OBJECTIVE: To explore the expression patterns, prognostic implications, and biological role of leukotriene B4 receptor (LTB4R) in patients with acute myeloid leukemia (AML). METHODS: We collected the data of mRNA expression levels and clinical information of patients with AML from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database for mRNA expression analyses, survival analyses, Cox regression analyses and correlation analyses using R studio to assess the expression patterns and prognostic value of LTB4R. The correlation of LTB4R expression levels with clinical characteristics of the patients were analyzed using UALCAN. The co-expressed genes LTB4R were screened from Linkedomics and subjected to functional enrichment analysis. A protein-protein interaction network was constructed using STRING. GSEA analyses of the differentially expressed genes (DEGs) were performed based on datasets from TCGA-LAML stratified by LTB4R expression level. We also collected peripheral blood mononuclear cells (PBMCs) from AML patients and healthy donors for examination of the mRNA expression levels of LTB4R and immune checkpoint genes using qRT-PCR. We also examined serum LTB4R protein levels in the patients using ELISA. RESULTS: The mRNA expression level of LTB4R was significantly increased in AML patients (4.898±1.220 vs 2.252±0.215, P < 0.001), and an elevated LTB4R expression level was correlated with a poor overall survival (OS) of the patients (P=0.004, HR=1.74). LTB4R was identified as an independent prognostic factor for OS (P=0.019, HR=1.66) and was associated with FAB subtypes, cytogenetic risk, karyotype abnormalities and NPM1 mutations. The co- expressed genes of LTB4R were enriched in the functional pathways closely associated with AML leukemogenesis, including neutrophil inflammation, lymphocyte activation, signal transduction, and metabolism. The DEGs were enriched in differentiation, activation of immune cells, and cytokine signaling. Examination of the clinical serum samples also demonstrated significantly increased expressions of LTB4R mRNA (P=0.044) and protein (P=0.008) in AML patients, and LTB4R mRNA expression was positively correlated with the expression of the immune checkpoint HAVCR2 (r= 0.466, P=0.040). CONCLUSION LTB4R can serve as a novel biomarker and independent prognostic indicator of AML and its expression patterns provide insights into the crosstalk of leukemogenesis signaling pathways involving tumor immunity and metabolism.
Humans ; Leukemia, Myeloid, Acute/metabolism* ; Leukocytes, Mononuclear/metabolism* ; Prognosis ; RNA, Messenger/metabolism* ; Receptors, Leukotriene B4/genetics*

OBJECTIVE: : To investigate the effects of cysteinyl leukotrienes receptor (CysLTR) antagonists on global cerebral ischemia/reperfusion (CI/R) injury in gerbils, and to explore its mechanism. METHODS: : Totally 40 gerbils weighting 45-65 g were randomized into sham, saline, Pranlukast and HAMI 3379 groups with 10 animals in each. The CI/R model was established in gerbils by bilateral common carotid occlusion for 10 min followed by reperfusion. After ischemia, the CysLTR antagonists Pranlukast (0.1 mg/kg) and HAMI 3379 (0.1 mg/kg) were injected intraperitoneally for 5 consecutive days in the last two groups,while the former two groups were injected with saline only (10 mL/kg). After 24 h or 14 d reperfusion, neurological deficit score was evaluated and the behavioral dysfunction was assessed, respectively. And 14 d after reperfusion, the neuron morphology of cerebral cortex was observed in brain sections stained with Cresyl violet. In addition, the Iba-1 (microgila) and GFAP (astrocyte) positive cells in cerebral cortex were observed by using immunohistochemitry method. RESULTS: : CI/R models were successfully established in 21 out of 30 gerbils with 7 in saline group, 6 in Pranlukast group, and 8 in HAMI 3379 group. Compared with saline group, Pranlukast and HAMI 3379 significantly attenuated neurological deficits, improved the behavioral function 24 h after reperfusion(all <0.01); Pranlukast and HAMI 3379 also significantly improved the behavioral function 14 days after reperfusion(<0.05 or <0.01). Compared with saline group, the neurological symptom scores in Pranlukast and HAMI 3379 groups presented a trend of amelioration 14 d after reperfusion, but it was not significant(>0.05). In addition, Pranlukast and HAMI 3379 also inhibited the neuron loss and injury, suppressed microgila and astrocyte activation 14 d after reperfusion(all <0.01). CONCLUSIONS : CysLTR antagonists Pranlukast and HAMI 3379 have long-term neuroprotective effect on chronic brain injury induced by global cerebral ischemia/reperfusion in gerbils.
Animals ; Behavior, Animal ; drug effects ; Brain Injury, Chronic ; drug therapy ; Brain Ischemia ; Gerbillinae ; Leukotriene Antagonists ; pharmacology ; therapeutic use ; Neuroprotective Agents ; pharmacology ; therapeutic use ; Random Allocation ; Receptors, Leukotriene ; metabolism ; Reperfusion Injury ; drug therapy

