Acute stress can cause emotional dysregulation and trigger various molecular changes, including increased neuroinflammation in limbic regions. These changes have the potential to induce anxiety by disrupting brain physiology and functional connectivity. In this study, we investigated whether an 8-day treatment with inflammation-resolving compounds, specifically Resolvin D5 (RvD5) and its precursor, the omega-3 fatty acid docosahexaenoic acid (DHA), could alleviate anxiety induced by acute restraint stress (ARS) in male and female rats. Additionally, we assessed whether these effects persisted one week after treatment cessation. Serum corticosterone levels and proinflammatory cytokine levels in the hippocampus (HIP) were also assessed. Our results confirmed that ARS induced significant anxiety-like behavior in both the short and long term, with females displaying greater exploratory activity than males. Both RvD5 and DHA prevented the development of pronounced anxiety-like behavior in stressed rats, without affecting anxiety levels in non-stressed rats. Notably, the effect persisted for at least one-week post-treatment in females. The treatments also prevented the elevation of TNF alpha and interleukin-1 beta levels in the HIP and serum corticosterone levels in stressed animals. In conclusion, our findings confirm the neuroprotective profile of these compounds and indicate that the continuous use of DHA or RvD5 may have promising effects in preventing anxiety responses triggered by acute stressful event, regardless of sex. Furthermore, this study is the first to demonstrate that RvD5 can downregulate corticosterone levels in stressed animals.

Neuroticism has been associated with numerous health outcomes. However, most research has focused on a single specific disorder and has produced controversial results, particularly regarding mortality risk. Here, we aimed to examine the association of neuroticism with morbidity and mortality and to elucidate how neuroticism affects trajectories from a healthy state, to one or more neuroticism-related disorders, and subsequent mortality risk.

We included 483,916 participants from the UK Biobank at baseline (2006-2010). Neuroticism was measured using the Eysenck Personality Questionnaire. Three clusters were constructed, including worry, depressed affect, and sensitivity to environmental stress and adversity (SESA). Cox proportional hazards regression and multistate models were used. Linear regression was used to examine the association between neuroticism and immune parameters and neuroimaging measures.

High neuroticism was associated with 37 non-overlapping diseases, including increased risk of infectious, cardiometabolic, neuropsychiatric, digestive, and respiratory diseases, and decreased risk of cancer. After adjustment for sociodemographic variables, physical measures, healthy behaviors, and baseline diagnoses, moderate-to-high neuroticism was associated with a decreased risk of all-cause mortality. In multistate models, high neuroticism was associated with an increased risk of transitions from a healthy state to a first neuroticism-related disease (hazard ratio [HR] [95% confidence interval (CI)] = 1.09 [1.05-1.13], P  <0.001) and subsequent transitions to multimorbidity (1.08 [1.02-1.14], P  = 0.005), but was associated with a decreased risk of transitions from multimorbidity to death (0.90 [0.84-0.97], P for trend = 0.006). The leading neuroticism cluster showing a detrimental role in the health-illness transition was depressed affect, which correlated with higher amygdala volume and lower insula volume. The protective effect of neuroticism against mortality was mainly contributed by the SESA cluster, which, unlike the other two clusters, did not affect the balance between innate and adaptive immunity.

This study provides new insights into the differential role of neuroticism in health outcomes and into new perspectives for establishing mortality prevention programs for patients with multimorbidity.

Ten undescribed sesquiterpenoids were isolated from Chloranthus japonicus Sieb., including (4R,5S,6R,8R,10R)-4-hydroxy-6-O-β-d-glucosyleudesman-7(11)-en-8,12-olide (1), (1R,4R,5R,8S,10R)-1,4-dihydroxy-15-(2-methylbutyryloxy)eudesman-7(11)-en-8,12-olide (2),(1R,4S,5R,8S,10R)-1,4-dihydroxy-15-(2-methylbutyryloxy)eudesman-7(11)-en-8,12-olide (3), (1R,3S,4R,5S,8S,9S,10S)-8,9-epoxy-15-hydroxylindenran-7(11)-en-8,12-olide (4), (1R,3S,4R,5S,8S,9S,10S)-8,9,15-trihydroxylindenran-7(11)-en-8,12-olide (5), (1R,3S,4R,5S,6R,8S,10S)-6-acetoxyl-4-hydroxy-15-O-β-d-glucosyllindenran-7(11)-en-8,12-olide (6), (1R,3S,4R,5S,6R,8S,10S)-15-hydroxy-4-O-β-d-glucosyllindenran-7(11),8(9)-dien-8,12-olide (7), japonilides A-C (8-10), along with 19 known compounds. Compounds 8-10 are rare 5,6-seco-germacrane-type sesquiterpenoids, and only one of this type sesquiterpenoid has been reported to be isolated from C. anhuiensis. 9-Ketocurzerene (27) was first reported from a natural source. The structures and absolute configurations of the compounds were elucidated through a combination of spectroscopic data interpretation, quantum-chemical calculation, DP4+ probability analysis, and single-crystal X-ray diffraction analysis. Compounds 8, 12, 16 and 22 exhibited significant inhibitory effects on NO production in lipopolysaccharide-stimulated RAW 264.7 macrophages, with IC50 values of 22.99 ± 2.71, 24.34 ± 1.36, 23.69 ± 2.83, and 21.23 ± 1.34 μmol/L, respectively. Western blotting studies demonstrated that compound 8 inhibited the expression of nitric oxide synthase and cyclooxygenase-2, which act as key mediators in the inflammatory response.

Vogt-Koyanagi-Harada (VKH) is a multisystemic autoimmune disorder characterized by bilateral panuveitis frequently accompanied by neurologic manifestations. While metabolic dysregulation is increasingly recognized in the context of autoimmune diseases, the role of specific metabolites in VKH disease remains unexplored.

Non-targeted and targeted metabolomics analysis, phospho-antibody array, proteome microarray, surface plasmon resonance, and molecular simulation were used to identify molecular target of OA.

We investigated metabolic profile of VKH disease and found that oleic acid (OA) was enriched in this disease. A series of functional assays showed that OA could exacerbate experimental autoimmune uveitis (EAU) in association with increased frequency of Th1 and Th17 cells and decreased proportion of Treg cells in vitro. However, the specific molecular target of OA remains elusive. Through proteome microarrays, molecular simulations and surface plasmon resonance assays, Ornithine decarboxylase 1 (ODC1) was identified as target protein of OA. OA could bind to ODC1, increase ODC1 protein expression in both a time- and concentration-dependent manner and promote subsequently putrescine production. Phospho-antibody array analysis revealed that OA inhibited phosphorylation of STAT5A (Y694) in CD4+T cells, leading to imbalance of Th1/Th17 and Treg cells and decreased transcription of IL-10. OA upregulated ODC1 protein and putrescine levels through binding to LYS-78, inhibited phosphorylation of STAT5A protein and subsequently decreased binding of STAT5A at IL-10 promoter.

