Cysteinyl Leukotriene Receptor Research Articles

Montelukast Influence on Lung in Experimental Diabetes

Background and Objectives: The influence of montelukast (MK), an antagonist of cysLT1 leukotriene receptors, on lung lesions caused by experimental diabetes was studied. Materials and Methods: The study was conducted on four groups of six adult male Wistar rats. Diabetes was produced by administration of streptozotocin 65 mg/kg ip. in a single dose. Before the administration of streptozotocin, after 72 h, and after 8 weeks, the serum values of glucose, SOD, MDA, and total antioxidant capacity (TAS) were determined. After 8 weeks, the animals were anesthetized and sacrificed, and the lungs were harvested and examined by optical microscopy. Pulmonary fibrosis, the extent of lung lesions, and the lung wet-weight/dry-weight ratio were evaluated. Results: The obtained results showed that MK significantly reduced pulmonary fibrosis (3.34 ± 0.41 in the STZ group vs. 1.73 ± 0.24 in the STZ+MK group p < 0.01) and lung lesion scores and also decreased the lung wet-weight/dry-weight (W/D) ratio. SOD and TAS values increased significantly when MK was administered to animals with diabetes (77.2 ± 11 U/mL in the STZ group vs. 95.7 ± 13.3 U/mL in the STZ+MK group, p < 0.05, and 25.52 ± 2.09 Trolox units in the STZ group vs. 33.29 ± 1.64 Trolox units in the STZ+MK group, respectively, p < 0.01), and MDA values decreased. MK administered alone did not significantly alter any of these parameters in normal animals. Conclusions: The obtained data showed that by blocking the action of peptide leukotrienes on cysLT1 receptors, montelukast significantly reduced the lung lesions caused by diabetes. The involvement of these leukotrienes in the pathogenesis of fibrosis and other lung diabetic lesions was also demonstrated.

Evaluation of Urtica dioica Phytochemicals against Therapeutic Targets of Allergic Rhinitis Using Computational Studies.

Allergic rhinitis (AR) is a prevalent inflammatory condition affecting millions globally, with current treatments often associated with significant side effects. To seek safer and more effective alternatives, natural sources like Urtica dioica (UD) are being explored. However, UD's mechanism of action remains unknown. Therefore, to elucidate it, we conducted an in silico evaluation of UD phytochemicals' effects on known therapeutic targets of allergic rhinitis: histamine receptor 1 (HR1), neurokinin 1 receptor (NK1R), cysteinyl leukotriene receptor 1 (CLR1), chemoattractant receptor-homologous molecule expressed on type 2 helper T cells (CRTH2), and bradykinin receptor type 2 (BK2R). The docking analysis identified amentoflavone, alpha-tocotrienol, neoxanthin, and isorhamnetin 3-O-rutinoside as possessing a high affinity for all the receptors. Subsequently, molecular dynamics (MD) simulations were used to analyze the key interactions; the free energy of binding was calculated through Generalized Born and Surface Area Solvation (MMGBSA), and the conformational changes were evaluated. Alpha-tocotrienol exhibited a high affinity while also inducing positive conformational changes across all targets. Amentoflavone primarily affected CRTH2, neoxanthin targeted NK1R, CRTH2, and BK2R, and isorhamnetin-3-O-rutinoside acted on NK1R. These findings suggest UD's potential to treat AR symptoms by inhibiting these targets. Notably, alpha-tocotrienol emerges as a promising multi-target inhibitor. Further in vivo and in vitro studies are needed for validation.

Site-specific immobilization of Cysteinyl leukotriene receptor 1 through enzymatic DNA-protein conjugation strategy for drug lead screening