OBJECTIVE: : To determine the effects of cysteinyl leukotriene receptors (CysLTR and CysLTR) on phagocytosis of mouse BV2 microglial cells. METHODS: : BV2 cells were stimulated with microglial activators lipopolysaccharide (LPS) or CysLT receptor agonists LTD. The phagocytosis of BV2 cells was observed by immunofluorescence analysis and flow cytometry. The intracellular distributions of CysLTR and CysLTR in BV2 cells were examined with immunofluorescence staining. RESULTS: : Both LPS and LTD could significantly enhance the phagocytosis of BV2 cells, and such effect could be inhibited by CysLTR selective antagonist Montelukast and CysLTR selective antagonist HAMI 3379. The activation of BV2 cells induced by LTD or LPS resulted in changes in intracellular distributions of CysLTR and CysLTR. CysLTR and CysLTR was co-localization with a similar distribution. CONCLUSIONS : CysLTR and CysLTR regulate the phagocytosis of mouse BV2 microglial cells with a synergistic effect.
Acetates ; pharmacology ; Animals ; Cell Line ; Cyclohexanecarboxylic Acids ; pharmacology ; Lipopolysaccharides ; pharmacology ; Mice ; Microglia ; cytology ; Phagocytosis ; drug effects ; Phthalic Acids ; pharmacology ; Protein Binding ; drug effects ; Quinolines ; pharmacology ; Receptors, Leukotriene ; agonists ; metabolism

Mastocytosis is a disorder characterized by abnormal mast cell proliferation and accumulation in one or more tissues. It presents in two major variants: cutaneous mastocytosis and systemic mastocytosis. Because the symptoms are related to mast cells, histamine receptor antagonists and leukotriene receptor antagonists are recommended as therapeutic options. Here, we report a 54-year-old male patient with a history of urticaria pigmentosa who presented with recurrent anaphylaxis. His serum tryptase level was 31.7 ng/mL and mast cell infiltration was observed in his bone marrow. He had frequent attacks of anaphylaxis despite treatment with ketotifen, levocetirizine, and montelukast. Symptoms related to systemic mastocytosis were controlled and the patient exhibited no recurrence of anaphylaxis following the introduction of monthly omalizumab injection. Omalizumab can be considered as a treatment option in patients with systemic mastocytosis unresponsive to conventional oral medications.
Anaphylaxis ; Bone Marrow ; Humans ; Ketotifen ; Leukotriene Antagonists ; Male ; Mast Cells ; Mastocytosis ; Mastocytosis, Cutaneous ; Mastocytosis, Systemic ; Middle Aged ; Omalizumab ; Receptors, Histamine ; Recurrence ; Tryptases ; Urticaria Pigmentosa