These results reveals that OA could be a crucial metabolite for modulation of CD4+T cell differentiation and that ODC1-mediated phosphorylation and transcriptional activity of STAT5A contributes to development of VKH disease progression, highlighting ODC1 as a novel therapeutic target in VKH disease.

Acute lung injury (ALI) is a lethal condition characterized by uncontrolled pulmonary inflammatory responses, with high morbidity and mortality rates that pose a significant threat to patient health. The persistent retention of neutrophils in lung tissue and subsequent inflammatory damage represents a primary mechanism underlying the early onset of ALI disorders. In recent years, pharmaceutical research targeting these pathological processes has garnered considerable attention. Traditional Chinese medicines (TCM) and their active ingredients, known for their safety and stability, show promising potential in treating ALI through their ability to modulate neutrophil function via multiple pathways.

This review examines the mechanisms of neutrophil involvement in the pathogenesis of ALI, investigates potential therapeutic targets and pathways through which Chinese medicines and their active ingredients regulate neutrophil function, and provides a theoretical foundation for developing novel clinical treatment strategies.

A comprehensive literature search was conducted using multiple databases, including Science Direct, PubMed, Google Scholar, and Web of Science. Search terms included 'lung injury,' 'acute lung injury,' 'inflammatory lung injury,' 'inflammation,' 'active ingredient,' 'herbal,' 'traditional Chinese medicine,' 'mechanism,' 'drug,' and 'neutrophils.' The selected literature was systematically categorized and analyzed.

Our review reveals that TCM and active ingredients influence neutrophil function through four primary mechanisms to impede ALI progression: 1) reduction of neutrophil-mediated uncontrolled inflammatory responses by suppressing neutrophil hyperactivation and inhibiting neutrophil migration and infiltration; 2) attenuation of lung tissue inflammatory damage by inhibiting neutrophil-produced cytotoxic substances, including elastase granules, neutrophil extracellular traps (NETs), and reactive oxygen species (ROS); 3) suppression of inflammatory responses by decreasing the secretion of neutrophil-derived cytokines, such as interleukin (IL) -1β, IL-6 and tumor necrosis factor-alpha (TNF-α); and 4) enhancement of neutrophil phagocytosis and accelerate the removal of apoptotic neutrophils to eliminate harmful pathogens and promote late-stage tissue repair. These findings demonstrate that Chinese medicines and their active ingredients exhibit significant therapeutic potential in ALI disorders through the modulation of neutrophil function, providing a robust theoretical framework for their clinical applications.

Traditional Chinese medicines and their active ingredients demonstrate significant anti-inflammatory efficacy through multiple mechanisms of neutrophil function regulation, showing considerable promise for the treatment of ALI with broad clinical applications.

Inflammation is a fundamental component of the body's response to injury or infection and is responsible for restoring tissue homeostasis and starting the wound healing process. To avoid excessive tissue damage, it is important to efficiently resolve inflammation once it is no longer necessary. In recent years, the discovery of pro-resolving lipid mediators derived from polyunsaturated fatty acids, such as Resolvin D1 (RvD1), has shed light on the resolution of inflammation. However, the impact of RvD1 on Spinal Cord Injury (SCI) remains unexplored. In this study, we provide direct evidence that the administration of RvD1 for one week after SCI fails to enhance resolution of inflammation and does not improve functional and histological outcomes. Our transcriptomic analysis reveals that RvD1 does not modulate inflammatory response pathways in the injured spinal cord but leads to significant changes in the expression of genes related to ribosomal function and extracellular matrix pathways. Unlike SCI, RvD1 treatment ameliorated neurological deficits in experimental autoimmune encephalomyelitis. Our findings represent the first report demonstrating that RvD1 treatment does not exert therapeutic actions in the context of SCI and suggest that this pro-resolving agonist may exert therapeutic actions in certain but not in all conditions involving an inflammatory component.

Inflammatory lung diseases (ILDs) represent a global public health crisis characterized by escalating prevalence, significant morbidity, and substantial mortality. In response to the complex immunopathogenic mechanisms driving these conditions, novel pharmacological strategies targeting resolution pathways have emerged throughout the discovery of specialized pro-resolving lipid mediator (SPM; resolvins, maresins, and protectins) dysregulation across the ILD spectra, positioning these endogenous molecules as promising therapeutic candidates for modulating maladaptive inflammation and promoting tissue repair. Over the past decade, this paradigm has catalyzed extensive translational research into SPM-based interventions as precision therapeutics for respiratory inflammation. In asthma, they reduce mucus hypersecretion, bronchial hyperreactivity, and airway inflammation, with prenatal SPM exposure potentially lowering offspring disease risk. In COPD, SPMs attenuate amyloid A-driven inflammation, normalizing cytokine/chemokine imbalances and oxidative stress and mitigating COVID-19-associated cytokine storm, enhancing survival. This review synthesizes SPMs' pharmacotherapeutic mechanisms in ILDs and evaluates current preclinical and clinical evidence.

Background/Objectives: Specialized pro-resolving lipid mediators, such as resolvins derived from omega-3 fatty acids, play a key role in resolving inflammation and restoring homeostasis. Resolvin D1 and D2, derived from docosahexaenoic acid (DHA), have demonstrated inflammation pro-resolving properties and potential anticancer effects. This study aimed to evaluate the effects of oral DHA supplementation on plasma resolvin D1 and D2 levels in breast cancer patients and in controls, and by stratifying the patients by disease presentation (sporadic, familial, BRCA1/2 mutated) and immunohistochemical characteristics. Methods: This is a single-center, interventional, controlled study conducted in women with breast cancer and women with benign breast disease, serving as controls. Participants consumed DHA (2 g/day) as algal oil syrup for 10 consecutive days. Plasma resolvin D1 and D2 levels were measured at baseline (T0) and after supplementation (T1) using ELISA kits. Results: At baseline, breast cancer patients exhibited higher plasma resolvin D1 levels compared to controls (median 21.3 vs. 7.3 pg/mL, p = 0.039), with no significant difference in resolvin D2. Following DHA supplementation, resolvin D1 and D2 significantly increased in BRCA1/2-mutated patients (+185.8% and +101.2%, p = 0.037, p = 0.028, respectively). Conversely, the familial breast cancer group showed a significant decrease in resolvin D1 (p = 0.015). Patients with low Ki67 expression showed greater increase over time of resolvin D2 levels compared to those with high Ki67 expression (p = 0.046). Conclusions: DHA supplementation modulated resolvin levels in breast cancer patients, with significant increase in BRCA1/2-mutated patients, suggesting enhanced inflammation pro-resolving responses. The reduction in resolvin D1 in the familial group highlights a potential dysregulated response. These findings indicate the potential of resolvins as biomarkers of resolution of inflammation and novel therapeutic targets in breast cancer.

