Leukotriene Research Articles

Exploring Advances in Natural Plant Molecules for Allergic Rhinitis Immunomodulation in Vivo and in Vitro.

Allergic rhinitis (AR) is a prevalent allergic disease that imposes significant economic burdens and life pressures on individuals, families, and society, particularly in the context of accelerating globalization and increasing pathogenic factors. Current clinical therapies for AR include antihistamines, glucocorticoids administered via various routes, leukotriene receptor antagonists, immunotherapy, and several decongestants. These treatments have demonstrated efficacy in alleviating clinical symptoms and pathological states. However, with the growing awareness of AR and rising expectations for improvements in quality of life, these treatments have become associated with a higher incidence of side effects and an elevated risk of drug resistance. Furthermore, the development of AR is intricately associated with dysregulation of the immune system, yet the underlying pathogenetic mechanisms remain incompletely understood. In contrast, widely available natural plant molecules offer multiple targeting pathways that uniquely modify the typical pathophysiology of AR through immunomodulatory processes. This review presents a comprehensive analysis of both in vivo and in vitro studies on natural plant molecules that modulate immunity for treating AR. Additionally, we examine their specific mechanisms of action in animal models to provide new insights for developing safe and effective targeted therapies while guiding experimental and clinical applications against AR.

P0117 Exploring the role and mechanism of leukotriene D4 in fistulizing Crohn's disease based on multi-omics research

Abstract Background Alterations in the gut microbiota and its metabolites are involved in the pathogenesis of Crohn's disease (CD). In a study targeting patients with different phenotypes of CD, we investigated the characteristics of the gut microbiota and metabolites between Crohn's disease with fistula and Crohn's disease without fistula. Methods We divided the research subjects into three groups, including 11 CD patients with fistulas, 9 CD patients without fistulas, and 5 healthy individuals (control group). Stool samples from patients were collected and sequenced. The fecal microflora was analyzed by 16S ribosomal RNA gene amplification sequence, and the metabolites were quantified by liquid chromatography tandem mass spectrometry (LC-MS/MS). Bioinformatics analysis was employed to explore the microbial and metabolite characteristics of CD fistulas. Then, we further verified through mouse experiments and cell experiments. Results Compared with healthy controls, CD patients mainly showed a reduction in the Firmicutes phylum and an increase in the Proteobacteria phylum. The reduction of these short-chain fatty acid-producing bacteria and the increase in harmful bacteria are likely important factors leading to CD. Compared with non-fistula patients, the beneficial bacteria such as the genus Romboutsia in fistula patients were significantly reduced. In addition, we also found structural disruption and functional dysregulation of microorganisms in fistula patients. Metabolomics analysis indicated that the increase in pro-inflammatory metabolites such as leukotriene D4 is a specific change in fistula. Spearman correlation analysis showed that the reduction of beneficial bacteria was significantly negatively correlated with the increase in leukotriene D4, suggesting that the reduction of beneficial bacteria may lead to an increase in leukotriene D4 and thus promote the formation of fistulas. In vitro experiments further demonstrated that leukotriene D4 can delay the healing of fistula in mice. Cell experiments also proved that leukotriene D4 can reduce the expression of E-cadherin and upregulate the expression of EMT-related genes (snail, vimentin). Transcriptome analysis revealed that leukotriene D4 may lead to the formation of fistulas by activating the AGE-RAGE signaling pathway in diabetic complications. Conclusion In CD patients, the reduction of beneficial bacteria may promote the upregulation of leukotriene D4, thus promoting the formation of fistula.

Biosynthetic pathway for leukotrienes is stimulated by lipopolysaccharide and cytokines in pig endometrial stromal cells

