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Respiratory Medicine Case Reports 2024Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and aspirin-exacerbated respiratory disease (AERD) have more severe sinus disease than those without...
INTRODUCTION
Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and aspirin-exacerbated respiratory disease (AERD) have more severe sinus disease than those without AERD. CRSwNP associated with type 2 inflammation and AERD can be difficult to control with standard medical therapy and sinus surgery.
CASE STUDY
74-year-old Japanese woman with chronic sinusitis since age 50 and asthma since age 60. At age 64, she began to experience asthma exacerbations and was started on short-term corticosteroid therapy with prednisolone. At age 70, she experienced urticaria, nasal congestion, and wheezing after taking an NSAID; based on an NSAID provocation test, we diagnosed the patient with AERD and CRSwNP. A diagnosis of severe eosinophilic chronic rhinosinusitis was also made based on the scoring system and algorithm used in the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis.
RESULTS
Treatment with benralizumab (30 mg), formoterol-fluticasone combination via pressurized metered inhaler (1000 μg), and leukotriene receptor antagonist improved the asthma symptoms and exacerbations so the short-term prednisolone was stopped; however, nasal congestion and olfactory dysfunction (hyposmia) persisted, and peripheral blood eosinophil count (peak, 1500 cells/μL) and fractional exhaled nitric oxide (peak, 42 ppb) became elevated. Swapping the benralizumab for monthly tezepelumab (210 mg) improved not only the asthma symptoms but also the nasal congestion, olfactory dysfunction, eosinophil count (<300 cells/μL), and fractional exhaled nitric oxide level [8ppb].
CONCLUSION
Changing from benralizumab to tezepelumab improved asthma symptoms, nasal obstruction, and olfactory dysfunction in elderly, female, Japanese patient with AERD and CRSwNP.
PubMed: 38828227
DOI: 10.1016/j.rmcr.2024.102041 -
Medicina (Kaunas, Lithuania) Apr 2024: The influence of montelukast (MK), an antagonist of cysLT1 leukotriene receptors, on lung lesions caused by experimental diabetes was studied. : The study was...
: The influence of montelukast (MK), an antagonist of cysLT1 leukotriene receptors, on lung lesions caused by experimental diabetes was studied. : 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. : 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 < 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, < 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, < 0.01), and MDA values decreased. MK administered alone did not significantly alter any of these parameters in normal animals. : 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.
Topics: Sulfides; Cyclopropanes; Animals; Quinolines; Acetates; Rats, Wistar; Diabetes Mellitus, Experimental; Male; Rats; Lung; Pulmonary Fibrosis; Leukotriene Antagonists; Streptozocin; Blood Glucose
PubMed: 38792932
DOI: 10.3390/medicina60050749 -
Molecules (Basel, Switzerland) Apr 2024Allergic rhinitis (AR) is a prevalent inflammatory condition affecting millions globally, with current treatments often associated with significant side effects. To seek...
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 (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.
Topics: Phytochemicals; Molecular Docking Simulation; Rhinitis, Allergic; Molecular Dynamics Simulation; Humans; Urtica dioica; Plant Extracts
PubMed: 38675586
DOI: 10.3390/molecules29081765 -
European Heart Journal May 2024The Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene is closely associated with myocardial ischaemia/reperfusion injury (I/RI). The effects of ALDH2...
BACKGROUND AND AIMS
The Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene is closely associated with myocardial ischaemia/reperfusion injury (I/RI). The effects of ALDH2 on neutrophil extracellular trap (NET) formation (i.e. NETosis) during I/RI remain unknown. This study aimed to investigate the role of ALDH2 in NETosis in the pathogenesis of myocardial I/RI.
METHODS
The mouse model of myocardial I/RI was constructed on wild-type, ALDH2 knockout, peptidylarginine deiminase 4 (Pad4) knockout, and ALDH2/PAD4 double knockout mice. Overall, 308 ST-elevation myocardial infarction patients after primary percutaneous coronary intervention were enrolled in the study.
RESULTS
Enhanced NETosis was observed in human neutrophils carrying the ALDH2 genetic mutation and ischaemic myocardium of ALDH2 knockout mice compared with controls. PAD4 knockout or treatment with NETosis-targeting drugs (GSK484, DNase1) substantially attenuated the extent of myocardial damage, particularly in ALDH2 knockout. Mechanistically, ALDH2 deficiency increased damage-associated molecular pattern release and susceptibility to NET-induced damage during myocardial I/RI. ALDH2 deficiency induced NOX2-dependent NETosis via upregulating the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/leukotriene C4 (LTC4) pathway. The Food and Drug Administration-approved LTC4 receptor antagonist pranlukast ameliorated I/RI by inhibiting NETosis in both wild-type and ALDH2 knockout mice. Serum myeloperoxidase-DNA complex and LTC4 levels exhibited the predictive effect on adverse left ventricular remodelling at 6 months after primary percutaneous coronary intervention in ST-elevation myocardial infarction patients.
