Search Results (88)

Asthma is defined as a chronic airway inflammatory disorder with over-activation of the immune system accompanied by the inability to resolve inflammation. SPMs are novel potent lipid mediators that play an important role in maintaining inflammation homeostasis and macrophages’ functional plasticity. This review will look into the potential function of SPM-programmed macrophage reprogramming as a novel therapeutic strategy for asthma. Unlike current anti-inflammatory treatments, which only focus on suppressing inflammation, SPMs can actively drive the inflammation resolution phase by promoting efferocytosis and wound healing while maintaining the defense against infection. In experimental asthma animal models, lipoxins, resolvins, protectins, and maresins have been demonstrated to alleviate inflammation and airway hyperresponsiveness, shift macrophages towards pro-resolving phenotypes and thus facilitate the resolution process. Levels of some SPM subclasses were found to be reduced in severe or uncontrolled asthmatics, indicating defective resolution pathways may contribute to asthma persistence. The mechanisms include down-regulation of pro-inflammatory cytokines, alteration of macrophage phenotype, improvement of immune homeostasis in the airway milieu, etc. These molecules have become highly promising therapeutic agents after the development of metabolically stable analogs, receptor-targeted agonists, and an improved delivery system. Multi-omics studies coupled with patient stratification based on biomarkers will potentially help in the future to develop personalized resolution-based therapy, in particular for those steroid-resistant and non-type 2 asthmatics. Nevertheless, the evidence provided so far is mainly preclinical; more challenges in terms of pharmacokinetics, formulation and formulation development, regulatory agency approval, and clinical validation remain and will be overcome through further studies, thus warranting investigation into SPM-mediated strategies for asthma and other chronic inflammatory diseases. Full article

Ferroptosis, a type of iron overload-induced cell death, is involved in diabetes-induced testicular dysfunction. Hence, this study was designed to investigate, for the first time, the impact of lipoxin A4 (LXA4) administration on testicular tissue in diabetic rats and explore its probable role in regulating ferroptosis in comparison with the standard ferroptosis inhibitor (ferrostatin-1, Fer-1). Albino rats of Wistar strain were divided into a control group, a type II diabetes mellitus (DM) group, a DM + Fer-1group, and a DM + LXA4 group. Serum levels of iron, insulin, glucose, total cholesterol, triglycerides, and testosterone were assayed. Testicular tissue markers of oxidative stress, ferroptosis, and inflammation were also assessed by different methods. Our results confirmed diabetes-induced testicular injury and disruption of its function via inducement of ferroptosis, but this was ameliorated with LXA4 and Fer-1 administration. However, Fer-1 showed a greater protective effect compared to LXA4 under the conditions of this study. We concluded that LXA4 partially secured the testicular tissue of diabetic rats against ferroptosis via augmenting the antioxidant Nrf2/SLC7A11/GPX4 pathway. Therefore, LXA4 may have a possible protective effect on the testicular tissue of diabetic patients. Full article

Chronic kidney disease (CKD) affects more than 10% of the population and is associated with a persistent, low-grade inflammatory state that accelerates tubulointerstitial fibrosis, worsens prognosis, and increases cardiovascular risk. This review aims to synthesize current knowledge on specialized pro-resolving mediators (SPMs) in the context of CKD pathophysiology, biomarkers, and therapeutic potential. We discuss key anti-inflammatory and pro-resolving mechanisms of SPMs that translate into nephroprotective and antifibrotic effects in experimental kidney models. The review summarizes data on EPA/DHA supplementation, including its impact on lipid profiles, inflammatory biomarkers (CRP, IL-6, TNF-α), and oxidative stress in patients with CKD. We also highlight contemporary analytical methods for biomarker assessment (LC-MS/MS, UHPLC-HRMS) and their potential for monitoring inflammatory activity across its phases (initiation, attenuation, resolution), CKD progression, and responses to ω-3/SPM-based interventions. Finally, we discuss the therapeutic potential of SPMs, as well as safety considerations and pharmacological interactions. In conclusion, SPMs and ω-3-derived mediators represent promising research and clinical targets as markers and modulators of inflammation in CKD, but require further validation in well-designed prospective studies. Full article

