune stimulatory effect against KMT2A/AFF1-positive ALL cells by treatment with the anti-allergy drug amlexanox, which we found to inhibit S100A6 expression in the presence of TNF-α. In KMT2A/AFF1-positive transgenic (Tg) mice, amlexanox enhanced tumor immunity and lowered the penetrance of leukemia development. Similarly, in a NOD/SCID mouse model of human KMT2A/AFF1-positive ALL, amlexanox broadened GVL responses and extended survival. Our findings show how amlexanox degrades the resistance of KMT2A/AFF1-positive ALL to TNFα by downregulating S100A6 expression, with immediate potential implications for improving clinical management of KMT2A/AFF1-positive ALL. Cancer Res; 77(16); 4426-33. ©2017 AACR.

Identification of Cyproheptadine as an Inhibitor of SET Domain Containing Lysine Methyltransferase 7/9 (Set7/9) That Regulates Estrogen-Dependent Transcription.

SET domain containing lysine methyltransferase 7/9 (Set7/9), a histone lysine methyltransferase (HMT), also methylates non-histone proteins including estrogen receptor (ER) α. ERα methylation by Set7/9 stabilizes ERα and activates its transcriptional activities, which are involved in the carcinogenesis of breast cancer. We identified cyproheptadine, a clinically approved antiallergy drug, as a Set7/9 inhibitor in a high-throughput screen using a fluorogenic substrate-based HMT assay. Kinetic and X-ray crystallographic analyses revealed that cyproheptadine binds in the substrate-binding pocket of Set7/9 and inhibits its enzymatic activity by competing with the methyl group acceptor. Treatment of human breast cancer cells (MCF7 cells) with cyproheptadine decreased the expression and transcriptional activity of ERα, thereby inhibiting estrogen-dependent cell growth. Our findings suggest that cyproheptadine can be repurposed for breast cancer treatment or used as a starting point for the discovery of an anti-hormone breast cancer drug through lead optimization.

A New Marmoset P450 4F12 Enzyme Expressed in Small Intestines and Livers Efficiently Metabolizes Antihistaminic Drug Ebastine.

Common marmosets (Callithrix jacchus) are attracting attention as animal models in preclinical studies for drug development. However, cytochrome P450s (P450s), major drug-metabolizing enzymes, have not been fully identified and characterized in marmosets. In this study, based on the four novel P450 4F genes found on the marmoset genome, we successfully isolated P450 4F2, 4F3B, 4F11, and 4F12 cDNAs in marmoset livers. Deduced amino acid sequences of the four marmoset P450 4F forms exhibited high sequence identities (87%-93%) to the human and cynomolgus monkey P450 4F homologs. Marmoset P450 4F3B and 4F11 mRNAs were predominantly expressed in livers, whereas marmoset P450 4F2 and 4F12 mRNAs were highly expressed in small intestines and livers. Four marmoset P450 4F proteins heterologously expressed in Escherichia coli catalyzed the ω-hydroxylation of leukotriene B4 In addition, marmoset P450 4F12 effectively catalyzed the hydroxylation of antiallergy drug ebastine, a human P450 2J/4F probe substrate. Ebastine hydroxylation activities by small intestine and liver microsomes from marmosets and cynomolgus monkeys showed greatly higher values than those of humans. Ebastine hydroxylation activities by marmoset and cynomolgus monkey small intestine microsomes were inhibited (approximately 60%) by anti-P450 4F antibodies, unlike human small intestine microsomes, suggesting that contribution of P450 4F enzymes for ebastine hydroxylation in the small intestine might be different between marmosets/cynomolgus monkeys and humans. These results indicated that marmoset P450 4F2, 4F3B, 4F11, and 4F12 were expressed in livers and/or small intestines and were functional in the metabolism of endogenous and exogenous compounds, similar to those of cynomolgus monkeys and humans.