Asthma, remains symptomatic despite ongoing treatment with high doses of inhaled corticosteroids (ICS) in conjunction with long-acting beta-agonists (LABA), is classified as “severe” asthma. In the course of caring for those patients diagnosed with severe asthma, stepping up from ICS/LABA to more aggressive therapeutic measures would be justified, though several aspects have to be checked in advance (including inhaler technique, adherence to therapy, and possible associated comorbidities). That accomplished, it would be advisable to step up care in accordance with the Global Initiative for Asthma (GINA) recommendations. Possible strategies include the addition of a leukotriene receptor antagonist or tiotropium (to the treatment regimen). The latter has been shown to be effective in the management of several subgroups of asthma. Oral corticosteroids have commonly been used for the treatment of patients with severe asthma in the past; however, the use of oral corticosteroids is commonly associated with corticosteroid-related adverse events and comorbidities. Therefore, according to GINA 2017 these patients should be referred to experts who specialize in the treatment of severe asthma to check further therapeutic options including biologics before starting treatment with oral corticosteroids.
Adrenal Cortex Hormones ; Asthma ; Biological Products ; Comorbidity ; Humans ; Immunoglobulin E ; Interleukin-5 ; Nebulizers and Vaporizers ; Receptors, Leukotriene ; Tiotropium Bromide

There have been few cases of albumin hypersensitivity reported, and there is limited information on this condition. When a patient is anaphylactic to a certain drug and no alternative drug is available to treat the underlying condition, desensitization is a reasonable option and can be performed successfully to treat the patient. A standard 12-step, 3-solution rapid desensitization protocol allows the safe readministration of a medication after certain types of immediate hypersensitivity. However, we demonstrated that a new 10-step, 1-solution desensitization protocol using antihistamine and leukotriene receptor antagonist as premedications, which was effective and safe in a patient with hypersensitivity. We report a 13-year-old boy with Gorham-stout syndrome who was presented with newly acquired albumin anaphylaxis and successfully treated with the 10-step rapid drug desensitization protocol.
Adolescent ; Anaphylaxis ; Desensitization, Immunologic ; Drug Hypersensitivity Syndrome ; Humans ; Hypersensitivity* ; Hypersensitivity, Immediate ; Male ; Premedication ; Receptors, Leukotriene

Recently, single-nucleotide polymorphisms (SNPs) in G-protein-coupled receptors (GPCRs) have been suggested to contribute to physiopathology and therapeutic effects. Leukotriene B4 receptor 2 (BLT2), a member of the GPCR family, plays a critical role in the pathogenesis of several inflammatory diseases, including cancer and asthma. However, no studies on BLT2 SNP effects have been reported to date. In this study, we demonstrate that the BLT2 SNP (rs1950504, Asp196Gly), a Gly-196 variant of BLT2 (BLT2 D196G), causes enhanced cell motility under low-dose stimulation of its ligands. In addition, we demonstrated that Akt activation and subsequent production of reactive oxygen species (ROS), both of which act downstream of BLT2, are also increased by BLT2 D196G in response to low-dose ligand stimulation. Furthermore, we observed that the ligand binding affinity of BLT2 D196G was enhanced compared with that of BLT2. Through homology modeling analysis, it was predicted that BLT2 D196G loses ionic interaction with R197, potentially resulting in increased agonist-receptor interaction. To the best of our knowledge, this report is the first to describe a SNP study on BLT2 and shows that BLT2 D196G enhances ligand sensitivity, thereby increasing cell motility in response to low-dose ligand stimulation.
Asthma ; Cell Movement* ; Humans ; Ligands ; Reactive Oxygen Species ; Receptors, G-Protein-Coupled ; Receptors, Leukotriene B4 ; Therapeutic Uses

PURPOSE: Chronic spontaneous urticaria (CSU) in children is a common skin disorder, but its clinical course varies. We investigated the clinical course and associated factors for CSU treatment in children. METHODS: A total of 107 children, diagnosed with CSU from 2001 to 2016 in Dong-A University Hospital, who had been followed up for more than 6 months after treatment, were enrolled. The laboratory findings, and clinical aspects and courses were retrospectively investigated by a medical record review. We divided the 152 patients into 3 groups according to the treatment modalities: group 1, 1 antihistamine; group 2, more than 2 kinds of antihistamines; and group 3, antihistamines plus leukotriene receptor antagonist. RESULTS: The mean age of patients in group 3 was 3.4 years (range, 2.6–4.2 years), which was significantly lower than those at the other 2 group patients (P=0.01). The urticaria activity score (UAS) of group 3 (6.1 [5.7–6.6]) was significantly higher compared to those of the other 2 groups (P=0.01). The improvement rate of the condition in children with positive specific immunoglobulin E (sIgE) reactivity to food or inhalant allergens was significantly lower than that of children with negative sIgE reactivity (P=0.01). Sex, age, history of allergic diseases, disease duration, UAS, previous treatment, and treatment modality were not correlated with the symptom improvement rate. CONCLUSION: Younger children and those with higher UAS needed more medication to ensure the improvement in symptoms. Moreover, it took more time for the improvement in symptoms in children who were sensitized to food or inhalant allergens.
Allergens ; Child* ; Histamine Antagonists ; Humans ; Immunoglobulin E ; Immunoglobulins ; Medical Records ; Receptors, Leukotriene ; Retrospective Studies ; Skin ; Urticaria*