An inflammatory response is related to different inflammatory mediators generated by immune and endometrial cells. The links between lipopolysaccharide (LPS), cytokines, and leukotrienes (LTs) in endometrial stromal cells remain unclear. This study aimed to examine the influence of LPS, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-4 and IL-10 on 5-lipooxygenase (5-LO), LTA4 hydrolase (LTAH) and LTC4 synthase (LTCS) mRNA and protein abundances, and LTB4 and cysteinyl (cys)-LTs release including LTC4, by the cultured pig endometrial stromal cells, as well as on cell viability. 24-hour exposure to LPS, TNF-α, IL-4 and IL-10 up-regulated 5-LO mRNA and protein abundances. LPS increased LTAH mRNA abundance, while TNF-α, IL-1β and IL-10 augmented LTAH mRNA and protein abundances. TNF-α and IL-4 increased LTCS mRNA and protein abundances. In addition, LTCS mRNA abundance was enhanced by LPS and IL-4, while LTCS protein abundance was increased by IL-1β. Cells responded to LPS, TNF-α, IL-1β and IL-10 with increased LTB4 release. TNF-α, IL-1β and IL-4 stimulated LTC4 release. Cys-LTs release was up-regulated by LPS, TNF-α, IL-1β and IL-4. All studied cytokines augmented cell viability. In summary, LPS, TNF-α, IL-1β, IL-4 and IL-10 are potential LTs immunomodulatory agents in endometrial stromal cells. These functional interactions could be one of the mechanisms responsible for local orchestrating events in inflamed and healthy endometrium.

Regular versus as-needed treatments for mild asthma in children, adolescents, and adults: a systematic review and network meta-analysis

BackgroundInhaled corticosteroids (ICS) are recommended treatment for mild asthma. We aimed to update the evidence on the efficacy and safety of ICS-containing regimens, leukotriene receptor antagonists (LTRA), and tiotropium relative to as-needed (AN) short-acting β2-agonists (SABA) in children (aged 6–11 years) and adolescents/adults.MethodsA systematic review of randomized controlled trials (RCTs) of regular and AN treatment for mild asthma was conducted (CRD42022352384). PubMed, Scopus, and ClinicalTrials.gov were searched up to 31st March 2024. RCTs in children or adolescents/adults with mild asthma were eligible if they compared any of the following treatments: ICS alone or in combination with fast-acting bronchodilators (FABA, i.e., formoterol or SABA) or long-acting β2-agonists (LABA), LTRA, tiotropium, and SABA alone, for the following outcomes: exacerbations, asthma symptoms, forced expiratory volume in 1 s (FEV1), asthma-specific quality-of-life (QoL), or severe adverse events (SAEs). The two-stage network meta-analysis (NMA) was used to pool risk ratios (RR) or mean differences for treatment outcomes. The risk of bias was assessed using the Revised Cochrane risk-of-bias tool for randomized trials (RoB2). This review followed the PRISMA reporting guideline and the PRISMA checklist is presented in Additional file 2.ResultsThirteen RCTs in children and 29 in adolescents/adults were included. Regular ICS ranked best for preventing exacerbations and improving FEV1 in children. NMA of RCTs suggested regular ICS were better in preventing exacerbations than LTRA (RR [95% confidence intervals], (0.81 [0.69,0.96]) and AN-SABA (0.61 [0.48,0.78]), and not different from AN-ICS (0.83 [0.62,1.12]). In adolescents/adults, for preventing severe exacerbations, regular ICS outperformed AN-SABA (0.58 [0.46,0.73]), but AN-ICS/FABA (0.73 [0.54,0.97]), and regular ICS/LABA (0.68 [0.48,0.97]) surpassed regular ICS. Symptom relief and improved FEV1 were not different among the ICS-containing regimens. Regular ICS ranked best for improved QoL and least likely for SAEs.ConclusionsRegular ICS use may be the most effective treatment for preventing exacerbation and increasing FEV1 in children with mild asthma. In adolescents/adults, ICS-containing regimens outperformed AN-SABA for exacerbation prevention. With varying degrees of heterogeneity, severe exacerbation risk in adolescents/adults might be lower with regular ICS/LABA or AN-ICS/FABA than regular ICS, where AN-ICS/FABA may not be suitable for patients with low FEV1. Additionally, regular ICS use may enhance FEV1 and QoL more than AN-SABA and LTRA.

Challenges in treating patients with comorbid asthma and bronchiectasis.