Immobilization of functional protein, especially G protein-coupled receptors (GPCRs), is particularly significant in various fields such as the development of assays for diagnosis, lead compound screening, as well as drug-protein interaction analysis. However, there are still some challenges with the immobilized proteins such as undefined loads, orientations, and the loss of activity. Herein, we introduced a DNA conjugation strategy into the immobilization of Cysteinyl leukotriene receptor 1(CysLTR1) which enables exquisite molecular control and higher activity of the receptor. We used the bacterial relaxases VirD2 as an immobilized tag fused at the C terminus of CysLTR1. Tyrosine residue(Y29) at the core binding site of the VirD2 tag can react with the single-strand piece of DNA(T-DNA) in the form of a covalent bond. Inspired by this strategy, we developed a new immobilization method by mixing the T-DNA-modified silica gel with the cell lysate containing the expressed VirD2-tagged CysLTR1 for 1 hour. We found that the successful formation of DNA-protein conjugate enables the immobilization of CysLTR1 fast, site-specific, and with minimal loss of activity. The feasibility of the immobilized CysLTR1 was evaluated in drug-protein binding interaction by frontal analysis and adsorption energy distribution analysis. The binding of pranlukast, zafirlukast, and MK571 to the immobilized CysLTR1 was realized, and the association constants presented good agreement between the two methods. Rosmarinic acid was retained in the immobilized CysLTR1 column, and the in-vitro test revealed that the compound binds to the receptor in one type of binding site mode. Despite these results, we concluded that the DNA-protein conjugate strategy will probably open up the possibilities for capturing other functional proteins in covalent and site-specific modes from the complex matrices and the immobilized receptor preserves the potential in fishing out lead compounds from natural products.

Abstract 6963: Cysteinyl leukotriene receptors promote melanoma progression and metastasis

Abstract Background: Cysteinyl leukotrienes (cys-LTs; LTC4, LTD4, LTE4) are pro-inflammatory mediators mainly produced by hematopoietic cells, which enhance inflammation through their receptors, CysLT1R and CysLT2R. They play a pivotal role in the development of chronic asthma in humans. Recent association of inflammation with cancer has led to immense interest on the role of cysteinyl leukotrienes in cancer progression and metastasis. However, the exact molecular mechanisms regarding how these inflammatory mediators regulate the tumor proliferation and metastasis remain unexplored. A thorough investigation of these precise molecular mechanisms and identification of the specific receptor/s responsible can aid in understanding the therapeutic potential of these receptors in various cancers like melanoma. Since the inhibitors of these receptors are already FDA approved for the treatment of asthma, our goal is to repurpose these drugs to treat melanoma progression. Objective: To determine the mechanistic aspects of how CysLTRs regulate melanoma tumor initiation, progression, and metastasis. Methods: Protein expression by western blotting and ELISA, transcript expression by qPCR, viability, and proliferation by XTT and BrDU, migration using trans-well assay, tumor growth and metastasis were confirmed through in vivo experiments. Results & Conclusion: B16F10 melanoma cells express high CysLT1R compared to CysLT2R and produce endogenous cys-LTs that function in an autocrine signaling pattern. Further, cys-LTs mediated the activation of several signaling proteins such as ERK, p38, AKT, and CREB that are important for melanoma survival and proliferation. Moreover, treatment with CysLTR antagonists significantly reduced melanoma cell proliferation, survival, and migration. Accordingly, we observed a significant reduction in the melanoma tumor volume in vivo in both Cysltr1−/- and Cysltr2−/− mice compared to the WT mice. Interestingly, angiogenesis was significantly reduced in Cysltr2−/- mice but not in Cysltr1−/−.Therefore, we speculate that while both receptors play a crucial role in tumor proliferation in vivo, CysLT2R is the main driver of angiogenesis and metastasis. Therefore, targeting both these receptors using their specific antagonists can offer potential therapy for melanoma progression and metastasis. Citation Format: Emma Elizabeth Sabu Kattuman, Lakshminarayan Reddy Teegala, Somayeh Darzi, Sailaja Paruchuri. Cysteinyl leukotriene receptors promote melanoma progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6963.