S. Typhimurium infection has the capacity to elicit enteric inflammation and metabolic dysfunction among poultry. Prior research conducted by our laboratory observed an increase in LXA4 titers within the gut of Wenchang chickens following infection with S. Typhimurium. Based on this observation, the present study analyzed the changes in body weight, immune organ indices, the levels of intestinal inflammatory cytokines, as well as cyclooxygenase-2 (COX-2) expression in Wenchang chickens before and after infection. The findings indicated that S. Typhimurium infection led to reduced body weight and significantly decreased thymus and bursa indices. Furthermore, a significant elevation was observed in the transcript levels of pro-inflammatory mediators, including IL-1β, along with IL-6, and TNF-α, concurrently with an increase in the mRNA transcript levels of the enzyme COX-2. Treatment with LXA4 attenuated these alterations and effectively alleviated the inflammatory response. Additionally, an in vitro system was employed to validate the anti-inflammatory properties of LXA₄ against S. Typhimurium-induced inflammation in chicken HD11 macrophages. The results demonstrated that LXA4 attenuated the transcript levels of IL-1β, as well as IL-6, TNF-α, and COX-2, at various intervals (2, 12, and 24 h), thereby alleviating inflammation elicited by S. Typhimurium challenge. We employed the LXA4 receptor antagonist Boc-2 to explore the ALX/FPR2 signaling axis and noted the successful neutralization of LXA4-mediated anti-inflammatory properties by this antagonist in S. Typhimurium–challenged HD11 macrophages. Collectively, these findings indicate that S. Typhimurium triggers pro-inflammatory reactions across both in vivo chicken models and in vitro HD11 macrophage systems, whereas LXA4 effectively mitigates this inflammatory process. This research establishes the conceptual underpinnings necessary to advance the design of therapeutic modalities aimed at counteracting S. Typhimurium challenges within poultry populations. Full article

Regulatory B cells (Bregs) are integral to the tumor microenvironment (TME) and influence immune responses through the secretion of immunosuppressive cytokines such as IL-10, IL-35, and TGF-β. This review highlights recent findings on the phenotype and mechanisms of Bregs, emphasizing their dual role in regulating immune responses within the TME. Importantly, we further explored the latest advances in Breg regulatory mechanisms from the novel perspectives of epigenetics and metabolic remodeling, including the effects of DNA methylation, histone acetylation, glycolysis, and oxidative phosphorylation on Bregs. We also investigate the therapeutic targeting of Bregs, with a focus on STAT3 inhibitors such as lipoxin A4, cucurbitacins, and resveratrol, which show promising potential in mitigating the suppressive function of Bregs. Furthermore, this review provides a detailed analysis of the impact of Bregs on tumorigenesis and metastasis, emphasizing the importance of inhibiting specific immune pathways to prevent tumor escape. Finally, this review offers a prospective outlook on immunotherapy strategies based on Bregs, foreseeing a more nuanced understanding of their TME function and the evolution of targeted treatments with enhanced therapeutic efficacy. Full article

