Search Results (291)

Background: Allergic rhinitis (AR) is commonly treated with intranasal and oral pharmacotherapy or allergen immunotherapy (AIT), each associated with distinct safety considerations. This study aimed to systematically evaluate and compare the safety profiles of these therapeutic approaches by analysing adverse events (AEs) reported in completed randomised controlled trials (RCTs). Methods: A meta-epidemiological analysis was conducted using completed RCTs registered in ClinicalTrials.gov up to 20 October 2023. Trials investigating intranasal drugs, oral medications, or AIT for AR were identified using predefined search terms. Adverse events were manually extracted and categorised according to treatment class and dosage. Other adverse events (OAEs) were classified using Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) and Medical Dictionary for Regulatory Activities (MedDRA) terminology. Meta-analyses compared OAE incidence across treatment groups, including standard-dose, higher-dose, and placebo arms. Results: A total of 216 RCTs were included. Intranasal therapies accounted for 55.56% of trials, predominantly intranasal corticosteroids (INCS) and intranasal antihistamines (INAH). OAE incidence was 16.37% for INCS, 29.43% for INAH, and 8.71% for combination therapy. INAH was associated with higher rates of dysgeusia and nasal discomfort, while higher INCS doses were linked to an increased risk of urinary tract infections. AIT trials comprised 22.69% of studies and demonstrated higher OAE rates, particularly for sublingual immunotherapy (64.96%), followed by subcutaneous (53.98%) and intralymphatic immunotherapy (62.50%). Oropharyngeal AEs were most frequent with sublingual immunotherapy. Oral medications (18.06%) showed the lowest OAE incidence, with upper respiratory tract infections occurring more frequently with oral antihistamines. Conclusions: Among intranasal therapies, INCS demonstrated the most favourable safety profile. Sublingual immunotherapy was associated with a higher frequency of OAEs compared with other AIT modalities. Combination oral antihistamine and leukotriene receptor antagonist therapy appeared to be the safest oral treatment option. Further well-designed studies are needed to refine comparative safety assessments across AR treatments. Full article

Allergic Rhinitis (AR) is an IgE-mediated inflammatory disorder that impairs quality of life and systemic function. Following the ‘one airway, one disease’ paradigm, AR-related inflammation often extends to the lower respiratory tract. This randomized controlled trial investigated the effects of an 8-week moderate-intensity aerobic exercise (MOA) program on clinical symptoms, nasal airflow, airway inflammation, pulmonary function, and cardiorespiratory parameters in young adults with physician-confirmed persistent AR. To isolate the exercise effects, all participants discontinued antihistamines, corticosteroids, and leukotriene antagonists before and during the study period. Eighteen participants were allocated to either the MOA group (n = 9), which performed treadmill walking or jogging at 50–60% heart rate reserve three times per week for eight weeks, or a control group (CON, n = 9) that maintained usual daily activities. Clinical symptoms, peak nasal inspiratory flow, fractional exhaled nitric oxide, pulmonary function, heart rate, blood pressure, aerobic fitness, and perceived exertion were assessed at baseline, week 4, and week 8 using standardized procedures. Compared with baseline and the CON group, the exercise intervention resulted in significant reductions in nasal congestion, itching, sneezing, and rhinorrhea, accompanied by increased nasal airflow and reduced airway inflammation. Pulmonary function indices and cardiorespiratory parameters also improved following training. These findings suggest that moderate-intensity aerobic exercise may offer a valuable non-pharmacological approach to support conventional care, potentially enhancing respiratory and physiological outcomes in young adults with persistent AR. Full article