A critical role for Macrophage-derived Cysteinyl-Leukotrienes in HIV-1 induced neuronal injury

Macrophages (MΦ) infected with human immunodeficiency virus (HIV)-1 or activated by its envelope protein gp120 exert neurotoxicity. We found previously that signaling via p38 mitogen-activated protein kinase (p38 MAPK) is essential to the neurotoxicity of HIVgp120-stimulated MΦ. However, the associated downstream pathways remained elusive. Here we show that cysteinyl-leukotrienes (CysLT) released by HIV-infected or HIVgp120 stimulated MΦ downstream of p38 MAPK critically contribute to neurotoxicity. SiRNA-mediated or pharmacological inhibition of p38 MAPK deprives MΦ of CysLT synthase (LTC4S) and, pharmacological inhibition of the cysteinyl-leukotriene receptor 1 (CYSLTR1) protects cerebrocortical neurons against toxicity of both gp120-stimulated and HIV-infected MΦ. Components of the CysLT pathway are differentially regulated in brains of HIV-infected individuals and a transgenic mouse model of NeuroHIV (HIVgp120tg). Moreover, genetic ablation of LTC4S or CysLTR1 prevents neuronal damage and impairment of spatial memory in HIVgp120tg mice. Altogether, our findings suggest a novel critical role for cysteinyl-leukotrienes in HIV-associated brain injury.

Montelukast: results and prospects for applications in pediatric practice

The Centers for Disease Control and Prevention reports that more than 4 million children have been diagnosed with asthma. Currently, there is no treatment that could prevent the development of asthma or change its natural course over long-term follow-up. However, the disease can be controlled using treatments used in clinical practice. For persistent asthma in children aged 5 years and younger, low doses of inhaled glucocorticosteroids are recommended, as well as the administration of montelukast, a leukotriene receptor antagonist. In addition, montelukast is prescribed to patients with allergic rhinitis as an alternative to or in combination with oral antihistamines or nasal corticosteroids. Leukotrienes are lipid mediators that play a key role in acute and chronic inflammation and allergic diseases. They exhibit their biological effects by binding to specific G-protein-coupled receptors. Each subtype of the leukotriene receptor has unique functions and expression patterns. Leukotrienes play an important role in various allergic diseases, including bronchial asthma and allergic rhinitis. Montelukast is a cysteinyl leukotriene receptor-1 antagonist widely used to suppress the inflammatory response in asthma and allergic rhinitis. This review briefly summarizes the biology of leukotrienes and their receptors, recent developments in the field of antileukotriene drugs and the prospects for their different therapeutic applications. The role of antileukotriene drugs and key indications for the use of montelukast in the complex therapy of asthma and allergic rhinitis in children have been determined.

Revealing the anti-inflammatory ingredients in wine-processed Radix et Rhizoma Rhei using immobilized cysteinyl leukotriene receptor type 1 as the stationary phase

Despite the tremendous progress of wine-processed Radix et Rhizoma Rhei (Jiudahuang, JDH) in removing toxic heat from the blood in the upper portion of the body for hundreds of years, the deep understanding of its functional material basis of the anti-inflammatory ingredients remains unclear due to the lack of high specific and efficient methods. Herein, taking Cysteinyl leukotriene receptor type 1(CysLT1R) as the target protein, we established a chromatographic method based on the immobilized CysLT1R using haloalkane dehalogenases (Halo) at the C-terminus of the receptor in one step. After careful characterization by X-ray photoelectronic spectroscopy, immune-fluorometric analysis, and chromatographic investigations, the immobilized receptor was used to screen the anti-inflammatory ingredients in JDH. Aloe-emodin, rhein, emodin, chrysophanol, and physcion were identified as the main anthraquinone exerting anti-inflammatory effects in the drug. The association constants for the five compounds to bind with the receptor were calculated as (0.30 ± 0.06)× 105, (0.35 ± 0.03)× 105, (0.46 ± 0.05)× 105, (1.05 ± 0.14)× 105, and (1.66 ± 0.17)× 105 M−1 by injection amount-dependent method. Meanwhile, hydrogen bonds were identified as the main driving force for the five compounds to bind with CysLT1R by molecular docking. Based on these results, we believe that the immobilized receptor chromatography preserves historic significance in revealing the functional material basis of the complex matrices.