Specialized pro-resolving mediators (SPMs), including lipoxins, resolvins, protectins, and maresins, actively terminate inflammation and restore tissue homeostasis. This review addresses how specialized pro-resolving mediators (SPMs) and their omega-3/omega-6 PUFA precursors influence inflammatory pathways, disease mechanisms, and therapeutic potential across major inflammatory skin disorders. MEDLINE/PubMed was searched on 4 October 2025. Eligible studies included experimental, animal, mechanistic human, and interventional research examining SPMs or omega-3/omega-6 fatty acids. Non-English articles, reviews, conference abstracts, and dietary questionnaire–only studies were excluded. Two reviewers independently screened and extracted data. Due to heterogeneity, a narrative synthesis was performed. No formal risk-of-bias assessment was undertaken Of 359 records, 57 studies were included (26 psoriasis, 24 atopic dermatitis, 7 acne; scarce hidradenitis suppurativa data). Preclinical data consistently demonstrated that SPMs modulate key inflammatory pathways, support epithelial repair, and help restore immune balance. Human studies revealed altered cutaneous and systemic lipid mediator profiles—characterized by reduced omega-3–derived SPMs and predominance of omega-6-driven inflammatory mediators—suggesting impaired resolution mechanisms across these disorders. Interventional studies showed that omega-3 supplementation may reduce inflammatory markers, improve barrier function, and alleviate clinical symptoms. Early evidence on SPMs analogues and receptor agonists indicates promising therapeutic potential, but clinical data remain sparse. The body of evidence is limited by scarce human data, small sample sizes, heterogeneous interventions and variable methods. Many studies rely on subjective or non-standardized clinical outcomes, and the predominance of experimental models further limits the translational relevance of current findings. In summary, disturbances in PUFA-derived lipid mediator pathways and insufficient activation of pro-resolving mechanisms may contribute to the persistence of cutaneous inflammation. Omega-3 supplementation and SPMs-based novel therapies therefore represent plausible adjunctive approaches; however, their therapeutic relevance requires confirmation in future mechanistic and clinical studies. Full article

Objectives: Periodontitis is a multifactorial inflammatory disease initiated by pathogenic bacteria, such as Porphyromonas gingivalis. Resolvin D1 (RvD1) plays a pivotal role in inflammation resolution. This study aimed to identify the mechanism of the regulatory effects of RvD1 on the inflammatory response of human periodontal ligament cells (hPDLCs). Methods: To investigate the mechanism of RvD1’s impact on the hPDLCs, RNA-sequencing (RNA-seq) was used and differentially expressed genes (DEGs) were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to assess the signaling pathways in which NF-κB and MAPK were determined to play a significant role. Alterations in NF-κB and MAPK pathways were verified by immunofluorescence (IF), quantitative real-time PCR (qRT-PCR), and Western blotting (WB). The expression of RvD1 and lipoxin A4/formyl peptide receptor 2 (ALX/FPR2) was assessed by IF and WB. Inflammatory cytokine interleukin (IL) 6 and IL-1β release was measured by ELISA. Results: GO and KEGG analyses indicated that RvD1 regulates the inflammatory process in PDLCs primarily via TLR4-MyD88-mediated NF-κB and MAPK signaling. RvD1 suppressed lipopolysaccharide (LPS)-induced TLR4 and MyD88 expression, inhibited phosphorylation of NF-κB p65 and its inhibitor IKBKB, and attenuated phosphorylation of p38 MAPK, ERK, and JNK. ALX/FPR2 was expressed on hPDLCs and was further upregulated upon treatment with RvD1. RvD1 significantly down-regulated the IL-6 and IL-1β levels in LPS-stimulated hPDLCs. Conclusions: RvD1 regulates the inflammatory response of LPS-stimulated hPDLCs by the TLR4-MyD88-MAPK and TLR4-MyD88-NF-κB signaling pathways, suggesting the potential role of RvD1 in restoring periodontal tissue homeostasis by regulating PDLC response to inflammatory and infectious stimuli. Full article