Skin Rash with Eosinophilia Resulting from Bendamustine Plus Rituximab Treatment: A Hematological and Pathological Analysis of 5 Cases

Introduction: There are several treatment options for follicular lymphoma (FL) ranging from watchful waiting to chemoimmunotherapy using rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). Recently, bendamustine plus rituximab (BR) therapy was shown to be more efficacious and less toxic when compared with R-CHOP. Significantly fewer hematological adverse events were observed in patients treated with BR therapy than in those treated with R-CHOP therapy. However, the development of a drug-associated skin rash was more common in BR-treated patients than in R-CHOP-treated patients. We examined 5 patients who developed skin rash following BR therapy. An interesting relationship between the development of skin rash and eosinophilia was noted using hematological and pathological analyses.Patients and Methods: We retrospectively evaluated 33 patients with indolent B cell lymphoma who were treated with BR therapy between January 2011 and June 2013 at the Nagasaki Genbaku Hospital. Of these 33 patients, 5 were diagnosed with BR-induced skin rash and required intervention.Results: Four patients developed skin rash after the first cycle of BR therapy and 1 patient after the third cycle of therapy. One patient had a grade 2 rash and 4 patients had a grade 3 rash. Two patients presented with an insect-bite like reaction and 3 had toxic dermatitis (Table 1). A skin biopsy was conducted in 3 patients, and the pathological diagnoses were erythema multiforme, chronic dermatitis, and superficial perivascular dermatitis with epidermal changes, respectively (Table 1). The 3 diagnoses differed from each other, but the presentation was similar in all 3 cases. Spongiosis, epidermal cell infiltration, and perivascular/accessory organ inflammatory cell infiltration were also observed in all 3 cases. Vesicle formation and eosinophil infiltration were seen in two cases (Table 2). The eosinophil level in the peripheral blood at the time that the skin rash appeared was elevated from 16% to 37%. Human leukocyte antigen (HLA) analysis was carried out for all patients, and it was found that 3 of the 5 patients had an A02:06:01/A24:02 haplotype. A typical clinical course is shown in Figure 1. The patient (Patient No. 3) had a grade 2 rash mainly on the body trunk following the first cycle of BR therapy. The diagnosis was toxic dermatitis. Elevation of the eosinophil level was observed at the same time as the appearance of the skin rash. Both the toxic dermatitis and eosinophilia gradually improved following treatment with steroid-containing ointment and fexofenadine hydrochloride, an anti-allergy drug. The fexofenadine hydrochloride was continuously administered until the last course of BR therapy without the recurrence of any skin rash and eosinophilia. The clinical course of the other 4 cases was similar to that seen in Patient No. 3.Conclusions: The findings from this study suggest that the skin rash that may develop after BR therapy can be accompanied by eosinophilia, and that the rash is treatable with steroid-containing ointment and anti-allergy drugs. The findings also suggest that the usage of anti-allergy drugs may prevent the occurrence of skin rashes and that they may be useful in preventing any delay in starting BR therapy. A specific HLA haplotype may correlate with the development of BR-induced skin rash. However, further studies are required to clarify this.Table 1The Diagnosis of the Type of RashPatient No.Dermatological diagnosisPathological diagnosis1 Insect-bite reactionErythema multiforme2 Insect-bite reactionChronic dermatitis3Toxic dermatitisSuperficial perivascular dermatitis with epidermal changes4Toxic dermatitis (Edematous erythema) 5Toxic dermatitis (Edematous erythema)Table 2Summary of Skin Biopsy ResultsPathologoical findingsPatient No.1Patient No.2Patient No.3Vesicle formation2++-Spongiosis+++Epidermal inflammatory cell infiltration+++Peri-vascular/accessory organ inflammatory cell infiltration2+++Eosinophil infiltration2++- [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Interaction between S100P and the anti-allergy drug cromolyn

The S100P protein has been known to mediate cell proliferation by binding the receptor for advanced glycation end products (RAGE) to activate signaling pathways, such as the extracellular regulated kinase (ERK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. S100P/RAGE signaling is involved in a variety of diseases, such as cancer, metastasis, and diabetes. Cromolyn is an anti-allergy drug that binds S100P to block the interaction between S100P and RAGE. In the present study, we characterized the properties of the binding between cromolyn and calcium-bound S100P using various biophysical techniques. The binding affinity for S100P and cromolyn was measured to be in the millimolar range by fluorescence spectroscopy. NMR-HSQC titration experiments and HADDOCK modeling was employed to determine the spatial structure of the proposed heterotetramer model of the S100P–cromolyn complex. Additional MD simulation results revealed the important properties in the complex stability and conformational flexibility of the S100P–cromolyn complex. This proposed model has provided an understanding of the molecular level interactions of S100P–cromolyn complex.

Identification of thyroid hormone receptor active compounds using a quantitative high-throughput screening platform.