Phagocytosis is a key process in human innate immune response. Human macrophages are important phagocytes engulfing and neutralizing pathogens and cell debris. In addition, they modulate the inflammatory process by releasing cytokines and lipid mediators. However, the link between oxylipins and phagocytosis in different macrophage phenotypes remains poorly understood. In order to better understand the link between phagocytosis and the arachidonic acid (ARA) cascade, we established a phagocytosis assay in primary human 'inflammatory' M1- and 'anti-inflammatory' M2-like macrophages from peripheral blood mononuclear cells (PBMC), representing extremes of macrophage phenotypes. The branches of the ARA cascade were investigated by quantitative targeted proteomics and metabolomics. M1-like macrophages show a higher abundance of cyclooxygenase (COX)-2 and its products particularly after LPS stimulus compared to M2-like macrophages. LPS increased phagocytosis in M2-like, but not in M1-like macrophages. We demonstrate that the COX product prostaglandin E2 (PGE2) modulates the differential effects of LPS on phagocytosis: Via the EP4 receptor PGE2 signaling suppresses phagocytosis in primary human macrophages. Thus, blockage of COX, e.g. by non-steroidal anti-inflammatory drugs (NSAID), leads to an increase of phagocytosis also in 'inflammatory' M1-like macrophages. This supports the well-described anti-inflammatory effects of these drugs and underscores the importance of the link between the COX branch of the ARA cascade and the regulation of phagocytosis in human macrophages.

Kidney diseases represent a diverse group of disorders with pathogenic mechanisms involving multiple pathological processes, including inflammation, immunity, and cell death. Neutrophils, as primary effector cells in inflammatory immune responses, participate in defending against renal infection and injury by releasing reactive oxygen species, proteases, and cytokines. However, persistent neutrophil activation is considered a crucial driver of kidney disease progression. Neutrophil apoptosis represents a critical turning point between inflammatory progression and resolution. Specialized pro-resolving mediators (SPMs) are endogenous anti-inflammatory mediators that play a critical role in resolving inflammation. They not only induce neutrophil programmed cell death and promote macrophage-mediated efferocytosis of apoptotic cells but also inhibit neutrophil infiltration and degranulation, ultimately facilitating the restoration of inflammatory microenvironment and tissue homeostasis. This review concentrates on elucidating the mechanisms by which SPMs regulate neutrophil apoptosis and systematically demonstrates their potential as novel therapeutic targets in kidney diseases.

Background/Objectives: Lipoxins, particularly Lipoxin A4 (LXA4), are endogenous lipid mediators with potent anti-inflammatory and pro-resolving properties, making them promising candidates for the treatment of inflammatory and neurodegenerative disorders. However, their therapeutic application is limited by poor stability and bioavailability. This study aimed to develop and characterize nanomicelles encapsulating LXA4 (nano-lipoxin A4) to improve its pharmacological efficacy against Alzheimer's disease (AD), a neurodegenerative condition marked by chronic inflammation and beta-amyloid (Aβ) accumulation. Methods: Nano-lipoxin A4 was synthesized using Pluronic F-127 as a carrier and characterized in terms of morphology, physicochemical stability, and in vitro activity against Aβ fibrils. Dissociation of Aβ fibrils was assessed via Thioflavin-T fluorescence assays and transmission electron microscopy. In vivo biodistribution and pharmacokinetic profiles were evaluated using technetium-99m-labeled nano-lipoxin A4 in rodent models. Hepatic biochemical parameters were also measured to assess potential systemic effects. Results: In vitro studies demonstrated that nano-lipoxin A4 effectively dissociated Aβ fibrils at concentrations of 50 nM and 112 nM. Electron microscopy confirmed the disruption of fibrillar structures. In vivo imaging revealed predominant accumulation in the liver and spleen, consistent with reticuloendothelial system uptake. Pharmacokinetic analysis showed a prolonged half-life (63.95 h) and low clearance rate (0.001509 L/h), indicating sustained systemic presence. Biochemical assays revealed elevated liver enzyme levels, suggestive of increased hepatic metabolism or potential hepatotoxicity. Conclusions: Nano-lipoxin A4 exhibits significant therapeutic potential for Alzheimer's disease through effective modulation of Aβ pathology and favorable pharmacokinetic characteristics. However, the elevation in liver enzymes necessitates further investigation into systemic safety to support clinical translation.

Women exhibit unique vulnerabilities in health, especially regarding mental health and neurodegenerative diseases. Biological, hormonal, and metabolic differences contribute to sex-specific risks that remain underrepresented in clinical studies. Diseases such as major depressive disorder (MDD) and Alzheimer's disease (AD) are more prevalent in women and may be influenced by hormonal transitions, particularly during menopause. Chronic low-grade inflammation is emerging as a shared mechanism underlying both conditions, and this inflammatory state can be worsened by dietary habits. During menopause, mood and sleep disturbances can influence dietary behavior, leading to enhanced snacking and consumption of high-glycemic and comfort foods. Such foods, low in nutritional value, promote weight gain and elevated inflammatory markers. Their consumption combined (or not) with a preexisting Western diet pattern-already linked to inflammation-could reinforce systemic inflammation involving the gut-brain axis. Moreover, the symptoms "per se" could act on inflammation as well. Peripheral inflammation may cross the blood-brain barrier, sustaining mood disorders and promoting neurodegenerative changes. Finally, MDD and AD are both associated with conditions such as obesity and diabetes, which occur more frequently in women. The review highlights how menopause-related changes in mood, sleep, and diet may heighten susceptibility to mental and neurodegenerative diseases.

The rapid onset of innate immune defenses is critical for early control of viral replication in an infected host and yet it can also lead to irreversible tissue damage, especially in the respiratory tract. Sensitive regulators must exist that modulate inflammation, while controlling the infection. In the present study, we identified acetylcholine (ACh)-producing B cells as such early regulators. B cells are the most prevalent ACh-producing leukocyte population in the respiratory tract demonstrated with choline acetyltransferase (ChAT)-green fluorescent protein (GFP) reporter mice, both before and after infection with influenza A virus. Mice lacking ChAT in B cells, disabling their ability to generate ACh (ChatBKO), but not those lacking ChAT in T cells, significantly, selectively and directly suppressed α7-nicotinic-ACh receptor-expressing interstitial, but not alveolar, macrophage activation and their ability to secrete tumor necrosis factor (TNF), while better controlling virus replication at 1 d postinfection. Conversely, TNF blockade via monoclonal antibody treatment increased viral loads at that time. By day 10 of infection, ChatBKO mice showed increased local and systemic inflammation and reduced signs of lung epithelial repair despite similar viral loads and viral clearance. Thus, B cells are key participants of an immediate early regulatory cascade that controls lung tissue damage after viral infection, shifting the balance toward reduced inflammation at the cost of enhanced early viral replication.