Fatty acids serve dual roles in cardiac physiology: as energy substrates and as precursors of bioactive lipid mediators (prostaglandins, leukotrienes, oxylipins) from n-3/n-6 PUFAs that regulate inflammation, thrombosis, and remodeling. Saturated, monounsaturated, and trans fatty acids modulate metabolism and membrane function, thereby shaping these pathways. Clinically, n-3 long-chain PUFAs (EPA and DHA) reduce cardiovascular mortality and aid postischemic remodeling; however, high doses increase the risk of atrial fibrillation. By contrast, trans and saturated fatty acids promote dyslipidemia, dysfunction, and higher rates of coronary artery disease and heart failure. Mechanistically, fatty acid uptake via FABPpm, CD36 (FAT), and FATPs, along with β-oxidation and PPAR signaling, regulates metabolism, while COX/LOX/CYP pathways generate eicosanoids and resolvins that influence inflammation and repair. This review synthesizes evidence on the roles of fatty acids and oxylipins in lipotoxicity, heart failure, ischemia–reperfusion, and arrhythmias, and evaluates dietary and supplemental interventions to optimize cardiac lipid metabolism, aligning with fatty acid signaling. Full article

Cross-reactivity among nonsteroidal anti-inflammatory drugs (NSAIDs) creates a significant clinical difficulty, especially in patients with NSAID hypersensitivity. These reactions are based on cyclooxygenase-1 (COX-1) inhibition and non-immunoglobulin E (IgE)-mediated reactions. COX-1 inhibition leads to dysregulation of arachidonic acid metabolism, with decreased prostaglandin synthesis and increased leukotriene production. Clinically, cross-intolerant reactions manifest in different phenotypes, including NSAID-exacerbated respiratory disease (NERD), NSAID-induced urticaria/angioedema (NIUA), and NSAID-exacerbated cutaneous disease (NECD). In contrast, true allergic reactions—such as single-NSAID-induced urticaria/angioedema and anaphylaxis (SNIUAA) and single-NSAID-induced delayed hypersensitivity reactions (SNIDHR)—are immunologically mediated and drug-specific. These phenotypes differ in underlying conditions, clinical manifestations, and patterns of NSAID tolerance. Paracetamol is generally considered a safer alternative due to its weak COX-1 inhibition; however, reactions may still occur, particularly at higher doses. Selective COX-2 inhibitors are usually better tolerated, however their safety should be confirmed, preferably through controlled drug provocation testing due to sporadic reactions in cross-intolerant patients. Understanding the distinction between pharmacologically mediated cross-intolerance and true allergic reactions is essential for accurate diagnosis, risk stratification, and therapeutic decision-making. This review summarizes current evidence on the mechanisms underlying NSAID hypersensitivity, analyzes the tolerability of paracetamol and alternative analgesics, and discusses practical management strategies to reduce the risk of adverse reactions. Full article

Background: Cysteinyl leukotrienes are components of slow-reacting substances of anaphylactic shock (SRS-A) and play a key role in asthma and inflammatory responses. Although chromone-2-carboxylic acids and substituted (aryloxy)alkanoic acids have the potential to be SRS-A antagonists, their comprehensive structure–activity relationships and pharmacokinetic characteristics remain understudied. Objective: This study integrated computational and experimental approaches, including QSAR modeling, molecular docking, ADMET analysis, molecular dynamics (MD) simulations, and antioxidant evaluation to identify and prioritize bifunctional compounds with anti-inflammatory and free radical-scavenging properties. Methods: A set of 68 compounds was analyzed using 2D and 3D quantitative structure–activity relationships (QSAR) (MLR, MNLR, SVR, ANN, and atom-based partial least squares). Molecular docking and 100 ns MD simulations were performed against the CysLT₁ receptor (PDB ID: 6RZ5). ADMET and drug-like properties of the compounds were predicted using ADMETlab 2.0 and SwissADME, and the in vitro antioxidant activity of the top-ranked compounds was evaluated using the DPPH method. Results: The atom-based 3D-QSAR model showed strong predictive power (R² = 0.9524, Q² = 0.5382). Compounds 25, 41, and 47 stood out with the most significant binding energies: −9.5 kcal/mol for 25, −10.0 kcal/mol for 41, and −9.4 kcal/mol for 47. MD simulations confirmed the structural stability and consistent interactions of the protein-compound 47 complex. ADMET analysis showed that compounds 25 and 41 had good pharmacokinetic properties, and in vitro antioxidant assays verified their free radical-scavenging efficacy. Conclusion: Our results highlight the utility of an integrated computational–experimental strategy for the discovery of dual-acting SRS-A antagonists. Compound 25 is highlighted as a promising lead compound for further preclinical development, which effectively combines leukotriene receptor antagonism and antioxidant activity. This framework provides an effective strategy for prioritizing lead compounds in anti-inflammatory drug development. Full article