Dilated cardiomyopathy is a major cause of heart failure and is one of the most common forms of cardiomyopathy worldwide. Although there has been significant progress in its clinical management, early diagnosis and precise prognosis remain challenging due to the lack of specificity in current biomarkers. As inflammation plays a key role in DCM, we determined the levels of systemic inflammatory markers and specific pro-resolving lipid mediators (SPMs) in a cohort of DCM patients. Our data show that the levels of lipoxin A4 significantly increased in DCM patients (343 + 75.1 pg/mL in controls vs. 482.2 ± 159.1 pg/mL in DCM patients), whereas the opposite was observed for resolving D1 (57.18 ± 32.68 pg/mL in controls vs. 38.55 ± 25.13 pg/mL in DCM patients). These results may indicate that SPMs could be considered new biomarkers related to the progression of this pathology. Moreover, since microRNAs (miRNAs) are also considered potential biomarkers at the molecular level, we conducted comprehensive miRNA expression profiling using a high-throughput array platform in our cohort. Of the differentially expressed miRNAs identified, we chose to focus on two that were significantly upregulated (miR378-3p and miR486-5p; more than two-folds) or downregulated (miR142-3p and miR328-3p < 20% and 40% vs. the control, respectively) in DCM patients, all of them strongly associated with inflammatory pathways. The selected miRNAs showed considerable potential as biomarkers, exhibiting statistical significance after ROC analysis. In fact, improved performance was observed when combining both miR142-3p and miR328-3p, using a LASSO regression model. However, we found no correlation between miRNAs and traditional inflammatory markers or SPMs ruling out the possibility to proposing them as combined biomarkers in this case. The heterogeneity of DCM leads to the need to identify new biomarkers that, either individually or in combination, may improve the prognosis of affected individuals. In our study, we have identified that some of the main SPMs can provide valuable information about disease progression, in addition to the combination of certain circulating miRNAs, which show promising prognostic values in our cohort. Thus, we have identified novel biomarkers that integrate inflammatory profiles with specific circulating miRNA expression patterns is an important step towards more targeted patient stratification in DCM. This approach can improve DCM diagnosis and prognosis, supporting the development of personalized treatments through a multi-parameter panel of biomarkers that can be measured in peripheral blood and used in routine clinical practice. Such a strategy can enable earlier treatment, resulting in better patient outcomes and quality of life. Full article

Severe Coronavirus disease 2019 (COVID-19) is associated with abnormal innate and adaptive immune responses, as well as systemic alterations, including a shift in lipid network. A case–control study was conducted to describe the systemic lipidomic profile in COVID-19 according to disease severity. Selected polyunsaturated fatty acids (PUFAs), oxylipins, and endocannabinoids were analysed using a targeted liquid chromatography coupled to mass spectrometry in tandem method. Multivariate receiver operating characteristic curve-based model evaluation was performed to define a lipidomic signature for the disease. A total of 135 hospitalized COVID-19 patients, of whom 85 had severe form, and 134 healthy individuals were included. Patients exhibited increased levels of free PUFAs, proinflammatory and pro-resolving oxylipins, and endocannabinoids compared to controls. A combination of five lipid mediators, i.e., prostaglandin D2, prostaglandin E2, thromboxane B2, lipoxin B4, and 2-archidonylglycerol, discriminates patients from control individuals with excellent accuracy [AUC, 0.977 (0.950–0.995)]. The severe form is characterized by an imbalance between proinflammatory and pro-resolving oxylipins and increased endocannabinoids. COVID-19 is associated with a lipid storm that conditions disease severity. Targeting lipid mediators-related metabolic and signalling pathways could be an interesting therapeutic option in severe forms. Full article

This comprehensive narrative review of bioactive plant compounds, pro-resolving anti-inflammatory lipids, and statins shows their potential in the inhibition of intervertebral disc degeneration (IVDD), pain resolution, tissue repair, and disc regeneration. IVDD is a multifactorial disease involving a multitude of signaling pathways, leading to the loss of normal disc function. An influx of nociceptive mechanoreceptors generate low back pain (LBP). IL6 and IL8 levels are elevated in patients undergoing spinal fusion to alleviate LBP, indicating these pro-inflammatory mediators may be major contributors to the generation of LBP. Apoptosis of disc cells leads to the depletion of key extracellular matrix components that equip the disc with its weight-bearing properties. A biomechanically incompetent degenerated IVD stimulates nociceptor mechanoreceptor activity, generating pain. Myo-tendinous, vertebral body, muscle, and facet joint tissues also contain pain receptors. Disturbance of the normal architecture of the IVD also generates pain in these tissues. Plant compounds have been used in folkloric medicine for centuries. This review attempts to provide a scientific basis for their purported health benefits; however, further studies are still required to substantiate this. Until this evidence is available, it would be prudent to be cautious in the use of such compounds. A diverse range of plant compounds (flavonoids, terpenoids, glycosides, alkaloids, and polyphenolics) inhibit inflammation and apoptosis, reduce spinal pain, and stimulate tissue repair by targeting cell signaling pathways in IVDD. Pro-resolving lipid mediators (lipoxin A4, resolvin D1, protectins, and maresins) also reduce inflammation, maintaining disc health and function. Cholesterol lowering statins disrupt phosphorylation in cell signaling pathways inhibiting IVDD, promoting tissue repair and regeneration. Full article