Formaldehyde (FA) is a common chemical linked to respiratory problems such as airway hyperresponsiveness and pulmonary inflammation. Due to its toxicological effects and ease of mass production, FA is also recognized as a significant chemical threat by the U.S. Department of Homeland Security. This study investigates the role of mast cells in the pulmonary inflammatory response to acute high-dose FA exposure. Using wild-type (C57BL/6J) and mast cell-deficient (KitW-sh) mouse models, we assessed the impact of oropharyngeal aspiration of FA on lung pathology. Our findings reveal that C57BL/6J mice experienced significant increases in cellular infiltration, altered immune cell populations, and changes in lipid mediator profiles. In contrast, KitW-sh mice exhibited significantly reduced inflammatory responses. Notably, the presence of mast cells was associated with enhanced dendritic cell migration and differential production of bioactive lipid mediators, such as specialized pro-resolving mediators and pro-inflammatory leukotrienes in C57BL/6J mice. These results highlight the crucial role of mast cells in the immune response to FA and suggest they could be therapeutic targets for treating FA-induced lung inflammation.

Atopic dermatitis (AD) is an inflammatory skin disease characterized by chronic pruritic eczema with an estimated prevalence of 10% in adults and 50% of them suffering from moderate-to-severe manifestations. Dupilumab, an IL-4/IL-13 inhibitor, is approved for treating moderate-to-severe AD. However, dupilumab-associated ocular surface disease (DAOSD) emerges in up to 60% of dupilumab-treated patients, constituting a major AD-specific adverse event. DAOSD pathogenesis has not been fully understood yet. To elucidate the metabolic changes occurring after dupilumab treatment in patients with AD, we focused in this prospective single-center cohort study particularly on patients who developed DAOSD. In total, 20 patients with AD underwent dupilumab therapy, with 6 developing DAOSD. Plasma and serum samples were collected at baseline, 4 and 16 weeks after treatment initiation, and during the conjunctivitis episode. In addition, 10 age- and sex-matched healthy controls were sampled solely at baseline. High-resolution mass spectrometry was employed for metabolomic and lipidomic analysis of all blood samples. Targeted metabolomics and lipidomic with multivariate analysis unveiled significant metabolic and lipidic disparities (such as increased activity of benzoic acid, tyrosine and indole metabolism, and others) between AD patients with and those without DAOSD. Metabolomics and lipidomic analysis further deepen our comprehension of DAOSD pathogenesis.

Periodontal diseases, including gingivitis and periodontitis, are chronic inflammatory conditions that compromise the supporting structures of the teeth, often leading to tooth loss and contributing to systemic comorbidities. Increasing evidence underscores the critical role of modifiable lifestyle factors, particularly diet and physical activity, in influencing periodontal health. This narrative review critically evaluates the current body of literature regarding the impact of dietary constituents and physical activity on the periodontium, with a focus on the molecular mechanisms, key biomarkers, and clinical implications. It aims to provide a deeper understanding of the complex interactions between nutrition, exercise, and periodontal health with potential implications for clinical management and preventive strategies.

Skin encounters many challenges that lead to an inflammatory response. Resolution of this inflammation is needed to return the skin to a healthy state. A review of the role of topical n-3 PUFAs, particularly DHA and EPA, in resolving skin inflammation and promoting skin health is presented. A review of the literature and Unilever data on DHA/EPA pro-resolution skin benefits. PubMed/MEDLINE, Google search of external literature as well as Unilever data relating to skin inflammation, pro-resolution, and the role of DHA and EPA. Evidence of DHA and EPA in providing pro-resolution of skin inflammation are summarized. DHA and EPA, and their derived specialized pro-resolving mediators (SPMs), can attenuate the skin inflammatory response induced by various stressors and maintain skin health.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, neuroinflammation, oxidative stress, and mitochondrial dysfunction. Despite extensive research efforts, effective curative treatments remain elusive, emphasizing the need for innovative therapeutic strategies. Grounding, or earthing, involves direct physical contact with the Earth's surface to facilitate the absorption of negatively charged electrons into the body. This practice has gained attention for its potential to reduce inflammation, oxidative stress, and cortisol dysregulation, which are significant contributors to AD pathology. This review examines the biological mechanisms by which grounding may influence AD, including its antioxidative effects that mitigate oxidative stress and its anti-inflammatory properties that reduce neuroinflammation. Grounding may also improve sleep quality and stress management, factors known to exacerbate AD progression. Evidence from preclinical and clinical studies highlights its potential to protect neuronal health by targeting oxidative and inflammatory pathways. Additionally, the safety, feasibility, and cost-effectiveness of grounding are discussed, making it a practical complementary approach to existing AD therapies. While the preliminary evidence is promising, the review emphasizes the need for robust clinical trials to validate grounding's efficacy specifically in AD populations. By integrating grounding into standard care protocols, it may be possible to enhance the overall therapeutic outcomes and improve the quality of life for individuals with AD. Grounding represents a novel, non-pharmacological intervention that could complement existing treatments by addressing both the physiological and psychological aspects of this complex disease.

To identify biomarkers for diagnosis and classification of interstitial cystitis/bladder pain syndrome (IC/BPS) by urinary lipidomics coupled with machine learning.

Urine samples from 138 patients with IC/BPS, including 116 with Hunner lesion (HL) and 22 with no HL, and 71 controls were assessed by lipid chromatography-tandem mass spectrometry. Single and paired lipid analyses of differentially expressed lipids in each group were conducted to assess their diagnostic ability. Machine learning models were constructed based on the identified urinary lipids and patient demographic data, and a five-fold cross-validation method was applied for internal validation. Levels of urinary lipids were adjusted to account for urinary creatinine levels.

A total of 218 urinary lipids were identified. Single lipid analysis revealed that urinary levels of C24 ceramide and LPC (14:0) distinguished HL and no HL, with an area under the receiver operating characteristics curve of 0.792 and 0.656, respectively. Paired lipid analysis revealed that summed urinary levels of C24 ceramide and LPI (18:3), and subtraction of PG (36:5) from PC (38:2) distinguished HL and no HL even more accurately, with an area under the curve of 0.805 and 0.752, respectively. A machine learning model distinguished HL and no HL, with the highest area under the curve being 0.873 and 0.750, respectively. Limitations include the opaque black box nature of machine learning techniques.