The management of patients with overlapping asthma and bronchiectasis requires a tailored approach, starting with a comprehensive assessment of the patient's clinical profile, including the severity of asthma and the extent of bronchiectasis. Inhaled corticosteroids (ICS) are often recommended, but their use should be carefully monitored because of the risk of increased infection. If the asthma is well controlled and the bronchiectasis remains stable, a gradual reduction in the dose of ICS may be considered. Adjunctive therapies such as macrolides, which have anti-inflammatory and antimicrobial effects, or leukotriene receptor antagonists may be beneficial. However, leukotriene receptor antagonists should be used with caution in patients with bronchiectasis. Long-acting muscarinic antagonists (LAMA), especially in combination with ICS and long-acting beta-agonists (LABA), can improve bronchodilation and reduce inflammation. Although triple therapy (ICS/LABA/LAMA) is promising, its efficacy in bronchiectasis has not yet been confirmed by randomised controlled trials (RCTs). Ongoing monitoring is essential to adjust treatment as the patient's condition evolves. Preventive measures, including vaccination and regular sputum cultures, are important to minimize the risk of infection. Further research and RCTs are needed to better understand the role of dual bronchodilators and triple therapy in the management of overlapping asthma-bronchiectasis.

Lipoxin A4 (LXA4) as a Potential Drug for Diabetic Retinopathy

The purpose of this review is to propose that lipoxin A4 (LXA4), derived from arachidonic acid (AA), a potent anti-inflammatory, cytoprotective, and wound healing agent, may be useful to prevent and manage diabetic retinopathy (DR). LXA4 suppresses inappropriate angiogenesis and the production of pro-inflammatory prostaglandin E2 (PGE2), leukotrienes (LTs), 12-HETE (12-hydroxyeicosatetraenoic acid), derived from AA by the action of 12-lioxygenase (12-LOX)) interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), as well as the expression of NF-κB, inducible NO (nitric oxide) synthase (iNOS), cyclooxygenase-2 (COX-2), intracellular adhesion molecule-1 (ICAM-1), and vascular endothelial growth factor (VEGF)—factors that play a role in DR. Thus, the intravitreal injection of LXA4 may form a new approach to the treatment of DR and other similar conditions such as AMD (age-associated macular degeneration) and SARS-CoV-2-associated hyperinflammatory immune response in the retina. The data for this review are derived from our previous work conducted in individuals with DR and from various publications on LXA4, inflammation, and DR.

Comparative Study on the Efficacy of Inhaled Corticosteroids Versus Leukotriene Receptor Antagonists in Pediatric Asthma Management

Comparative Study on the Efficacy of Inhaled Corticosteroids Versus Leukotriene Receptor Antagonists in Pediatric Asthma Management

A retrospective study on potential drug‒drug interactions in patients with severe asthma receiving biological therapy: a single-center experience

BackgroundPrevalence of potential drug-drug interactions (pDDIs) in adult patients with severe asthma on biological therapy and their clinical significance have not been fully addressed, thus the aim of this study was to investigate them.MethodsIn this retrospective observational study, patients who were diagnosed with severe asthma and to whom biological therapy was prescribed between September 2015 and December 2020, were enrolled. The study was conducted at the Department of Allergic and Obstructive Pulmonary Diseases, Clinic for Lung Diseases Jordanovac, Clinical Hospital Center Zagreb. Data on demographic characteristics as well as concomitant medication were collected. The analysis of pDDIs was conducted via Lexicomp® online software. Interactions of significance levels A and B were only recorded, while those of levels C, D and X were further analysed. The collected data was processed via Microsoft Excel 365 software.Results60 adult patients, 60% female and 40% male, with median age of 56.2 years, were enrolled. The incidence of pDDIs was 86.67%. Total number of pDDIs detected was 518, out of which 43.24%, 45%, 4.44% and 7.3% of clinical significance B, C, D and X. Interactions of level C, D and X were recorded in, as follows: 83.33%, 25% and 33.33% patients with an average of 4.66, 1.53 and 1.9 interactions per patient. Only 13.33% of the patients had none of the potential clinically significant DDI. Most drug pairs contained at least one antiasthmatic drug. Muscarinic receptor antagonists, oral corticosteroids, β2 agonists and methylxanthines showed potential of entering into clinically significant DDIs, while leukotriene antagonists and biologicals showed no potential for the above.ConclusionPrevalence of potential drug-drug interactions in patients with severe asthma on biological therapy is high. The majority of identified interactions have moderate to high level of clinical significance. Their identification, prevention and resolution could contribute to optimizing therapy, maximizing its therapeutic effect and avoiding undesirable adverse events.

Fecal Microbiota Transplantation Alleviates Airway Inflammation in Asthmatic Rats by Increasing the Level of Short-Chain Fatty Acids in the Intestine.