1,4-dihydroxy quininib activates ferroptosis pathways in metastatic uveal melanoma and reveals a novel prognostic biomarker signature

Uveal melanoma (UM) is an ocular cancer, with propensity for lethal liver metastases. When metastatic UM (MUM) occurs, as few as 8% of patients survive beyond two years. Efficacious treatments for MUM are urgently needed. 1,4-dihydroxy quininib, a cysteinyl leukotriene receptor 1 (CysLT1) antagonist, alters UM cancer hallmarks in vitro, ex vivo and in vivo. Here, we investigated the 1,4-dihydroxy quininib mechanism of action and its translational potential in MUM. Proteomic profiling of OMM2.5 cells identified proteins differentially expressed after 1,4-dihydroxy quininib treatment. Glutathione peroxidase 4 (GPX4), glutamate-cysteine ligase modifier subunit (GCLM), heme oxygenase 1 (HO-1) and 4 hydroxynonenal (4-HNE) expression were assessed by immunoblots. Biliverdin, glutathione and lipid hydroperoxide were measured biochemically. Association between the expression of a specific ferroptosis signature and UM patient survival was performed using public databases. Our data revealed that 1,4-dihydroxy quininib modulates the expression of ferroptosis markers in OMM2.5 cells. Biochemical assays validated that GPX4, biliverdin, GCLM, glutathione and lipid hydroperoxide were significantly altered. HO-1 and 4-HNE levels were significantly increased in MUM tumor explants from orthotopic patient-derived xenografts (OPDX). Expression of genes inhibiting ferroptosis is significantly increased in UM patients with chromosome 3 monosomy. We identified IFerr, a novel ferroptosis signature correlating with UM patient survival. Altogether, we demontrated that in MUM cells and tissues, 1,4-dihydroxy quininib modulates key markers that induce ferroptosis, a relatively new type of cell death driven by iron-dependent peroxidation of phospholipids. Furthermore, we showed that high expression of specific genes inhibiting ferroptosis is associated with a worse UM prognosis, thus, the IFerr signature is a potential prognosticator for which patients develop MUM. All in all, ferroptosis has potential as a clinical biomarker and therapeutic target for MUM.

Montelukast Ameliorates 2K1C-Hypertension Induced Endothelial Dysfunction and Associated Vascular Dementia.

Declined kidney function associated with hypertension is a danger for cognitive deficits, dementia, and brain injury. Cognitive decline and vascular dementia (VaD) are serious public health concerns, which highlights the urgent need for study on the risk factors for cognitive decline. Cysteinyl leukotriene (CysLT1) receptors are concerned with regulating cognition, motivation, inflammatory processes, and neurogenesis. This research aims to examine the consequence of montelukast (specific CysLT1 antagonist) in renovascular hypertension 2-kidney-1-clip-2K1C model-triggered VaD in experimental animals. 2K1C tactics were made to prompt renovascular hypertension in mature male rats. Morris water maze was employed to measure cognition. Mean arterial pressure (MAP), serum nitrite levels, aortic superoxide content, vascular endothelial activity, brain's oxidative stress (diminished glutathione, raised lipid peroxides), inflammatory markers (IL-10, IL-6, TNF-α), cholinergic activity (raised acetylcholinesterase), and cerebral injury (staining of 2, 3, 5- triphenylterazolium chloride) were also examined. Montelukast in doses of 5.0 and 10.0 mg kg-1 was used intraperitoneally as the treatment drug. Along with cognitive deficits, 2K1C-operated rats showed elevated MAP, endothelial dysfunction, brain oxidative stress, inflammation, and cerebral damage with diminished serum nitrite/nitrate. Montelukast therapy significantly and dose-dependently mitigated the 2K1Chypertension-provoked impaired behaviors, biochemistry, endothelial functions, and cerebral infarction. The 2K1C tactic caused renovascular hypertension and associated VaD, which was mitigated via targeted regulation of CysLT1 receptors by montelukast administration. Therefore, montelukast may be taken into consideration for the evaluation of its complete potential in renovascular-hypertension-induced VaD.

Promising Effects of Montelukast for Critically Ill Asthma Patients via a Reduction in Delirium.