Urinary levels of C24 ceramide, along with those of C24 ceramide plus LPI (18:3), could be potential biomarkers for HL. Machine learning-coupled urinary lipidomics may play an important role in the next-generation AI- driven diagnostic systems for IC/BPS.

Bone loss, linked with numerous oral conditions such as periodontal diseases and periimplantitis, poses a significant challenge for dental clinicians. The current study evaluated the in vivo effects of local application of Resolvin E1 (RvE1) on bone regeneration in critical size calvarial defects in rats. Thirty female Wistar rats with 5 mm induced calvarial defects were randomly allocated into four groups: no treatment (negative control, n = 5), treatment using bovine bone grafts (positive control, n = 5), treatment using local delivery of RvE1 (n = 11) and treatment using RvE1 mixed with bovine bone graft (n = 9). After 12 weeks, the animals were sacrificed and the calvarial defects with the adjacent tissues were sectioned en-bloc and prepared for histological examination. A comprehensive qualitative and quantitative histological examination was performed to assess bone regeneration and its relation to the defect, the presence of remnant bone and RvE1 particles, the integration of the native bone with the newly formed bone, bone density and bony trabeculae, the inflammatory reaction, the connective tissue bridging in the defect, and the encapsulating fibrous tissue. Signs of neovascularization, increased cellularity, lack of the organized lamellated appearance of mature bone, disorganized arrangement of osteocytes, osteoblasts and osteoclasts were also assessed. Comparisons of the quantitative values between all studied groups indicated statistically significant differences (p ≤ 0.05) in all parameters except for the increased cellularity and granulation tissue. Histological findings indicate that RvE1 with adjunct bone graft significantly enhanced the bone formation compared to RvE1 or bovine graft alone.

Sepsis, a life-threatening condition characterized by a dysregulated immune response to infection, remains a significant cause of mortality in both humans and veterinary patients. This study explores oxylipins as potential indicators of sepsis in dogs through in vivo plasma analysis and an ex vivo lipopolysaccharide (LPS)-treated skin organ culture model. By employing a robust analytical platform, 52 oxylipins and 4 polyunsaturated fatty acids were profiled in plasma and skin cultures. Results revealed distinct biochemical and morphological changes, with LPS triggering capillary vasodilation and time-dependent increases in pro-inflammatory mediators such as PGE2 and isoprostanes. Importantly, PGE2 exhibited consistent trends across both models, highlighting its potential as a diagnostic biomarker. This study underscores the utility of the skin organ culture model in mimicking early inflammatory events, offering novel insights into oxylipin dynamics during sepsis and their implications for disease resolution.

Activation of the endocannabinoid system (ECS) elicits negative effects on the reproductive system in mammals. Supplementation with n-3 fatty acid (FA) lowers ECS activation and has anti-inflammatory effects. Thus, we hypothesized that supplementing cows with n-3 FA will downregulate components of the ECS and immune system in preovulatory follicles and in the endometrium. Twenty-four multiparous Holstein dairy cows were supplemented from d 256 of pregnancy to d 70 postpartum as follows: (1) control (CTL; n = 12), prepartum with 250 g/d per cow calcium salts of FA and postpartum at 1.6% of the diet (DM basis); or (2) extruded flaxseed (FLX; n = 12) supplement rich in α-linolenic acid (C18:3n-3), prepartum with 700 g/d per cow and postpartum at 6.4% of diet (DM basis). Ovaries were monitored at 30 DIM, and following estrous cycle synchronization we aspirated the follicular fluids (FF) of follicles ≥7 mm, separated the granulosa cells (GRC), and performed endometrium biopsies at 58 ± 5 DIM. The FF were analyzed for concentrations of estradiol (E2) and progesterone (P4), and E2-active follicles were declared when E2/P4 was >1. The FA and endocannabinoid (eCB) profiles were determined in plasma and in the reproductive tissues. Proteomic analyses and mRNA abundances were determined in GRC and endometrium. Supplementation of n-3 FA increased the proportion of total n-3 FA and decreased the ratio of n-6 to n-3 ratio in plasma, FF and GRC compared with CTL. In plasma and FF, n-3 FA supplementation decreased the proportion of the n-6 FA eCB precursor arachidonic acid (ARA; C20:4n-6), and increased the abundance of the n-3 FA-derived eCB eicosapentaenoyl ethanolamide compared with CTL. In the endometrium, n-3 FA supplementation reduced the abundance of the n-6 FA-derived eCB 2-arachidonoylglycerol (2-AG) compared with CTL. Proteomic analysis of GRC showed that n-3 FA supplementation increased the abundance of FA-binding-protein-5, which is involved in intracellular transport of eCB, as well as the abundances of the cytokine receptor like factor-2 and glutathione-S-transferase-LANCL1, whereas it reduced the abundances of several complement proteins: complement factors I, D, H, complement components C7 chain and C8 β chain, and complement component 1 Q subcomponent-binding protein, mitochondrial (C1QBP). In addition, the abundance of superoxide dismutase (SOD3) was lower in FLX GRC than in CTL. In the endometrium, n-3 FA supplementation decreased the abundance of a few immune-related proteins. In the GRC, n-3 FA supplementation reduced the relative mRNA abundances of cannabinoid receptors 1 and 2 compared with CTL. Across treatments, a positive correlation was found between the relative abundance in FF of the eCB anandamide with C7, C1QBP, and SOD3 in GRC, whereas FF 2-AG had a negative correlation with them. Overall, in line with our premise, dietary n-3 FA supplementation attenuated the levels of some eCB and reduced the expression of several proteins and genes related to the ECS and immune system in the preovulatory follicle and in the endometrium, which may be part of the etiology of the positive effects of n-3 FA on the reproductive system in dairy cows.