Background/Objectives: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most consumed drugs worldwide and the main cause of drug hypersensitivity reactions (HSRs). The most common NSAID-HSR class is cross-hypersensitivity (CR), with patients reacting to NSAIDs from different chemical groups without specific immunological recognition, with NSAID-induced acute urticaria/angioedema (NIUA) being the most frequent clinical phenotype. Although CR-HSRs are triggered by arachidonic acid (AA) alterations following cyclooxygenase (COX)-1 inhibition and cysteinyl-leukotrienes synthesis by 5-lypoxygenase (5-LO), current evidence supports the participation of additional mechanisms. As COX-1 and 5-LO head oxidative pathways, it is conceivable that enzymes participating in antioxidant control are involved in these mechanisms. In addition, as the CR-HSR susceptibility seems to be influenced by genetic factors, the possibility of genetic variants playing a role in such enzymes should not be excluded. Methods: In this observational case–control study, we analysed for the first time in NIUA the overall genetic variability in key antioxidant defence enzymes genes, including catalase (CAT), glutathione peroxidase (GPX)-1 and 3, and superoxide dismutase (SOD)-1. We selected a set of tagging single nucleotide polymorphisms (tSNPs) in these genes using data from Europeans in the 1000 Genomes Project. Two independent Spanish populations (discovery and replication) of NIUA patients and NSAID-tolerant individuals were included. Results: Twenty-six tSNPs were genotyped in the discovery population, with three that were significantly associated with NIUA: rs3448 (GPX-1), rs3792798 (GPX-3), and rs10432782 (SOD-1). They were then genotyped in the replication group, with rs3792798 being protective and rs10432782 being associated with an increased NIUA risk. Conclusions: Our results suggest that a role for antioxidant enzyme polymorphisms in NIUA is required. Nevertheless, further research is needed to replicate our findings in other populations and their meaning at the molecular level and to investigate the role of such variants in other CR-HSR-induced phenotypes. Full article

Colorectal cancer (CRC) is a prevalent malignant tumour, with its incidence and mortality rates consistently ranking among the highest and exhibiting an upward trend. Extensive screening and early diagnosis are crucial for managing CRC progression and improving patient prognosis. This study aims to construct a novel analytical framework for integrating the sequencing data from tumour tissue and peripheral blood. By integrating and analysing the multi-omics data and clinical data from tumour tissues and peripheral blood, we confirmed that the LTB4R gene is significantly upregulated not only in tumour tissues but also in the peripheral blood of CRC patients. Further single-cell RNA sequencing (scRNA-seq) and immune cell correlation analyses revealed that Leukotriene B4 receptor 1 (LTB4R) is primarily expressed in macrophages, T cells, and other immune cells, with a significant negative correlation observed with M1-type macrophages, suggesting its potential pro-tumourigenic role in CRC by suppressing M1 macrophage. Additionally, simulated gene knockout analysis (scTenifoldKnk) demonstrated that LTB4R knockout significantly impacts immune-related pathways, including immune response and immune receptor activity. These findings not only highlight the potential of LTB4R as a peripheral blood diagnostic marker for CRC but also elucidate its involvement in tumour progression, offering novel insights for early clinical diagnosis and tumour screening systems. Full article