Background: Montelukast (MTK), a potent antagonist of cysteinyl leukotriene receptor 1, has shown therapeutic promise for the treatment of neuropsychiatric disorders. Delirium, a common complication in critically ill patients, lacks effective treatment. This study aims to explore the impact of pre-intensive care unit (ICU) MTK use on in-hospital delirium incidence and, subsequent, prognosis in critically ill patients. Methods: A retrospective cohort study (n = 6344) was conducted using the MIMIC-IV database. After propensity score matching, logistic/Cox regression, E-value sensitivity analysis, and causal mediation analysis were performed to assess associations between pre-ICU MTK exposure and delirium and prognosis in critically ill patients. Results: Pre-ICU MTK use was significantly associated with reduced in-hospital delirium (OR: 0.705; 95% CI 0.497-0.999; p = 0.049) and 90-day mortality (OR: 0.554; 95% CI 0.366-0.840; p = 0.005). The association was more significant in patients without myocardial infarction (OR: 0.856; 95% CI 0.383-0.896; p = 0.014) and could be increased by extending the duration of use. Causal mediation analysis showed that the reduction in delirium partially mediated the association between MTK and 90-day mortality (ACME: -0.053; 95% CI -0.0142 to 0.0002; p = 0.020). Conclusions: In critically ill patients, MTK has shown promising therapeutic benefits by reducing the incidence of delirium and 90-day mortality. This study highlights the potential of MTK, beyond its traditional use in respiratory disease, and may contribute to the development of novel therapeutic strategies for delirium.

CYSLTR1 antagonist inhibits Th17 cell differentiation by regulating the NF-κB signaling for the treatment of psoriasis.

Cysteinyl leukotriene receptor 1 (CYSLTR1) is observed to increase in psoriatic skin lesions. Montelukast, a CYSLTR1 antagonist, effectively treats inflammatory disorders, such as rheumatoid arthritis, multiple sclerosis, and atopic dermatitis. Thus, blocking CYSLTR1 may be a promising strategy for psoriasis immunotherapy. We prepared a montelukast sodium cream and solution and investigated their effects on psoriasis-like skin lesions induced by imiquimod (IMQ). After the treatment, serum, skin, and spleen samples were collected for evaluation. We treated human T helper (Th) 17 cells with montelukast in vitro to study its effect on Th17 differentiation and nuclear factor kappa-B (NF-κB) signaling. We also created a keratinocyte proliferation model induced by M5 cytokines and assessed the influence of montelukast on key psoriasis-related genes. We induced psoriasis in CYSLTR1 knockout (KO) mice using IMQ to explore the role of CYSLTR1 in psoriasis development. Montelukast sodium cream and solution effectively reduced the psoriasis area and severity index (PASI) and alleviated disease symptoms in IMQ-induced mice. Furthermore, reduced infiltration of inflammatory cells (Th1, Th17, and T follicular helper [Tfh] cells), decreased mRNA expression of cytokines in the skin (interleukin [IL]-17/F and IL-23), and lower serum concentrations of various cytokines (IL-2, IL-6, IL-13, and IL-17A/F) were observed. Montelukast cream and solution also decreased spleen size and the proportion of Th17 and Tfh cells, and significantly inhibited NF-κB signaling-related genes after application. Moreover, montelukast inhibited Th17 cell differentiation and suppressed NF-κB signaling in vitro. CYSLTR1 KO mice induced with IMQ showed improvement in PASI scores, serum IL-17A/F levels, and lower Th1 and Th17 cells in the spleen and skin compared to wild-type mice. Montelukast also suppressed the proliferation and inflammatory response of keratinocytes by regulating NF-κB signaling. Collectively, our results strongly indicate that inhibition of CYSLTR1 signaling to target the Th17 response holds significant promise as a therapeutic approach to manage psoriasis.

Design, Synthesis, and Structure-Activity Relationship of Novel Potent and Highly Selective Cysteinyl Leukotriene Receptor 1 (CysLT1R) Antagonists

Design, Synthesis, and Structure-Activity Relationship of Novel Potent and Highly Selective Cysteinyl Leukotriene Receptor 1 (CysLT₁R) Antagonists

Comparative efficacy of combined antihistamine and montelukast therapy in adult patients with atopic dermatitis.