PURPOSE: Some studies report a role of leukotrienes in the pathogenesis of atopic dermatitis and suggest a rationale for the use of leukotriene receptor antagonist (LTRA) in the treatment of atopic dermatitis. This study aimed to evaluate the treatment effectiveness of montelukast in children with atopic dermatitis. METHODS: Fifty-four children between the ages of 2 and 6 years with moderate to severe atopic dermatitis were enrolled. Group A received montelukast for 8 weeks, followed by a crossover to 8 weeks of placebo after a 2-week washout period. Group B reversed the administration according to a randomized, double-blind, placebo-controlled, crossover design. The SCORing atopic dermatitis (SCORAD) index, urinary leukotriene E4 (LTE4), and eosinophil-derived neurotoxin (EDN) were assessed at every visit. RESULTS: Forty-three patients (21 males) completed the study. Although the SCORAD index was decreased in both groups, there was no statistically significant difference between montelukast and placebo (-3.0±11.2 vs -5.7±11.3, P=0.43). The level of urinary LTE4 was decreased after taking montelukast when compared to placebo, but there was no statistically significant difference (-65.9±556.2 vs 87.7±618.3, P=0.26). The changes in urinary EDN after taking montelukast and placebo had no significant difference (37.0±1,008.6 vs -195.8±916.7, P=0.10). When analyzing SCORAD indices, urinary LTE4, and EDN, we could not prove the effectiveness of montelukast in the atopic, non-atopic or high ECP (ECP ≥15 µg/L) subgroups. CONCLUSIONS: There was no statistically significant difference in clinical improvement or biomarkers between montelukast and placebo treatment. Therefore, conventional treatments with skin care and infection control might be more important strategies in the treatment of atopic dermatitis.
Biological Markers ; Child* ; Cross-Over Studies* ; Dermatitis, Atopic* ; Eosinophil-Derived Neurotoxin ; Humans ; Infection Control ; Leukotriene E4 ; Leukotrienes ; Receptors, Leukotriene ; Skin Care ; Treatment Outcome

BACKGROUND: Imidacloprid has been commonly used as a pesticide for crop protection and acts as nicotinic acetylcholine receptor agonists. Little information about the relationship between imidacloprid and allergy is available. OBJECTIVE: This study aims to examine the effects of imidacoprid on IgE-mediated mast cell activation. METHODS: The rat basophilic leukemia cell line RBL-2H3 (RBL-2H3 cells) were treated with 10⁻³ – 10⁻¹² mol/L imidacloprid, followed by measuring the mediator production, influx of Ca²⁺ in IgE-activated RBL-2H3 cells, and the possible effects of imidacoprid on anti-dinitrophenyl IgE-induced passive cutaneous anaphylaxis (PCA). RESULTS: It was shown that imidacoprid suppressed the production of histamine, β-hexosaminidase, leukotriene C4, interleukin-6, tumor necrosis factor-α, and Ca²⁺ mobilization in IgE-activated RBL-2H3 cells and decreased vascular extravasation in IgE-induced PCA. CONCLUSION: It is the first time to show that imidacloprid suppressed the activation of RBL-2H3 cells.
Animals ; Basophils ; Cell Degranulation ; Cell Line ; Crop Protection ; Histamine ; Hypersensitivity ; Interleukin-6 ; Leukemia ; Leukotriene C4 ; Mast Cells ; Necrosis ; Passive Cutaneous Anaphylaxis ; Rats ; Receptors, Nicotinic