CONCLUSIONS
ALDH2 deficiency exacerbates myocardial I/RI by promoting NETosis via the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/LTC4/NOX2 pathway. This study hints at the role of NETosis in the pathogenesis of myocardial I/RI, and pranlukast might be a potential therapeutic option for attenuating I/RI, particularly in individuals with the ALDH2 mutation.
Topics: Animals; Aldehyde Dehydrogenase, Mitochondrial; Myocardial Reperfusion Injury; Extracellular Traps; Mice, Knockout; Humans; Mice; Protein-Arginine Deiminase Type 4; Leukotriene C4; Male; Disease Models, Animal; Neutrophils; Leukotriene Antagonists; Female; ST Elevation Myocardial Infarction; Middle Aged; Benzamides; Benzodioxoles
PubMed: 38666340
DOI: 10.1093/eurheartj/ehae205 -
Multiple Sclerosis (Houndmills,... May 2024Effective and safe treatment options for multiple sclerosis (MS) are still needed. Montelukast, a leukotriene receptor antagonist (LTRA) currently indicated for asthma...
Montelukast as a repurposable additive drug for standard-efficacy multiple sclerosis treatment: Emulating clinical trials with retrospective administrative health claims data.
BACKGROUND
Effective and safe treatment options for multiple sclerosis (MS) are still needed. Montelukast, a leukotriene receptor antagonist (LTRA) currently indicated for asthma or allergic rhinitis, may provide an additional therapeutic approach.
OBJECTIVE
The study aimed to evaluate the effects of montelukast on the relapses of people with MS (pwMS).
METHODS
In this retrospective case-control study, two independent longitudinal claims datasets were used to emulate randomized clinical trials (RCTs). We identified pwMS aged 18-65 years, on MS disease-modifying therapies concomitantly, in de-identified claims from Optum's Clinformatics Data Mart (CDM) and IQVIA PharMetrics Plus for Academics. Cases included 483 pwMS on montelukast and with medication adherence in CDM and 208 in PharMetrics Plus for Academics. We randomly sampled controls from 35,330 pwMS without montelukast prescriptions in CDM and 10,128 in PharMetrics Plus for Academics. Relapses were measured over a 2-year period through inpatient hospitalization and corticosteroid claims. A doubly robust causal inference model estimated the effects of montelukast, adjusting for confounders and censored patients.
RESULTS
pwMS treated with montelukast demonstrated a statistically significant 23.6% reduction in relapses compared to non-users in 67.3% of emulated RCTs.
CONCLUSION
Real-world evidence suggested that montelukast reduces MS relapses, warranting future clinical trials and further research on LTRAs' potential mechanism in MS.
Topics: Humans; Sulfides; Cyclopropanes; Quinolines; Acetates; Adult; Middle Aged; Female; Male; Retrospective Studies; Leukotriene Antagonists; Multiple Sclerosis; Young Adult; Case-Control Studies; Adolescent; Aged; Administrative Claims, Healthcare; Recurrence
PubMed: 38660773
DOI: 10.1177/13524585241240398 -
Journal of Epidemiology and Global... Apr 2024This study examines incidence, mortality, medical expenditure and prescription patterns for asthma on a national scale, particularly in Asian countries for asthma is...
BACKGROUND
This study examines incidence, mortality, medical expenditure and prescription patterns for asthma on a national scale, particularly in Asian countries for asthma is limited. Our aim is to investigate incidence, mortality, prescription patterns and provide a comprehensive overview of healthcare utilization trends for asthma from 2009 to 2018.
METHODS
We included patients diagnosed with asthma between 2009 and 2018. We excluded patients with missing demographic data. Our analysis covered comorbidities, including diabetes mellitus, hypertension, allergic rhinitis, eczema, atopic dermatitis, coronary artery disease, congestive heart failure, chronic kidney disease, chronic hepatitis, stroke, and cancer. Investigated medications comprised oral and intravenous steroids, short-acting beta-agonists, inhaled corticosteroids (ICS), combinations of ICS and long-acting beta-agonists, long-acting muscarinic antagonists, and leukotriene receptor antagonists montelukast. We also assessed the number of outpatient visits, emergency visits, and hospitalizations per year, as well as the average length of hospitalization and average medical costs.
RESULTS
The study included a final count of 88,244 subjects from 1,998,311 randomly selected samples between 2000 and 2019. Over the past decade, there was a gradual decline in newly diagnosed asthma patients per year, from 10,140 to 6,487. The mean age annually increased from 47.59 in 2009 to 53.41 in 2018. Over 55% of the patients were female. Eczema was diagnosed in over 55% of the patients. Around 90% of the patients used oral steroids, with a peak of 97.29% in 2018, while the usage of ICS varied between 86.20% and 91.75%. Intravenous steroids use rose from 40.94% in 2009 to 54.14% in 2018. The average annual hospital stay ranged from 9 to 12 days, with a maximum of 12.26 days in 2013. Lastly, the average medical expenses per year ranged from New Taiwan dollars 5558 to 7921.