Asthma is a prevalent chronic inflammatory disorder of the respiratory tract that not only manifests with respiratory symptoms but also often involves intestinal flora disorders and gastrointestinal dysfunction. Recent studies have confirmed the close relationship between the gut and lungs, known as the "gut-lung axis" theory. Fecal microbiota transplantation (FMT), a method for restoring normal intestinal flora, has shown promise in treating common gastrointestinal diseases. The "gut-lung axis" theory suggests that FMT may have significant therapeutic potential for asthma. In this study, we established an Ovalbumin (OVA)-induced rat model of asthma to investigate the protective effect of FMT on airway inflammation and the restoration of intestinal short-chain fatty acids (SCFAs), aiming to explore its underlying mechanism. Rats in the Control group underwent fecal treatment via gavage (Control-FMT, C-FMT group), while rats in the Asthma group underwent fecal treatment via gavage after asthma induction (Asthma-FMT, A-FMT group). Following a two-week period of continuous intragastric administration, various measurements were conducted to assess pulmonary function, peripheral blood neutrophil, lymphocyte, and eosinophil content, lung tissue pathology, and collagen fiber deposition in the lungs. Additionally, neutrophil and eosinophil content in bronchoalveolar lavage fluid (BALF), expression levels of Interleukin-4 (IL-4), IL-5, IL-13, IL-17, IL-33, leukotrienes (LT), thymic stromal lymphopoietin (TSLP), prostaglandin D2 (PGD2) protein and mRNA in lung tissue, and SCFAs content in stool were evaluated. In the C-FMT group, lung function significantly improved, inflammatory cell content in peripheral blood and BALF decreased, lung tissue pathology and collagen fiber deposition significantly improved, the protein and mRNA levels of lung inflammatory factors IL-4, IL-5, IL-13, IL-17, IL-33, LT, TSLP, PGD2 were significantly decreased, and SCFAs such as acetate (C2), propionate (C3), butyrate (C4), isobutyric acid (I-C4), valeric acid (C5), and isovaleric acid (I-C5) content in stool significantly increased. However, the indexes in the A-FMT group did not show significant recovery, and the treatment effect on asthma symptoms in rats was inferior to that in the C-FMT group. Asthma induced intestinal flora disorders in rats, and FMT treatment improved the inflammatory response in asthmatic rat models and corrected their intestinal SCFAs disorders. Encouraging the recovery of intestinal SCFAs may play a significant role, and beneficial bacteria present in feces may improve asthma symptoms by promoting the remodeling of intestinal flora. This experiment provides further scientific evidence supporting the "gut-lung axis" theory.

Trends in prescribing montelukast in patients with asthma in real-life: Results from the Turkish adult asthma registry.

Montelukast, a leukotriene receptor antagonist (LTRA) approved for the treatment of asthma and allergic rhinitis, is widely used, though real-world data on its application in asthma management remain limited. This registry-based study evaluated the use of montelukast in adult asthma patients, examining demographic and disease characteristics, asthma control status, asthma phenotypes, presence of atopy, and treatment regimens. Among 2053 patients analyzed, 61.76% (n = 1268; mean age: 46.2 ± 14.3 years), predominantly females (~76%), received montelukast. Montelukast users showed higher rates of allergic rhinitis (P < 0.001), hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) (P = 0.008), and chronic rhinosinusitis (P = 0.008). Montelukast group also had higher atopy and total IgE levels and tended to be more eosinophilic. Montelukast was commonly preferred in allergic, eosinophilic, NSAID-exacerbated respiratory disease, and severe asthma phenotypes (P < 0.001). Patients receiving Steps 4 and 5 treatments are more likely to be prescribed montelukast (P < 0.001). Montelukast usage was higher among patients with uncontrolled asthma [ACT< 20 (OR:1.29, 95%CI:1.052-1.582, P = 0.014)]. In addition, logistic regression analyses identified the main factors associated with increased montelukast use as; female gender (OR:1.33, 95%CI:1.041-1.713, P = 0.02), presence of atopy (OR:1.46, 95%CI:1.157-1.864, P = 0.002), comorbid allergic rhinitis (OR:2.12, 95%CI:1.679-2.293, P < 0.001), and severe asthma (OR:2.18, 95%CI:1.712-2.784, P < 0.001). These findings reveal that montelukast use is prevalent among asthma patients, particularly in females, middle-aged adults, and those with comorbid allergic rhinitis, uncontrolled asthma, or specific asthma phenotypes, underscoring the factors that influence its prescription in asthma management.