Lipid dyshomeostasis and neuroinflammation are key hallmarks of neuropsychiatric and neurodegenerative disorders, including major depressive disorder and Alzheimer's disease. In particular, polyunsaturated fatty acids (PUFAs) and their derivatives called oxylipins gained specific interest in this context, especially considering their capacity to orchestrate neuroinflammatory responses via direct modulation of microglia. The hippocampus and hypothalamus are crucial brain regions for regulating mood and cognition that are implicated in a variety of neuropsychiatric and neurodegenerative disorders and there is ample evidence for the sex-bias in risks for the development as well as sex-bias in the presentation of such psychiatric diseases, including the neuroinflammatory response. To better understand the local PUFA/oxylipin profiles and microglia responses in disease, we here assessed their brain region and sex-dependent profiles in homeostatic brains. In 2-month-old male and female mice, we measured non-esterified (free) PUFA/oxylipin profiles using liquid chromatography-tandem mass spectrometry and characterized microglia morphology via immunohistochemistry. The hypothalamus and hippocampus exhibit a different free PUFA/oxylipin profile, independent of sex. The hippocampus was characterized by a higher density of complex Iba1+ microglial cells than the hypothalamus, without sex effects. Hypothalamic microglial morphology correlated more strongly with free PUFA- and oxylipin species than hippocampal microglia, correlating with species from both the N-3 and N-6 PUFA metabolization pathways, while hippocampal microglial parameters correlated only with N-6 pathway-related species. Our findings provide a basis for future studies to investigate the relationship between PUFAs, their derivatives and neuroinflammation in the context of diseases.

The complex nature of pain pathophysiology complicates the establishment of objective diagnostic criteria and targeted treatments. The heterogeneous manifestations of pain stemming from various primary diseases contribute to the complexity and diversity of underlying mechanisms, leading to challenges in treatment efficacy and undesirable side effects. Recent evidence suggests the presence of apoptotic cells at injury sites, the distal dorsal root ganglia (DRG), spinal cord, and certain brain regions, indicating a potential link between the ineffective clearance of dead cells and debris and pain persistence. This review highlights recent research findings indicating that efferocytosis plays a significant yet often overlooked role in lesion expansion while also representing a potentially reversible impairment that could be targeted therapeutically to mitigate chronic pain progression. We examine recent advances into how efferocytosis, a process by which phagocytes clear apoptotic cells without triggering inflammation, influences pain initiation and intensity in both human diseases and animal models. This review summarizes that efferocytosis contributes to pain progression from the perspective of defective and inefficient efferocytosis and its subsequent secondary necrocytosis, cascade inflammatory response, and the shift of phenotypic plasticity and metabolism. Additionally, we investigate the roles of newly discovered genetic alterations or modifications in biological signaling pathways in pain development and chronicity, providing insights into innovative treatment strategies that modulate efferocytosis, which are promising candidates and potential avenues for further research in pain management and prevention.

This study investigated the effects of fish oil (FO) supplementation on the hypothalamus heat resistance gene expressions and fatty acid composition of chicks under acute high-temperature stress, for treating Cholestasis. A total of 48 chicks (Ross 308) at age of 14 days were acclimatized to corn oil or FO (n = 24 for each) by oral gavaging for 10 days, and then subjected to heat stress (35 ± 1 °C, HT) for 3 h or maintained at the normal temperature (26 ± 1 °C, NT) as grouped as NT and FO-NT control and HT and FO-HT (n = 12 for each).. The results showed that FO supplementation had no significant (P > 0.05) effect on feed intake or body weight. The FO-HT group exhibited (P<0.05) a lower rectal temperature, and plasma interleukin-6 (IL-6), triglyceride and corticosterone levels, in accompany with lower expressions of hypothalamic adenine nucleotide translocators (ANT) and uncoupling protein (UCP) but increased (P<0.05) plasma superoxide dismutase activity and hypothalamic neuropeptide-Y (NPY) and heat shock protein-70 (HSP-70) expressions.. Additionally, the FO-HT group (P < 0.05) demonstrated a higher unsaturated fatty acid/saturated fatty acid (UFA/SFA) ratio in the breast muscle. These findings suggest that FO supplementation can enhance the heat resistance of broiler chicks under acute heat stress and alter the fatty acid composition of their breast muscle. However, further studies are needed to determine whether desirable fatty acids can cross the blood-brain barrier and their implications for human health.

The impact of testosterone administration on the circulating lipidome in females remains unexplored, despite its relevance to understanding metabolic disorders like polycystic ovary syndrome (PCOS). This study addresses this gap by examining the effects of testosterone gel on the plasma lipidome of healthy women over three menstrual cycles. A cohort of 14 women aged 22-37 years with regular cycles was analyzed, with plasma samples collected at baseline, during peak testosterone levels (D45), and post-treatment (D59, D80). Testosterone gel treatment lasted 28 days, administered between day 29 and day 57 of the study. Using a deep-targeted lipidomic approach, 597 lipids were quantified to provide a detailed profile of the lipidome and capture subtle changes in lipid species and their associations with testosterone fluctuations. Extensive profiling revealed a significant decrease in 17 lipid species, especially ether- and ester-linked lysophosphatidylcholines (LPC), at peak testosterone. These lipid reductions were strongly negatively correlated with free and total testosterone, as well as dihydrotestosterone (DHT), and positively correlated with SHBG levels. Notably, intra-individual lipid variability was consistently lower than inter-individual variability, indicating a highly personalized lipidome regulation. Despite testosterone-induced changes, overall plasma lipidome alterations were minimal, suggesting mechanisms that maintain lipid homeostasis. This study highlights the complex interplay between testosterone and lipid metabolism in women. The minimal overall lipidome changes and high inter-individual variability point to the need for further research to assess the clinical relevance of these findings, particularly in hyperandrogenic conditions like PCOS. Clinical Trial Registration number: This study was registered on https://www.isrctn.com/ (ISRCTN10122130) on 09/01/2019.

This study aimed to evaluate the ability of ω-3 to modulate the tissue response in rats with MRONJ, focusing on histopathological and immunohistochemical parameters. Forty Wistar rats were subjected to bilateral ovariectomy and, three months later, the medication regimen with ZOL (100μg/kg; groups ZOL and ZOL-ω3) of vehicle (VEH and VEH-ω3) was initiated. Following 3 weeks of ZOL or VEH, experimental periodontitis was induced around the mandibular left first molars of all animals. Then, 14 days later (one day before tooth extraction), daily dietary supplementation with ω-3 was given to animals belonging to groups VEH-ω3 or ZOL-ω3. Euthanasia was performed 21 days after tooth extraction. Histologic, histometric (newly-formed bone tissue [NFBT] and non-vital bone tissue [NVBT]), and immunohistochemical (TNF-α, α-SMA, ALP, IL-1β, VEGF, OCN, and TRAP) analyses were performed. Dietary supplementation with ω-3 reduced the amount of NVBT and controlled the intensity and extension of the inflammatory infiltrate in ZOL-ω3, as compared with ZOL. Osteoclast and osteoblast activity were not statistically different between groups ZOL and ZOL-ω3. The structure of the epithelium and the underlining connective tissue were improved by the supplementation with ω-3 in animals under ZOL therapy. Oral supplementation with omega-3 controlled the inflammation and reduced the amount of non-vital bone at the tooth extraction site of ovariectomized rats treated with ZOL and attenuating the severity of MRONJ.