CONCLUSIONS
In summary, both asthma incidence and all-cause mortality rates decreased in Taiwan from 2009 to 2018. Further analysis of medical expenses in patients with asthma who required multiple hospitalizations annually revealed an increase in outpatient and emergency visits and hospitalizations, along with longer hospital stays and higher medical costs.
PubMed: 38656730
DOI: 10.1007/s44197-024-00230-8 -
International Journal of Biological... 2024Cysteinyl leukotriene receptor 1 (CYSLTR1) is observed to increase in psoriatic skin lesions. Montelukast, a CYSLTR1 antagonist, effectively treats inflammatory...
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 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 . 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.
Topics: Humans; Animals; Mice; NF-kappa B; Interleukin-17; Th17 Cells; Psoriasis; Cell Differentiation; Cytokines; Acetates; Cyclopropanes; Quinolines; Sulfides
PubMed: 38617532
DOI: 10.7150/ijbs.92514 -
JMIR Dermatology Apr 2024
PubMed: 38607671
DOI: 10.2196/50434 -
Cell Communication and Signaling : CCS Mar 2024In normal colon tissue, oestrogen receptor alpha (ERα) is expressed at low levels, while oestrogen receptor beta (ERβ) is considered the dominant subtype. However, in...
In normal colon tissue, oestrogen receptor alpha (ERα) is expressed at low levels, while oestrogen receptor beta (ERβ) is considered the dominant subtype. However, in colon carcinomas, the ERα/β ratio is often increased, an observation that prompted us to further investigate ERα's role in colorectal cancer (CRC). Here, we assessed ERα nuclear expression in 351 CRC patients. Among them, 119 exhibited positive ERα nuclear expression, which was significantly higher in cancer tissues than in matched normal tissues. Importantly, patients with positive nuclear ERα expression had a poor prognosis. Furthermore, positive ERα expression correlated with increased levels of the G-protein coupled cysteinyl leukotriene receptor 1 (CysLTR) and nuclear β-catenin, both known tumour promoters. In mouse models, ERα expression was decreased in Cysltr1 CAC (colitis-associated colon cancer) mice but increased in Apc mice with wild-type Cysltr1. In cell experiments, an ERα-specific agonist (PPT) increased cell survival via WNT/β-catenin signalling. ERα activation also promoted metastasis in a zebrafish xenograft model by affecting the tight junction proteins ZO-1 and Occludin. Pharmacological blockade or siRNA silencing of ERα limited cell survival and metastasis while restoring tight junction protein expression. In conclusion, these findings highlight the potential of ERα as a prognostic marker for CRC and its role in metastasis.
Topics: Humans; Mice; Animals; Estrogen Receptor alpha; beta Catenin; Zebrafish; Colonic Neoplasms; Wnt Signaling Pathway; Estrogen Receptor beta; Disease Models, Animal; Colorectal Neoplasms
PubMed: 38549115
DOI: 10.1186/s12964-024-01582-1 -
Viruses Feb 2024Koi herpesvirus (KHV, CyHV-3) causes severe economic losses in carp farms. Its eradication is challenging due to the establishment of latency in blood leukocytes and...
Koi herpesvirus (KHV, CyHV-3) causes severe economic losses in carp farms. Its eradication is challenging due to the establishment of latency in blood leukocytes and other tissues. To understand the molecular mechanisms leading to KHV infection in leukocytes, common carp were bath-exposed to KHV at 17 °C. After confirming the presence of viral transcripts in blood leukocytes at ten days post infection, RNA-Seq was performed on peripheral blood leukocytes on the Illumina NovaSeq. KHV infection triggered a robust immune response mediated by pattern recognition receptors, mainly toll-like receptors (, , tlr7, and ), -like, galectin proteins, and lipid mediators such as . Enriched pathways showed increased mitochondria oxidative phosphorylation and the activation of signalling pathways such as mitogen-activated protein kinases (MAPKs) and vascular endothelial growth factor (VEGF). KHV-infected leukocytes showed low production of reactive oxygen species (ROS) and glutathione metabolism, high iron export and phagocytosis activity, and low autophagy. Macrophage polarization was deduced from the up-regulation of genes such as -like, , , , and receptors, while markers for cytotoxic T cells were observed to be down-regulated. Further work is required to characterise these leukocyte subsets and the molecular events leading to KHV latency in blood leukocytes.
Topics: Animals; Herpesviridae Infections; Vascular Endothelial Growth Factor A; Herpesviridae; Carps; Gene Expression Profiling; Leukocytes; Fish Diseases
PubMed: 38543746
DOI: 10.3390/v16030380