Antiviral and Immunomodulatory Effects of Zafirlukast Against Flaviviruses via Inhibition of the TNF Signaling Pathway.

The two most clinically important members of the flavivirus genus, Zika virus (ZIKV) and dengue virus (DENV) pose a significant public health challenge. They cause a range of diseases in humans, from hemorrhagic to neurological manifestations, leading to economic and social burden worldwide. Nevertheless, there are no approved antiviral drugs to treat these infections. Zafirlukast is an orally available Food and Drug Administration (FDA) approved drug for the prophylaxis and treatment of chronic asthma. It is a leukotriene receptor antagonist (LTRA) with high selectivity of the cysteinyl leukotriene-1 receptor (CYSLTR1) that acts as an immune modulator. Thus, we evaluated the antiviral potential of Zafirlukast against ZIKV and DENV in SK-N-SH cells. We showed that Zafirlukast exhibited potent antiviral activity against ZIKV, which could be linked to Zafirlukast's immune blockade of TNF signaling pathways and its downstream signaling pathways such as MAPK and ERK1/2. In addition, our results showed that Zafirlukast also counteracts ZIKV-induced changes in key genes involved in cellular lipid metabolism. Thus, these findings highlight the translational potential of optimizing Zafirlukast as a therapeutic agent for the treatment of ZIKV and DENV.

A Pharmacovigilance Study on Anti-Asthmatic Agent

Pharmacovigilance plays a critical role in ensuring the safety and efficacy of anti-asthmatic agents, including inhaled corticosteroids (ICS), long-acting beta-agonists (LABAs), and leukotriene receptor antagonists (LTRAs). This study evaluates adverse drug reactions (ADRs) associated with these medications, emphasizing their clinical impact, risk factors, and patient outcomes. A systematic approach, including spontaneous ADR reporting, database reviews, and post-marketing surveillance, was utilized to identify patterns of drug-related complications, such as dysphonia, oral candidiasis, and cardiovascular risks. Findings highlight the importance of monitoring combination therapies, optimizing medication use, and enhancing patient education to improve asthma management while minimizing risks. Future directions include integrating pharmacogenomic data into safety assessments to personalize asthma treatment

Effect of the COVID-19 Lockdown on Pediatric Bronchial Asthma Patients in Saudi Arabia: A Comparative Study.

The lockdowns imposed during the COVID-19 pandemic and social distancing measures may have decreased traffic and air pollution, which may contribute to reducing asthma exacerbation. However, there is not enough information about the relationship between asthma and COVID-19 lockdown, especially in children. Therefore, the aim of this study is to identify the effects of the COVID-19 lockdown on pediatric patients with moderate to severe bronchial asthma. This is a retrospective cross-sectional analytical study of pediatric patients with moderate to severe asthma who came to King Abdullah Specialist Children's Hospital (KASCH) in Riyadh, Saudi Arabia. The study was conducted for a period of 14 months from March 2019 to May 2020, using the charts of children aged 3 to 14 years. We investigated changes in the severity of asthma using indirect parameters including hospital visits, ER visits, and changes in medications used before and during the COVID-19 lockdown. A total of 343 asthmatic patients aged mean±SD of 8±3 years were included in the study. More than half 233 (68%) of them were male. The number of patients admitted to the hospital in 2019 was 46 patients (85%), while in 2020, it was only 17 patients (32%). In 2020, the usage of oral steroids has been decreased from 96 (28%) to 50 (15%). The number of people using the leukotriene inhibitor reduced from 171 in 2019 to 162 in 2020. The ER mean visit was 1.6±1.3in 2019; however, ER visits in 2020 were 0.6 ±0.7showing a considerable reduction in the ER visits (p < 0.001). The COVID-19 lockdown had a positive impact on asthma patients, with our study showing a significant reduction in ER visits, hospitalizations, and the use of oral steroids between March-May 2019 and 2020, suggesting lower asthma severity. However, a holistic approach is needed post-pandemic to improve asthma management, including increased awareness, better healthcare access, and reduction of environmental triggers to promote better control and overall well-being.