Background: Xiebai San (XBS), a classical Traditional Chinese Medicine formula comprising Cortex mori, Lycii Radicis Cortex, and Glycyrrhizae Radix et Rhizoma, has long been used for pulmonary inflammatory disorders. However, its underlying mechanisms remain un-clear. This study aimed to investigate the mechanisms by which XBS alleviates allergic pulmonary inflammation. Methods: Two murine models were established, consisting of a chronic ovalbumin (OVA)-induced model simulating adaptive immune responses and an acute compound 48/80-induced model triggering non-IgE-dependent mast cell activation. Pharmacodynamic indices including serum IgE, histamine, inflammatory cytokines, leukocyte profiles, and lung histopathology were evaluated. Network pharmacology was employed to predict core pathways. Arachidonic acid metabolites (AAMs) in lung tissues were quantified by targeted UPLC-MS/MS, and p38 MAPK signaling proteins were assessed by Western blot. Results: XBS significantly alleviated lung injury in both models. In the chronic OVA-induced model, XBS significantly reduced serum immunoglobulin E levels and inflammatory cell infiltration. In the acute model, XBS suppressed histamine release and mast cell-mediated inflammatory responses. Targeted metabolomics revealed differential regulatory mechanisms: XBS reduced lipoxygenase-derived metabolites, including leukotrienes and 12-hydroxyeicosatetraenoic acid in chronic inflammation, while suppressing cyclooxygenase-related prostaglandins in acute inflammation. Network pharmacology analysis identified arachidonic acid (AA) metabolism as a potential central pathway. The p38 mitogen-activated protein kinase pathway was partially involved. Conclusions: XBS effectively alleviates both chronic and acute allergic pulmonary inflammation through differential modulation of AA metabolism, providing mechanistic insights supporting its traditional use in allergic airway diseases. Full article

Heat stress-induced systemic metabolic disorder serves as the core pathological basis of organismal damage. Although mung bean polyphenols (MBPs) had been preliminarily validated in cellular heat-stress models for their intestinal tissue-protective potential, whether they can alleviate heat-stress injury in vivo by remodeling the metabolic crosstalk network between the gut and systemic circulation remains mechanistically unclear. In this study, we innovatively employed an integrated multi-omics approach combining physiological phenotype, gut metabolome, and serum metabolome analyses based on a Balb/c heat stress (41 °C) mouse model, systematically constructing the metabolic phenotype regulatory network of MBPs. The results demonstrated that MBPs not only significantly improved oxidative stress (elevating GSH-Px and T-AOC, reducing MDA), immune-inflammation (down-regulating IL-1β and TNF-α), and stress hormone (lowering cortisol) phenotypes, but also specifically reversed the disturbances in intestinal and serum metabolic profiles induced by heat stress, particularly restoring key pro-inflammatory mediators such as Leukotriene E4 and 5-HETE. Arachidonic acid metabolism, tryptophan metabolism, histidine metabolism, and Fc epsilon RI signaling pathway constituted the core network of heat-stress metabolic disorder and MBP regulation. Furthermore, the study revealed that alterations in hub metabolites—Indolelactic Acid, Trans-Cinnamic Acid, Leukotriene E4, 5-HETE, and N(omega)-Hydroxyarginine—were significantly correlated with phenotypic improvements. This confirms that mung bean polyphenols dynamically dismantle the “pro-inflammatory-oxidative stress” pathological coupling by constructing a novel protective axis centered on the indole metabolism–melatonin–endogenous antioxidant system and successfully established a novel protective axis driven by gut-derived beneficial metabolites that promotes systemic antioxidant function, thereby elucidating the systemic mechanism underlying the alleviation of heat-stress injury at the metabolic network level. Full article

Although particulate matter (PM) is strongly associated with allergic reactions, the potential risk of the ability of PM derived from poultry houses to induce allergic reactions remains unclear. This study investigated the effects of duck housing PM on allergic reactions in mice. PM samples and fungi were collected from a duck farm. Ovalbumin (OVA) was used as a positive control, with ambient-level concentrations of PM, high-concentration PM (HPM), and fungal experimental groups. Aerosol exposure was performed on the mice. Serum IgE, allergic mediators (histamines and leukotrienes), cytokines, and pulmonary histopathology were analyzed. Furthermore, HPM-induced metabolic profiles in bronchoalveolar lavage fluid were measured. The results revealed that all the treatment groups of mice presented allergic symptoms, including sneezing and coughing; higher concentrations of IgE, His, and LTs in the serum; upregulation of allergic reaction-related cytokines, such as IL4, IL5, and IL33; and microscopic lesions of the lungs characterized by inflammatory cell infiltration were observed in all the treatment groups, indicating that PM and fungi can cause allergic reactions. Notably, allergic reactions were more pronounced in the HPM and fungal groups than in the PM group. In addition, metabolomics analyses revealed that HPM exposure caused metabolic disorders in mouse lungs. The key pathway with the highest correlation to metabolite differences was pyrimidine metabolism, which is associated with allergic reactions. In conclusion, this study demonstrated that exposure to PM in duck houses can cause allergic reactions in mice and significant metabolomic changes in the lungs, especially HPM. Moreover, the contribution of fungal components in the PM cannot be ignored. These findings highlight the potential health risks associated with PM from the poultry industry. Full article