Lipoxygenases (LOXs) are a family of dioxygenases that catalyze the peroxidation of polyunsaturated fatty acids, such as linoleic acid and arachidonic acid, initiating the synthesis of bioactive lipid mediators. The LOX-mediated production of these bioactive molecules in various cell types plays a critical role in the pathophysiology of cardiovascular diseases, including atherosclerosis, hypertension, and myocardial ischemia-reperfusion injury. In this review, we summarize the roles of LOXs and their products in different cardiovascular cells and conditions, offering valuable insights may contribute to the development of novel therapeutic strategies for cardiovascular diseases.

Overview: SARS CoV-2 infection is accompanied by the development of acute inflammation, resolution of which determines the course of infection and its outcome. If not resolved (brought back to preinjury status), the inflamed state progresses to a severe clinical presentation characterized by uncontrolled cytokine release, systemic inflammation, and in some death. In severe CoV-2 disease, the required balance between protective inflammation and its resolution appears missing, suggesting that the ω-3-derived specialized proresolving mediators (SPMs) needed for resolution are either not present or present at ineffective levels compared to competing ω-6 polyunsaturated fatty acid (PUFA) metabolic derivatives. Aim: To determine whether ω-6 PUFA linoleic acid (LA) metabolites increased in those infected with severe disease compared to uninfected controls. Findings: Increased levels of ω-6 LA metabolites, e.g., arachidonic acid (AA), epoxyeicosatrienoic (EET) acid derivatives of AA (8,9-, 11,12-, and 14,15-EETs), AA-derived hydroxyeicosatetraenoic (HETE) acid, dihydroxylated diols (leukotoxin and isoleukotoxin), and prostaglandin E2 with decreased levels of ω-3-derived inflammation resolving SPMs. Therapeutic treatment of SARS CoV-2 patients with ω-3 PUFA significantly increased 18-HEPE (SPM precursor) and EPA-derived diols (11,12- and 14,15-diHETE), while toxic 9,10- and 12,13-diHOMEs (leukotoxin and iosleukotoxin, respectively) decreased. Conclusion: Unbalanced dietary intake of ω-6/ω-3 PUFAs contributed to SARS CoV-2 disease severity by decreasing ω-3-dependent SPM resolution of inflammation and increasing membrane-associated ferroptotic AA peroxidation.

Aging naturally involves a decline in biological functions, often triggering a disequilibrium of physiological processes. A common outcome is the altered response exerted by the immune system to counteract infections, known as immunosenescence, which has been recognized as a primary cause, among others, of the so-called long-COVID syndrome. Moreover, the uncontrolled immunoreaction leads to a state of subacute, chronic inflammatory state known as inflammaging, responsible in turn for the chronicization of concomitant pathologies in a self-sustaining process. Anti-inflammatory and immunosuppressant drugs are the current choice for the therapy of inflammaging in post-COVID complications, with contrasting results. The increasing knowledge of the biochemical pathways of inflammaging led to disclose new small molecules-based therapies directed toward different biological targets involved in inflammation, immunological response, and oxidative stress. Herein, paying particular attention to recent clinical data and preclinical literature, we focus on the role of endocannabinoid system in inflammaging, and the promising therapeutic option represented by the CB2R agonists, the role of novel ligands of the formyl peptide receptor 2 and ultimately the potential of newly discovered monoamine oxidase (MAO) inhibitors with neuroprotective activity in the treatment of immunosenescence.

Diplotaxis muralis (L.) DC (Brassicaceae) is an edible plant commonly used in Mediterranean diets. This study investigates its nutritional composition, secondary metabolites, and antioxidant activity. The results show that this plant is rich in fibre and essential minerals. Analysis of amino acids shows a diverse profile, with glutamic acid and aspartic acid being the most abundant. Regarding fatty acids, α-linolenic acid was identified as predominant. Importantly, levels of toxic metals such as cadmium, lead, and mercury were found to be within established safety limits, confirming the plant's suitability for consumption. A leaf decoction using 80% methanol exhibited the highest concentrations of total phenolic compounds (68.36 mg eq. gallic acid g-1), total flavonoids (3.50 mg eq. quercetin g-1), and antioxidant activity (IC₅₀ of 78.87 µg mL-1 for ABTS, 392.95 µg mL-1 for DPPH, and a FRAP value of 731.20 µmol Fe(II) g-1). HPLC-PDA-ESI-MSⁿ characterization identified flavonols as the main polyphenols. Additionally, several glucosinolates were identified. These compounds, along with their hydrolysis products, not only contribute to the health benefits of D. muralis, but also impart its distinctive pungent and spicy notes, playing a crucial role in shaping its unique sensory profile. These findings highlight the contribution of phenolic compounds and glucosinolates to the health benefits of D. muralis, reinforcing its potential as a promising plant for the development of new functional foods.

Over a century ago, Virchow proposed that cancer represents a chronically inflamed, poorly healing wound. Normal wound healing is represented by a transitory phase of inflammation, followed by a pro-resolution phase, with prostaglandin (PGE2/PGD2)-induced 'lipid class switching' producing inflammation-quenching lipoxins (LXA4, LXB4).

We explored if lipid dysregulation in colorectal cancers (CRCs) is driven by a failure to resolve inflammation.

We performed liquid chromatography and tandem mass spectrometry (LC-MS/MS) untargeted analysis of 40 human CRC and normal paired samples and targeted, quantitative analysis of 81 human CRC and normal paired samples. We integrated analysis of lipidomics, quantitative reverse transcription-PCR, large scale gene expression, and spatial transcriptomics with public scRNASEQ data to characterize pattern, expression and cellular localisation of genes that produce and modify lipid mediators.

Targeted, quantitative LC-MS/MS demonstrated a marked imbalance of pro-inflammatory mediators, with a dearth of resolving lipid mediators. In tumours, we observed prominent over-expression of arachidonic acid derivatives, the genes encoding their synthetic enzymes and receptors, but poor expression of genes producing pro-resolving synthetic enzymes and resultant lipoxins (LXA4, LXB4) and associated receptors. These results indicate that CRC is the product of defective lipid class switching likely related to inadequate or ineffective levels of PGE2/PGD2.

We show that the lipidomic profile of CRC tumours exhibits a distinct pro-inflammatory bias with a deficiency of endogenous resolving mediators secondary to defective lipid class switching. These observations pave the way for 'resolution medicine', a novel therapeutic approach for inducing or providing resolvins to mitigate the chronic inflammation driving cancer growth and progression.