To adapt the use of GH3.TRE-Luc reporter gene cell line for a quantitative high-throughput screening (qHTS) platform, we miniaturized the reporter gene assay to a 1536-well plate format. 1280 chemicals from the Library of Pharmacologically Active Compounds (LOPAC) and the National Toxicology Program (NTP) 1408 compound collection were analyzed to identify potential thyroid hormone receptor (TR) agonists and antagonists. Of the 2688 compounds tested, eight scored as potential TR agonists when the positive hit cut-off was defined at ≥10% efficacy, relative to maximal triiodothyronine (T3) induction, and with only one of those compounds reaching ≥20% efficacy. One common class of compounds positive in the agonist assays were retinoids such as all-trans retinoic acid, which are likely acting via the retinoid-X receptor, the heterodimer partner with the TR. Five potential TR antagonists were identified, including the antiallergy drug tranilast and the anxiolytic drug SB 205384 but also some cytotoxic compounds like 5-fluorouracil. None of the inactive compounds were structurally related to T3, nor had been reported elsewhere to be thyroid hormone disruptors, so false negatives were not detected. None of the low potency (>100µM) TR agonists resembled T3 or T4, thus these may not bind directly in the ligand-binding pocket of the receptor. For TR agonists, in the qHTS, a hit cut-off of ≥20% efficacy at 100 µM may avoid identification of positives with low or no physiological relevance. The miniaturized GH3.TRE-Luc assay offers a promising addition to the in vitro test battery for endocrine disruption, and given the low percentage of compounds testing positive, its high-throughput nature is an important advantage for future toxicological screening.

Inhibition of Interleukin-1β-Induced Matrix Metalloproteinase Expression in Human Corneal Fibroblasts by Tranilast

Purpose: Matrix metalloproteinases (MMPs) mediate the degradation of extracellular matrix proteins and are implicated in the pathogenesis of corneal ulceration. Tranilast, a clinically approved antiallergy drug, has been found to exert various anti-inflammatory effects. We examined the effects of this agent on MMP expression in cultured corneal fibroblasts.Methods: Human corneal fibroblasts were cultured in the absence or presence of interleukin-1β (IL-1β) or tranilast. The release of MMPs into culture supernatants was assessed by immunoblot analysis and gelatin zymography, and the cellular abundance of MMP mRNAs was determined by reverse transcription and real-time polymerase chain reaction analysis. The phosphorylation of mitogen-activated protein kinases (MAPKs) and the nuclear factor-κB (NF-κB) inhibitor IκB-α was examined by immunoblot analysis.Results: The IL-1β-induced expression of MMP-1, -2, and -3 in corneal fibroblasts was inhibited by tranilast in a concentration- and time-dependent manner. It was also attenuated by synthetic inhibitors of MAPK or NF-κB signaling pathways. Tranilast inhibited the IL-1β-induced phosphorylation of the MAPKs extracellular signal-regulated kinase (ERK), p38, and c-Jun NH2-terminal kinase (JNK) as well as the phosphorylation and degradation of IκB-α. Tranilast did not exhibit cytotoxicity for corneal fibroblasts.Conclusions: Tranilast inhibits the IL-1β-induced production of MMP-1, -2, and -3 by human corneal fibroblasts, with this action likely being mediated through suppression of MAPK and NF-κB signaling pathways. Tranilast thus warrants further investigation as a potential treatment for corneal ulceration on the basis of its inhibition of MMP expression in corneal fibroblasts.

Activation of Aryl Hydrocarbon Receptor (AhR) by Tranilast, an Anti-allergy Drug, Promotes miR-302 Expression and Cell Reprogramming

MiR-302 has been shown to regulate pluripotency genes and help somatic cell reprogramming. Thus, promotion of endogenous miR-302 expression could be a desirable way to facilitate cell reprogramming. By using a luciferase reporter system of the miR-302 promoter, we screened and found that an anti-allergy drug, tranilast, could significantly promote miR-302 expression. Further experiments revealed that two aryl hydrocarbon receptor (AhR) binding motifs on the miR-302 promoter are critical and that activation of AhR is required for tranilast-induced miR-302 expression. Consistently, not only tranilast but other AhR agonists promoted miR-302 expression. Furthermore, the activation of AhR facilitated cell reprogramming in a miR-302-dependent way. These results elucidate that miR-302 expression can be regulated by AhR and thus provide a strategy for promoting somatic cell reprogramming by AhR ligands.