The arachidonic acid pathway plays a pivotal role in the biosynthesis of important inflammatory and signal transducing agents such as prostaglandins, leukotrienes and thromboxanes. When this pathway is deregulated, it leads to pathological conditions such as cardiovascular diseases, metabolic diseases, and cancer. Two key enzymes of the pathway are cyclooxygenases (COXs) and lipoxygenases (LOXs), which are responsible for the production of prostaglandins and leukotrienes, respectively. Consequently, these enzymes have long been recognized as key therapeutic targets for the treatment and management of inflammatory disorders and other pathological conditions associated with inflammation. In this review, we describe the new evidence over the last 4 years regarding the arachidonic acid pathway. Moreover, we will pay attention to the structure and function of the COX-2 and 5-LOX enzymes and their role in inflammation, as well as define their active sites. Later, we will discuss the most potent, dual inhibitors of COX-2 and 5-LOX enzymes, based on in vitro and in vivo experiments, from 2020–2024. Structure–activity relationship (SAR) analysis of these compounds revealed four key structural features required for potent dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX). We refer to these criteria as “The Rule of Four for Inflammation”. Full article

Nonsteroidal anti-inflammatory drugs (NSAIDs) can exacerbate urticaria and/or angioedema in up to 30% of patients with chronic urticaria (CU), representing a distinct subtype characterized by heightened inflammation and leukotriene-driven pathophysiology. MicroRNAs (miRNAs) are post-transcriptional regulators that modulate immune and inflammatory responses. This study aimed to identify differentially expressed miRNAs (DEMs) according to NSAID hypersensitivity status and to elucidate their molecular networks in CU. Serum miRNA profiles were analyzed in 14 NSAID-exacerbated CU (NECU) and 16 NSAID-tolerant CU (NTCU) patients using an Affymetrix GeneChip^® miRNA 4.0 Array. DEMs were identified (fold difference > 1.5, p < 0.05), and validated targets were retrieved from the multiMiR database for network construction and Gene Ontology enrichment analyses. NECU patients exhibited a higher frequency of angioedema and systemic corticosteroid use than NTCU patients. Eight DEMs were identified, including upregulated miR-5001-5p, miR-4270, and miR-6869-5p, and downregulated miR-6511b-5p, miR-2277-5p, and miR-378h in NECU. Network integration revealed AGO2-BTG2-LMNB2, NFIC-ZZZ3, and NUFIP2-GLG1 as central clusters, implicating dysregulation of mRNA decay and inflammatory signaling pathways. Reduced miR-6511b-5p expression may derepress BRG1, enhancing chromatin accessibility for inflammatory and leukotriene-synthetic genes. Distinct miRNA signatures differentiate NECU from NTCU, implying a miR-5001-5p/miR-6511b-5p–mRNA decay axis that links impaired post-transcriptional regulation with leukotriene-driven inflammation in CU. These findings highlight candidate miRNAs as potential biomarkers for disease endotyping and therapeutic stratification. Full article