Interleukin-8 (IL-8), a proinflammatory factor in human tissues, plays an important role in inflammation. Type IV collagen, a key component of the basement membrane, interacts with integrins, which are primary receptors in the extracellular matrix (ECM). Integrins are essential for the regulation of various cellular behaviors and signal transduction pathways. However, the relationship between type IV collagen, β1 integrin, and gingival epithelial cells is poorly understood. The aim in this study was to elucidate the effect of the interaction between type IV collagen and β1 integrin on IL-8 secretion in human gingival epithelial cells (Ca9-22).

Ca9-22 cells were treated with or without type IV collagen, and IL-8 production was assessed using an enzyme-linked immunosorbent assay (ELISA). The role of β1 integrin was investigated using a β1 integrin-neutralizing antibody. Western blotting was performed to measure the phosphorylation levels of the relevant proteins. The effects of the focal adhesion kinase (FAK) inhibitor Y15 and the MEK inhibitor U0126 on β1 integrin/FAK and Erk1/2 MAPK pathways in IL-8 production were evaluated to explore the involvement of these signaling pathways.

β1 integrin induced IL-8 secretion in the Ca9-22 cells by regulating FAK, Erk1/2, and p130Cas proteins. p130Cas was independent of FAK, whereas Erk1/2 functioned downstream of FAK. Inhibition of FAK or Erk1/2 substantially reduced IL-8 secretion, highlighting their pivotal roles in this signaling pathway.

β1 integrin promotes IL-8 secretion in Ca9-22 cells via the β1 integrin/FAK/Erk1/2 signaling pathway. These findings elucidate the pathogenesis of periodontitis and provide a foundation for the development of targeted therapeutic strategies.

High-density lipoprotein (HDL) oxylipins regulate inflammation, and acute systemic inflammation can precipitate cognitive impairment. Females have more HDL and stronger immune responses than males, yet higher dementia risk. Little is known about sex differences in oxylipin responses to inflammatory stimuli and potential crosstalk between acute systemic inflammation and central oxylipin signaling in either sex. In this targeted lipidomics study, we used liquid chromatography with tandem mass spectrometry (LC/MS/MS) to characterize oxylipin profiles in plasma HDL and cerebrospinal fluid (CSF) of male and female rats following an intraperitoneal interleukin-1β (IL-1β)-induced inflammatory challenge to determine whether and how peripheral and central oxylipins respond to acute systemic inflammation in both sexes. We hypothesized that females mount a greater oxylipin response to IL-1β than males and that acute activation of peripheral inflammatory pathways changes central oxylipin concentrations. We found that IL-1β altered the abundance of omega (ω)6 and ω3 oxylipins in plasma HDL and CSF of both sexes. However, IL-1β reduced global concentrations of peripheral and central oxylipins in plasma HDL and CSF, respectively, in female rats only. Reduced oxylipin concentrations in IL-1β-treated females were driven by a loss of anti-inflammatory ω3 eicosapentaenoic acid (EPA)-derived dihydroxyeicosatetraenoic acids (DiHETEs) in plasma HDL and CSF. Interestingly, plasma HDL and CSF concentrations of EPA-derived DiHETEs were only correlated in IL-1β-treated rats, suggesting increased periphery-brain crosstalk during acute systemic inflammation. Overall, the sexually dimorphic responses of peripheral and central oxylipins to acute systemic inflammation provide molecular insight into sex differences in both innate immunity and neuroinflammatory responses.NEW & NOTEWORTHY This study examines previously unexplored sex differences in oxylipin signaling cascade activation in the central nervous system and periphery during the acute phase response. This is the first study to assess and correlate oxylipins in plasma HDL and CSF in males and females following an acute systemic inflammatory challenge. This work showing reduced concentrations of anti-inflammatory ω3 EPA-derived DiHETEs in acutely inflamed females provides molecular insight into sex differences in immunity and inflammation-induced neurological changes.

Specialised pro-resolving mediators (SPMs) are endogenously produced lipid mediators (LMs) that regulate the propagation of inflammation and promote tissue repair. We hypothesised that SPM production is dysregulated in COPD and is associated with disease severity, defined by patients with stable COPD (no exacerbations) versus patients with frequent exacerbations.

LMs were measured in plasma samples from patients with COPD (stable patients and patients with frequent exacerbations) and from healthy controls, matched for age, sex and body mass index, using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The LM profiles of controls were compared with those of stable COPD patients, and the LM profiles of stable COPD patients were compared with those of COPD patients with frequent exacerbations. We explored whether or not there was an association between LM profile and ever having a severe COPD exacerbation over 4.1 years of follow-up. Data are presented as mean±sem in pg·mL-1 for LMs, or mean±sd.

49 stable COPD patients had increased levels of pro-inflammatory mediators and some SPMs, compared with 28 controls (prostaglandin (PG)D2: 13.97±2.44 versus 0.53±0.13; p<0.001; lipoxins: 226.83±23.84 versus 59.84±20.25; p<0.01, respectively). 52 patients with frequent exacerbations had lower levels of PGD2 (3.07±0.97 versus 13.97±2.44; p<0.01) and SPMs (D-resolvins: 8.73±1.25 versus 34.53±8.95; p<0.01; lipoxins: 53.93±9.23 versus 226.83±23.84; p<0.01) than stable COPD patients, despite having a higher neutrophil count (5.28±2.16×109 L-1 versus 4.28±1.60×109 L-1; p=0.004). Among patients with frequent exacerbations, D-resolvin levels were independently inversely associated with occurrence of severe exacerbation (OR 0.88, 95% confidence interval (CI) 0.79-0.97; p=0.03) during follow-up.

These findings demonstrate distinct LM profiles of stable COPD patients and patients with frequent exacerbations. In those with exacerbations, D-resolvins were downregulated, compared with stable COPD patients, and associated with future risk of severe exacerbations during follow-up. Further work is needed to understand these findings.

Leukotriene C4 synthase (LTC4S) is a glutathione S-transferase that mediates the biosynthesis of cysteinyl leukotriene C4 (LTC4). Cysteinyl leukotrienes (CysLTs) are lipid mediators that drive type 2 inflammation, bronchoconstriction, and itch. Thus, LTC4S represents an attractive drug target for the treatment of allergic inflammatory diseases, but to date, no LTC4S inhibitor has been tested in patients. Herein, we disclose the discovery and preclinical profiling of the highly selective, oral LTC4S inhibitor GJG057 (compound 1), which exhibits 20-fold improved potency (IC50 = 44 nM) versus clinical candidate AZD9898 (IC50 = 900 nM) in a human whole blood LTC4 release assay. GJG057 showed efficacy in a murine asthma exacerbation model as well as in a mastoparan-induced skin challenge PK/PD model and was profiled in GLP toxicology studies. Despite its promising properties, GJG057 was not progressed into clinical trials as an oral drug. Its potential as a topical drug is currently being evaluated.