Cysteinyl Leukotriene Receptor Antagonism by Montelukast to Treat Visual Deficits.

Montelukast, a Food and Drug Administration-approved drug for asthma and allergic rhinitis modulates leukotriene (LT) receptors and serves as a critical anti-inflammatory agent. Recent research suggests that the LT signaling pathway targeted by montelukast has broader implications for diseases such as fibrosis, cardiovascular diseases, cancer, cerebrovascular disease, and immune defense. This expanded understanding highlights montelukast's potential for repurposing in conditions involving aberrant stress mechanisms, including ocular diseases marked by inflammation, oxidative stress, ER stress, and apoptosis, among several others. This review delves into montelukast's therapeutic mechanisms across various diseases, draws parallels to ocular conditions, and examines clinical trials and associated adverse effects to underscore the unmet need for cysteinyl LT receptor antagonism by montelukast as an effective therapy for visual deficits.

The regulatory action of acetylcholine and its receptors on B4 and C4 leukotriene formation in the porcine endometrium after experimental inflammogenic Escherichia coli infection.

Endometritis is a very common pathology in animals which changes endometrial leukotriene (LT) formation and muscarinic 2 and 3 receptor subtypes (M2R/M3R) and α-7 nicotinic acetylcholine (ACh) receptor (α-7 nAChR) expression patterns. With the relationship between ACh, its receptors and LT production remaining unclear, the role of M2R, M3R and α-7 nAChR in action of ACh on the 5-lipoxygenase (5-LO), LTA4 hydrolase (LTAH) and LTC4 synthase (LTCS) protein abundances in the inflamed porcine endometrium and on the tissue secretion of LTB4 and LTC4 were studied. On day three of the oestrous cycle in gilts aged 7-8 months, 50 mL of either saline solution (control group, n = 5) or an E. coli suspension at 109 colony-forming units/mL (E. coli group, n = 5), was injected into each uterine horn. Endometrial explants obtained eight days later, were incubated with ACh alone, antagonists of M2R, M3R and α-7 nAChR alone, or with ACh together with particular antagonists for 16 h. Enzyme abundances in endometrial tissue were estimated by Western blotting, and LT concentrations in medium by ELISA. Severe acute endometritis developed in the E. coli group. In the endometrial explants from both groups, ACh elevated 5-LO, LTAH and LTCS protein abundances and LTB4 and LTC4 release. In the E. coli group, ACh-induced 5-LO and LTCS abundances and LTB4 release were increased versus the control group. In both groups, the M3R antagonist with ACh reduced all ACh-stimulated enzyme abundances and LT release in comparison to the abundances and release mediated by ACh alone. This effect on LTCS protein abundance and LTB4 release was also produced by the M2R antagonist with ACh in the E. coli group. Compared to the effect of ACh alone, exposure of the E. coli group endometrium to the α-7 nAChR antagonist with ACh led to a rise in LTAH and LTCS protein abundances and LTB4 and LTC4 secretion. In the inflamed pig endometrium, ACh increased 5-LO, LTAH and LTCS protein abundances and LTB4 and LTC4 release by M3R, and LTCS protein abundance and LTB4 release also by M2R. By interaction with α-7 nAChR, ACh reduced LTAH and LTCS protein abundances and the release of these LTs. Thus, in an indirect manner, ACh can affect LT-controlled processes.

Role of leukotriene receptor antagonist in improvement of symptoms after functional endoscopic sinus surgery for chronic rhinosinusitis with or without sinonasal polyposis

Background: Chronic rhinosinusitis is one of the common ENT diseases encountered daily. Due to its chronicity, it leads to patient morbidity and decreased quality-of-life of the patient. Although various medical and surgical management options are available, none can manage the condition effectively. So, the aim of the study is to evaluate the efficacy of the montelukast in the subjective and objective improvement after the FESS for patients with chronic rhino sinusitis. Methods: This randomized controlled trial was conducted among 50 patients diagnosed with chronic rhino sinusitis. All the patients underwent FESS, and after that, they were divided into two groups; one group received the Montelukast tablet in addition to the standard post-operative regimen, and the other group received the standard post-operative medications only. The subjective and objective measurements were made using SNOT-22 and Lund-Kennedy endoscopic scores during the pre- and post-operative periods. Results: The study showed a significant reduction in the various parameters of SNOT-22, viz runny nose (p=0.013), cough (p=0.003), post-nasal discharge (p=0.037), thick nasal discharge (p=0.013), ear fullness (p=0.021), difficulty in falling asleep (p=0.018), walking up at night (p&lt;0.001), reduced concentration (p=0.001) in Group-A than in Group-B. The study also showed a significant reduction in the overall SNOT-22 score in the Group-A. The Lund-Kennedy endoscopic score (p=0.006) also showed a significant reduction during the postoperative period in Group-A. Conclusion: The Montelukast positively affects the reduction of the various domains in the SNOT-22 and the Lund-Kennedy endoscopic score. It can be used as adjuvant therapy during the post-operative period in patients operated with FESS for CRS.