Radiation-induced lung inflammation (RILI) is a major complication of thoracic radiotherapy, characterized by excessive inflammation and subsequent fibrosis that compromise pulmonary function and treatment outcomes. This study explores the pharmacological properties of a newly synthesized Lipoxin A4 analogue (CYNC-2) to mitigate RILI by modulating the AMP-activated protein kinase (AMPK)/NOD-like receptor family pyrin domain containing 3(NLRP3) inflammasome pathway. A murine RILI model was established in mice by delivering a single high-dose (ablative) X-ray irradiation to the left lung. Mice in the treatment group received CYNC-2 via tail-vein injection three times per week for 2 weeks. The effects of CYNC-2 on RILI were evaluated histological, immunohistochemical analysis of lung tissues, cytokine profiling, lung function testing using a FlexiVent system, and micro-computed tomography (micro-CT) imaging of lung damage. In parallel, two human lung cell lines—L132 (normal bronchial epithelial cells) and A549 (lung carcinoma cells)—were irradiated with 6 Gy X-rays and treated with CYNC-2 to assess cell viability and changes in AMPK/NLRP3 pathway markers via qPCR and immunofluorescence. Lung tissue sample from patients who underwent thoracic radiotherapy were also examined to validate key findings. CYNC-2 activated AMPK and inhibited mTOR signaling, which suppressed NLRP3 inflammasome activation and led to reduced secretion of pro-inflammatory cytokines (IL-1β, IL-6, and TGF-β1). In vitro, CYNC-2 mitigated radiation-induced inflammatory responses and preserved cellular viability. Overall, CYNC-2 effectively dampened acute pulmonary in the RILI model. These findings suggest that targeting the AMPK/NLRP3 inflammasome pathway via a stable LXA4 analogue such as CYNC-2 is a promising therapeutic strategy to improve clinical outcomes for patients receiving thoracic radiation therapy. Full article

Objective: Transient tachypnea of the newborn (TTN) is a common condition observed in neonates. Since its management often requires intensive care and leads to maternal–infant separation, it is a major source of parental concern. The present study aimed to evaluate the effects of lipoxin A4 and resolvin D1 on the clinical course of TTN and to determine whether complete blood count parameters could serve as predictors of disease severity. Materials and Methods: A total of 62 neonates admitted to the neonatal intensive care unit with a diagnosis of TTN were included. According to Silverman scoring, infants were divided into a mild group (n = 31) and a severe group (n = 31). Lipoxin A4 and resolvin D1 levels, together with complete blood count parameters, were compared between the two groups. Logistic regression and receiver operating characteristic (ROC) curve analyses were performed to assess the predictive value of these parameters for the clinical course. Results: Serum lipoxin A4 (p = 0.005) and resolvin D1 (p = 0.002) levels were significantly higher in the mild group compared with the severe group, whereas the neutrophil-to-lymphocyte ratio (p = 0.044) and platelet-to-lymphocyte ratio (p = 0.027) were significantly lower. Resolvin D1 and the platelet-to-lymphocyte ratio were identified as significant predictors of severe disease. In predicting a mild course, lipoxin A4 demonstrated the highest sensitivity (80.6%), while resolvin D1 exhibited the highest specificity (87.1%). Conclusions: Lipoxin A4 and resolvin D1 appear to play a protective role in preventing severe clinical progression of transient tachypnea of the newborn. Full article