Background: Triple-negative breast cancer (TNBC), defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression, is associated with increased BRCA1/2 mutation rates. Extracellular vesicles (EVs) play a pivotal role in TNBC progression. This study aimed to analyze BRCA1/2 mutations and identify EV-related biomarkers for TNBC by employing TNBC-related datasets and EV-related genes (EVRGs). Methods: Initially, BRCA1/2 mutations in TNBC patients were examined. Differentially expressed EVRGs (DE-EVRGs) were identified by integrating the results of both differential expression analysis and weighted gene co-expression network analysis (WGCNA). Biomarkers were identified using Receiver Operating Characteristic (ROC) and Kaplan–Meier (K–M) analyses. Finally, functional enrichment, drug prediction, molecular docking, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) analyses were performed. Results: Waterfall plots indicated that TP53 exhibited the highest mutation frequency in both the mutation (MUT) and wild-type (WT) group. Four distinct types of immune cells (for example, eosinophils and neutrophils) showed significantly elevated expression levels in the WT group. Notably, PLA2G5 was identified as a biomarker of TNBC and its expression was significantly lower in TNBC (p = 0.0025). Functional analysis demonstrated that PLA2G5 is enriched in the “drug metabolism cytochrome P450” pathway. Finally, 20 drugs targeting PLA2G5 were identified, among which leukotriene C4 demonstrated a binding affinity of −7.2 kcal/mol. This finding suggests that leukotriene C4 has potential therapeutic applications for the treatment of TNBC. Conclusions: Our study found significant differences between the MUT and WT groups, identifying PLA2G5 as a biomarker for TNBC and offering a theoretical basis for TNBC treatment. Full article

Background: Oxazolidinone derivatives are a novel class of synthetic antibacterial agents, characterized by a five-membered heterocyclic ring containing oxygen and nitrogen and a carbonyl functionality at position 2. This pharmacophore is responsible not only for antibacterial activity but also for a variety of other biological activities, including anticancer activity, anticoagulant activity, and several others. A series of novel oxazolidinone derivatives containing a hydroxamic acid moiety were synthesized in our laboratories and identified as potent inhibitors of the enzyme 5-lipoxygenase (5-LO), a key enzyme involved in the biosynthesis of leukotrienes (LTs). LTs are proinflammatory mediators implicated in allergic and inflammatory diseases. Currently, zileuton is the only FDA-approved 5-LO inhibitor, emphasizing the need to develop new agents for the treatment of such diseases. This project aims to develop validated stability-indicating analytical methods for the four most potent novel 5-(hydroxamic acid)methyl oxazolidinone derivatives (PH-211, PH-247, PH-249, and PH-251). Methods: The compounds were analyzed using Waters Acquity Ultra-High-Performance Liquid Chromatography (UHPLC-UV) with an ultraviolet detector to determine their stability in human plasma and under various forced degradation conditions, including acidic, basic, oxidative, and thermal conditions. Liquid chromatography–quadrupole time-of-flight mass spectrometry (LC-QToF-MS) was used to identify possible degradation products. Results: The compounds were found to be stable in human plasma and under thermal degradation conditions with high extraction recoveries (82–90%) but unstable in acidic, basic, and oxidative conditions. Conclusions: The findings show that the compounds are stable in biological conditions; they hold promise for the treatment of inflammatory and allergic diseases. Full article

Asthma is a chronic inflammatory disorder of the airways affecting over 260 million people worldwide and remains a major clinical and socioeconomic challenge. Despite substantial advances in pharmacological management (including inhaled corticosteroids, β₂-agonists, leukotriene receptor antagonists, and biologic therapies), many patients continue to experience uncontrolled symptoms or corticosteroid resistance. This persistent unmet need has prompted interest in adjunctive and alternative treatment strategies. Oxygen therapy during asthma exacerbations and worsening pulmonary obstruction is a standard life-saving procedure. However, various forms of oxygen therapy are being considered for long-term treatment to reduce the number of exacerbations. Experimental and preliminary clinical data indicate that oxygen therapy may offer multiple benefits, including improved oxygenation, anti-inflammatory effects, reduced oxidative stress, modulation of nitric oxide signaling, enhanced immune responses, and promotion of angiogenesis. These mechanisms may collectively alleviate airway inflammation and improve pulmonary function. Nevertheless, clinical evidence on hyperbaric oxygen therapy (HBOT) in asthma remains limited. Existing small-scale studies suggest its safety but provide inconclusive results regarding its efficacy. Potential adverse effects such as barotrauma, oxygen toxicity, and transient anxiety necessitate careful patient selection and standardized treatment protocols. Further large-scale, randomized controlled trials are required to determine the therapeutic value of HBOT and to define its role as an adjunctive therapy in the comprehensive management of asthma. Full article