Dual anti-inflammatory activities of COX-2/5-LOX driven by kratom alkaloid extracts in lipopolysaccharide-induced RAW 264.7 cells

Cyclooxygenase (COX) and lipoxygenase (LOX) enzymes play a pivotal role in producing pro-inflammatory eicosanoids, including prostaglandins (PGs) and leukotrienes (LTs), in the inflammation process. Mitragynine is a primary alkaloid contained in the kratom’s leaves and has been reported to show anti-inflammatory activity by suppressing COX-2 mRNA translation to lowering PGs synthesis. In this study, the Kratom’s alkaloid extract containing ~ 46% mitragynine was found to exhibit dual inhibition activity towards COX-2/5-LOX enzymes at concentrations below 25 ppm in the LPS-induced RAW 264.7 macrophage cells. At these levels, no cell toxicity was observed while the cells became death (e.g., 10–46% viability at 50–100 ppm) and only COX-2 inhibition activity was observed after exposed with more than 25 ppm of alkaloid extract. In contrast, the methanolic-crude extract of Kratom’s leaf containing ~ 5% mitragynine showed no inhibition toward COX-2/5-LOX enzymes and did not toxic onto the cells, even after treated at 100 ppm. The alkaloid extract suppressed several antiinflammation parameters, including ROS (64% reduction at 25 ppm), NO (30% reduction at 25 ppm), TNF-α (~ 50% reduction at 25 ppm), and IL-6 production (60% reduction at 6.25 ppm). In silico molecular studies indicated strong binding affinity of Kratom alkaloids to COX-2 and 5-LOX active sites, supporting the Kratom’s alkaloids to have great potential dual inhibition activity towards COX-2/5-LOX enzymes and to be developed as a safer NSAIDs with fewer side effects.

Circulating microRNAs associated with bronchodilator response in childhood asthma

BackgroundBronchodilator response (BDR) is a measure of improvement in airway smooth muscle tone, inhibition of liquid accumulation and mucus section into the lumen in response to short-acting beta-2 agonists that varies among asthmatic patients. MicroRNAs (miRNAs) are well-known post-translational regulators. Identifying miRNAs associated with BDR could lead to a better understanding of the underlying complex pathophysiology.ObjectiveThe purpose of this study is to identify circulating miRNAs associated with bronchodilator response in asthma and decipher possible mechanism of bronchodilator response variation.MethodsWe used available small RNA sequencing on blood serum from 1,134 asthmatic children aged 6 to 14 years who participated in the Genetics of Asthma in Costa Rica Study (GACRS). We filtered the participants into the highest and lowest bronchodilator response (BDR) quartiles and used DeSeq2 to identify miRNAs with differential expression (DE) in high (N = 277) vs. low (N = 278) BDR group. Replication was carried out in the Leukotriene modifier Or Corticosteroids or Corticosteroid-Salmeterol trial (LOCCS), an adult asthma cohort. The putative target genes of DE miRNAs were identified, and pathway enrichment analysis was performed.ResultsWe identified 10 down-regulated miRNAs having odds ratios (OR) between 0.37 and 0.76 for a doubling of miRNA counts and one up-regulated miRNA (OR = 2.26) between high and low BDR group. These were assessed for replication in the LOCCS cohort, where two miRNAs (miR-200b-3p and miR-1246) were associated. Further, functional annotation of 11 DE miRNAs were performed as well as of two replicated miRs. Target genes of these miRs were enriched in regulation of cholesterol biosynthesis by SREBPs, ESR-mediated signaling, G1/S transition, RHO GTPase cycle, and signaling by TGFB family pathways.ConclusionMiRNAs miR-1246 and miR-200b-3p are associated with both childhood and adult asthma BDR. Our findings add to the growing body of evidence that miRNAs play a significant role in the difference of asthma treatment response among patients as it points to genomic regulatory machinery underlying difference in bronchodilator response among patients.Trial registrationLOCCS cohort [ClinicalTrials.gov number NCT00156819, Registration date 20050912], GACRS cohort [ClinicalTrials.gov number NCT00021840].