Atopic dermatitis (AD) is one of the most common chronic skin conditions affecting about 20% of children and 5% of adults. However, the studies assessing novel therapies for AD have been focused mainly on paediatric patients and only few studies have involved adult participants. To compare the treatment outcomes between the antihistamine monotherapy and combined intervention with an antihistamine agent and a cysteinyl leukotriene receptor antagonist in adult patients with atopic dermatitis. Patients were randomized into two groups to receive 5 mg oral desloratadine or the combined therapy with 5 mg oral desloratadine and 10 mg montelukast. Both groups were also administered topical treatment using the same protocol (topical Elocon and moisturizer). To estimate the efficacy of the implemented therapy methods, different skin health scores (SCORAD, GISS, EASI, PPNRS and DLQI) and skin functional assessment outcomes (corneometry, pH and transepidermal water loss) were evaluated before and after the treatment. Significant differences were revealed in compared measurement results for scales of the Extent and Severity of Eczema assessment, Global Individual Signs Score, Eczema Area and Severity Index, Pruritus Numerical Rating Scale, Dermatology Life Quality Index and Skin Functional Properties (p > 0.05). Comparison of data presenting the therapy outcomes in two groups showed that administration of the combined therapy was significantly more effective compared to the antihistamine monotherapy. The results revealed considerable efficacy of the combined therapy reinforced by the use of cysteinyl leukotriene receptor antagonist, montelukast.

A review of the therapeutic potential of the cysteinyl leukotriene antagonist Montelukast in the treatment of bronchiolitis obliterans syndrome following lung and hematopoietic-stem cell transplantation and its possible mechanisms.

Lung and hematopoietic stem cell transplantation are therapeutic modalities in chronic pulmonary and hematological diseases, respectively. One of the complications in these patients is the development of bronchiolitis obliterans syndrome (BOS). The efficacy and safety of available treatment strategies in BOS remain a challenge. A few mechanisms have been recognized for BOS in lung transplant and graft-versus-host disease (GVHD) patients involving the TH-1 and TH-2 cells, NF-kappa B, TGF-b, several cytokines and chemokines, and cysteinyl leukotrienes (CysLT). Montelukast is a highly selective CysLT receptor antagonist that has been demonstrated to exert anti-inflammatory and anti-fibrotic effects in abundant experiments. One area of interest for the use of montelukast is lung transplants or GVHD-associated BOS. Herein, we briefly review data regarding the mechanisms involved in BOS development and montelukast administration as a treatment modality for BOS, and finally, the possible relationship between CysLTs antagonism and BOS improvement will be discussed.

DYSREGULATED LEUKOTRIENE METABOLISM IN COVID-19 PATIENTS.

The aim of this study was to examine leukotriene metabolism in COVID-19. A total of 180 people were included in the study. Of these, 60 were healthy controls, 60 were patients who needed intensive care unit (ICU), and 60 were patients who did not need intensive care (non-ICU). Serum levels of 5-lipoxygenase (5-LO), 5-LO activating protein (ALOX5AP) and cysteinyl leukotriene (CYSLT) were measured and mRNA expressions of 5-LO, ALOX5AP and cysteinyl leukotriene receptor 1 (CYSLTR1) were investigated. As compared to the control group, both non-ICU and ICU groups had lower levels of 5-LO and mRNA expression. ICU patients had lower levels of 5-LO and mRNA expression compared with non-ICU patients. The expression of CYSLTR1 mRNA was higher in patients compared to healthy controls. CYSLTR1 mRNA expression was found to be higher in ICU group than in non-ICU group. CYSLT levels were higher in the control group compared to both non-ICU and ICU patients. Due to the higher expressions of CYSLTR1 in patients than control group, selective leukotriene receptor blockers can be used as a treatment option. CYSLTR1 expressions were also higher in ICU group than non-ICU group. Thus, CYSLTR1 mRNA expression could be a promising biomarker of COVID-19 severity.

The IL‐31/CysLT2R axis is associated with itching in patients with allergic rhinitis