Ischemic stroke is a leading cause of mortality and disability in adults. The inflammatory cascade is driven by various inflammatory molecules, such as interleukin-1β (IL-1β), and counteracted by its antagonist, interleukin-1 receptor antagonist (IL-1Ra). Eicosanoids are inflammatory derivatives of free fatty acids. Arachidonic acid (AA) derivatives exhibit pro-inflammatory activity, while eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) derivatives, known as specialized pro-resolving mediators, have anti-inflammatory properties. This study aimed to analyze potential associations between eicosanoids and key inflammatory molecules, including IL-1β and its antagonist IL-1Ra. In this prospective study, we investigated inflammatory molecules in 73 ischemic stroke patients. We analyzed interactions between IL-1β, IL-1Ra, and eicosanoids as follows: resolvin E1, prostaglandin E2, resolvin D1, lipoxin A4 (5S, 6R, 15R), protectin DX, maresin 1, leukotriene B4, 18RS-HEPE, 13S-HODE, 9S-HODE, 15S-HETE, 17 HDHA, 12S-HETE, 5-oxo-ETE, and 5-HETE. In 73 ischemic stroke patients, mean IL-1β was 1.31 ± 1.54 pg/mL and IL-1Ra 810.8 ± 691.0 pg/mL. Spearman correlations showed positive associations between IL-1β and protectin DX (ρ = 0.56, p < 0.001), and 17 HDHA (ρ = 0.26, p < 0.05) and 5-oxo-ETE (ρ = 0.27, p < 0.05). IL-1Ra correlated negatively with protectin DX (ρ = −0.58, p < 0.001) and 17 HDHA (ρ = −0.29, p < 0.05), and positively with leukotriene B4 (ρ = 0.34, p < 0.005). After multivariable adjustment, associations with IL-1β lost statistical significance, whereas the inverse relationships between IL-1Ra and protectin DX/17 HDHA remained significant (p < 0.005). Despite the known anti-inflammatory roles of protectin DX and 17 HDHA, and the pro-inflammatory role of leukotriene B4, their activity in the early subacute phase of ischemic stroke appears to be influenced by complex interplays, possibly mediated by IL-1β and IL-1Ra. The activity of protectin DX, 17 HDHA, and leukotriene B4 is correlated with IL-1β and IL-1Ra levels in the early subacute phase of stroke. Full article

Lipoxins were discovered 40 years ago, and since then, their beneficial roles for human health have been confirmed in numerous studies. These small molecules belong to the eicosanoid class of compounds, which are generated metabolically by lipoxygenases. Lipoxins are released during various diseases and conditions, including but not limited to systemic inflammation, infection, asthma, cancer, diabetes, and cardiovascular disorders. Recently, several synthetic lipoxin analogs have been developed that also exhibit potent anti-inflammatory properties. In this review, we discuss the inflammation-resolving roles of lipoxins in various major diseases. Further, we summarize the latest reports on the use of synthetic lipoxins as potential therapeutic agents and discuss the role of aspirin-dependent lipoxin production in alleviating various diseases, including cancer. Full article

Crotoxin (CTX), the main toxin in Crotalus durissus terrificus venom, is a heterodimeric complex known for its antitumoral, anti-inflammatory, and immunomodulatory properties. In macrophages, CTX stimulates energy metabolism, pro-inflammatory cytokines, superoxide production, and lipoxin A₄ secretion while inhibiting macrophage spreading and phagocytosis. These effects are completely blocked by Boc-2, a selective formyl peptide receptors (FPRs) antagonist. Despite the correlation between FPRs and CTX-mediated effects, their involvement in mediating CTX entry into macrophages remains unclear. This study aimed to investigate the involvement of FPRs in CTX entry into monocytes and macrophages. For this, THP-1 cells were silenced for FPRs or treated with Boc-2. Results demonstrated that FPR-related signaling pathways, which influence macrophage functions such as ROS release, phagocytosis, and spreading, were reduced in FPR-silenced cells. However, even in the absence of FPRs, CTX was efficiently internalized by macrophages. These findings suggest that FPRs are essential for the immunomodulatory effects of CTX, but are not involved in CTX internalization. Full article