Salidroside attenuates sepsis-induced acute lung injury by inhibiting ferroptosis-dependent pathway.

Sepsis triggers a systemic inflammatory response that can lead to acute lung injury (ALI). Salidroside (SAL) has many pharmacological activities such as antiinflammatory and anti-oxidation. The objective of the study was to explore the mechanism of SAL on ALI caused by sepsis. A model of ALI in septic mice was established by cecal ligation and puncture. Following SAL treatment, the effect of SAL on the ferroptosis pathway in mice was analyzed. The pathological damage of lung tissue, the levels of inflammatory factors and apoptosis in bronchoalveolar lavage fluid (BALF) of mice were evaluated, and the changes of gene expression level and metabolite content abundance were explored by combining transcriptomics and metabolomics analysis. The effect of SAL on ferroptosis in mice with lung injury was observed by intraperitoneal injection of ferroptosis activator Erastin or ferroptosis inhibitor Ferrostatin-1 to promote or inhibit ferroptosis in mice. SAL significantly alleviated the pathological damage of lung tissue, decreased the number of TUNEL positive cells and the levels of TNF-α, IL-1β, IL-6 in BALF, and increased the level of IL- 10 in lung injury mice. Moreover, the Fe2+ content and malondialdehyde decreased significantly, the reactive oxygen species and glutathione content increased significantly, and the arachidonic acid metabolites 20-hydroxyeicosatetraenoic acid (20- HETE), (5Z, 8Z, 10E, 14Z)-12-Oxoeicosa-5,8,10,14-tetraenoic acid (12-OxOETE), (5Z, 8Z, 10E, 14Z)-(12S)-12-Hydroxyeicosa-5,8,10,14-tetraenoic acid (12(S)-HETE), (5Z, 8Z, 14Z)-11,12-Dihydroxyeicosa-5,8,14-trienoic acid (11,12-DHET), (5Z, 11Z, 14Z)-8,9- Dihydroxyeicosa-5,11,14-trienoic acid, Leukotriene B4, Leukotriene D4 were significantly up-regulated after SAL treatment. Salidroside alleviates ALI caused by sepsis by inhibiting ferroptosis.

An Overview of Pathological Pathway of Asthma and Molecular Mechanisms of Anti-Asthmatic Phytoconstituents

: Asthma presents with chronic inflammation and airway constriction triggered by allergens or pollution. Inflammatory mediators such as histamine and leukotrienes, released in response to inflammation, prompt bronchoconstriction, contracting the smooth muscles around the airways. This constriction obstructs airflow and worsens symptoms such as coughing, wheezing, and breathlessness. Additionally, airways become hyperresponsive, reacting excessively even to harmless stimuli. Persistent inflammation leads to the production of thick mucus, further blocking airflow and worsening symptoms. Mast cell-released histamine triggers bronchoconstriction, leukotrienes, and prostaglandins (eg, Interleukin-4, Interleukin-13) and promotes airway inflammation while cytokines drive Th2-mediated immune responses. Current therapies in asthma include long-acting beta agonists, leukotriene modifiers, inhaled corticosteroids, and immunomodulators. Natural products, due to their anti-inflammatory, antioxidant and immunomodulatory properties, have emerged as promising anti-asthmatic candidates. Polyphenols (quercetin, resveratrol, curcumin, etc.) and Omega-3 fatty acids offer anti-inflammatory benefits by suppressing cytokines and oxidative stress. Natural products intervene at various levels of these pathways. Quercetin inhibits the release of mast cell histamines, alleviating bronchoconstriction. Curcumin suppresses Th2 cytokines, mitigating the allergic response. Omega-3 fatty acids modulate leukotriene and prostaglandin production, reducing airway inflammation. This review concludes that natural phytobioactives have potential in asthma management due to their complex mechanisms that target various immuno-inflammatory mediators.