AbstractBackgroundItching is a troublesome symptom that disturbs patients with allergic rhinitis (AR). The molecular mechanisms underlying itching in AR need to be further illuminated. The aim of this study was to investigate the role of epithelial cell‐derived interleukin‐31 (IL‐31) in nasal itching in AR.MethodsA total of 33 patients and 20 healthy control subjects were enrolled in this prospective study. The disease severity of patients with AR was assessed by the total visual analog scale score. The levels of IL‐31, cysteinyl leukotriene receptor 1 (CysLT1R), and CysLT2R in the nasal brush specimens from the enrolled subjects were measured by quantitative real‐time polymerase chain reaction (RT–PCR) and immunohistochemical staining. The expression of CysLT2R in a human nasal epithelial cell line (HNEpC) was assessed by immunofluorescence staining.ResultsCompared with the control subjects, the protein and mRNA levels of IL‐31 and CysLT2R were significantly increased in patients with AR. Higher levels of IL‐31 and CysLT2R in nasal epithelial cells were associated with itching but not nasal congestion, rhinorrhea, or sneezing in AR. A significant relationship was found between IL‐31 and CysLT2R in nasal epithelial cells, with a correlation coefficient of 0.93. Furthermore, RT–PCR and immunofluorescence staining revealed that IL‐31 directly induced CysLT2R expression in HNEpCs. Nasal steroid treatment inhibited IL‐31 and CysLT2R expression in 13 patients with AR in vivo.ConclusionsNasal epithelial cell‐derived IL‐31 might be associated with itching symptoms via CysLT2R in AR.

Innate immunity response of zafirlukast treated-tilapia during foreign body inflammation

There is limited knowledge regarding the blockade of cysteinyl leukotriene receptors (CysLTRs) and their effects in teleost fish. The present study investigated the effects of Zafirlukast, antagonist of CysLTR1 receptor, on the foreign body inflammatory reaction in Nile tilapia (Oreochromis niloticus). Zafirlukast-treated tilapia demonstrated a decrease in the formation of multinucleated foreign body giant cells and Langhans cells on the round glass coverslips implanted in the subcutaneous tissue, along with a significant reduction in white blood cell counts and decreased production of reactive oxygen species. There was an increase in serum levels of α2-macroglobulins, as well as a decrease in ceruloplasmin and haptoglobin. Zafirlukast treatment led to a significant decrease in the area of splenic melanomacrophage centers and a reduction in the presence of lipofuscin. These findings highlight the potential anti-inflammatory effects of zafirlukast treatment in tilapia and indicate its action on CysLTR1 receptor, modulating the innate immune response of tilapia during the foreign body reaction. The comprehension of chronic inflammation mechanisms in fish has become increasingly relevant, especially concerning the utilization of biomaterials for vaccine and drug delivery.

Epigenomic Profiling Advises Therapeutic Potential of Leukotriene Receptor Inhibitors for a Subset of Triple-Negative Breast Tumors.

Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype, with a poor survival rate compared to others subtypes. For a long time, chemotherapy was the only systemic treatment for TNBC, and the identification of actionable molecular targets might ultimately improve the prognosis for TNBC patients. We performed a genome-wide analysis of DNA methylation at CpG islands on a collection of one hundred ten breast carcinoma samples and six normal breast tissue samples using reduced representation bisulfite sequencing with the XmaI restriction enzyme (XmaI-RRBS) and identified a subset of TNBC samples with significant hypomethylation at the LTB4R/LTB4R2 genes' CpG islands, including CpG dinucleotides covered with cg12853742 and cg21886367 HumanMethylation 450K microarray probes. Abnormal DNA hypomethylation of this region in TNBC compared to normal samples was confirmed by bisulfite Sanger sequencing. Gene expression generally anticorrelates with promoter methylation, and thus, the promoter hypomethylation detected and confirmed in our study might be revealed as an indirect marker of high LTB4R/LTB4R2 expression using a simple methylation-sensitive PCR test. Analysis of RNA-seq expression and DNA methylation data from the TCGA dataset demonstrates that the expression of the LTB4R and LTB4R2 genes significantly negatively correlates with DNA methylation at both CpG sites cg12853742 (R = -0.4, p = 2.6 × 10-6; R = -0.21, p = 0.015) and cg21886367 (R = -0.45, p = 7.3 × 10-8; R = -0.24, p = 0.005), suggesting the upregulation of these genes in tumors with abnormal hypomethylation of their CpG island. Kaplan-Meier analysis using the TCGA-BRCA gene expression and clinical data revealed poorer overall survival for TNBC patients with an upregulated LTB4R. To this day, only the leukotriene inhibitor LY255283 has been tested on an MCF-7/DOX cell line, which is a luminal A breast cancer molecular subtype. Other studies compare the effects of Montelukast and Zafirlukast (inhibitors of the cysteinyl leukotriene receptor, which is different from LTB4R/LTB4R2) on the MDA-MB-231 (TNBC) cell line, with high methylation and low expression levels of LTB4R. In our study, we assess the therapeutic effects of various drugs (including leukotriene receptor inhibitors) with the DepMap gene effect and drug sensitivity data for TNBC cell lines with hypomethylated and upregulated LTB4R/LTB4R2 genes. LY255283, Minocycline, Silibinin, Piceatannol, Mitiglinide, 1-Azakenpaullone, Carbetocin, and Pim-1-inhibitor-2 can be considered as candidates for the additional treatment of TNBC patients with tumors demonstrating LTB4R/LTB4R2 hypomethylation/upregulation. Finally, our results suggest that the epigenetic status of leukotriene B4 receptors is a novel, potential, predictive, and prognostic biomarker for TNBC. These findings might improve individualized therapy for TNBC patients by introducing new therapeutic adjuncts as anticancer agents.

Association of oral montelukast with reduced odds of developing exudative age-related macular degeneration.

This study was conducted to evaluate the association of oral montelukast, selective antagonism for cysteinyl leukotriene receptor 1, with reduced odds of exudative age-related macular degeneration (exAMD) development. This case-control study was conducted using Institutional Cohort Finder tool, and included 1913 patients with exAMD (ICD: H35.32 and 362.52) and 1913 age- and gender-matched control subjects without exAMD. Sub-analysis among 1913 exAMD and 324 non-exudative AMD was also conducted. A total of 47 (2.5%) exAMD cases were identified to have a history of oral montelukast use prior to exAMD diagnosis, compared to 84 (4.4%) controls. Montelukast usage was significantly associated with reduced odds of exAMD in the multivariable analysis (adjusted OR: 0.50, 95% CI: 0.31 - 0.80) as well as NSAID usage (adjusted OR: 0.69). Caucasian race, history of smoking, non-exudative macular degeneration in either eye were also found to have significant relationship with increased odds of exAMD. In the sub-analysis, montelukast usage showed significant association with reduced odds of developing exAMD from non-exudative AMD (adjusted OR: 0.53 95% CI: 0.29 - 0.97) as well as the presence of atopic disease (adjusted OR: 0.60). The study results suggested that oral montelukast is linked to reduced odds of exAMD development.

CysLTR1 antagonism by montelukast can ameliorate diabetes-induced aortic and testicular inflammation

AimsMontelukast, a cysteinyl leukotriene receptor (CysLTR)1 antagonist, is emerging as an attractive strategy to curtail diabetic complications; however, its role in aortic and testicular tissues is unknown. This study investigated the effect of CysLTR1 antagonism by montelukast on toll-like receptor (TLR)4 and nuclear factor kappa B (NF-κB) pathways in diabetes-induced aortic and testicular injury. MethodsAdult male Sprague-Dawley rats were made diabetic with Streptozotocin (STZ, 55 mg/kg). Following this, Streptozotocin-induced diabetic (SD) rats were administered montelukast (10 and 20 mg/kg, orally) for 8 weeks. Blood glucose, serum malondialdehyde (MDA), inflammatory markers, and histopathology were evaluated. ResultsMontelukast showed protection against diabetic complications, as evidenced by the ameliorative effect against STZ-induced alterations in oxidative stress as indicated by serum MDA levels. Moreover, montelukast conferred a significant decrease in the aortic and testicular levels of CysLTR1, TLR4, and NF-κB with a subsequent decrease in the levels of NOD-like receptor family pyrin domain containing (NLRP)3, caspase 1, interleukin (IL)-1β, IL-6, monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF)-α. Additionally, administration of montelukast resulted in autophagy stimulation, as shown by decreased p62/Sequestosome (SQSTM)1 levels. Finally, montelukast protection resulted in normal thickness of whole aortic wall, regular tunica (t.) intima, mild vacuolation of smooth muscle fibers in aorta, increased size of seminiferous tubules, and increased spermatogenesis in testis as demonstrated by histopathology. ConclusionsThe protective effect of montelukast against diabetes-induced aortic and testicular injury is due to its antioxidant, anti-inflammatory, and autophagy stimulation characteristics.