Search Results (141)

Nowadays, two major pathways seem to be responsible for the development and progression of atherosclerosis, namely, high levels of low-density lipoprotein-cholesterol (LDL-C) and low-grade vascular inflammation. Indeed, the concentration of C-reactive protein (CRP), mirroring low-grade systemic inflammation, has been recognized as a more powerful determinant of recurrent cardiovascular (CV) events, death, and all-cause mortality than LDL-C levels. Gut microbiota (GM) dysbiosis is a causal factor for the development of different inflammatory-based pathologies, such as CV disease (CVD). In addition, pre/probiotics showed beneficial effects on GM dysbiosis, by influencing both inflammation and immunity. It has been well documented that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) exert triglyceride (TG)-lowering and antithrombotic effects and play a seminal role in the resolution of inflammatory processes. We showed the recent studies indicating the relationship between pharmacological reduction in inflammatory cytokines and CV outcomes. The principal aim of our review is to highlight the anti-inflammatory and immune-modulatory activities of GM, EPA, and DHA. Then, we pointed out how developing patient-specific pre/probiotic and EPA/DHA interventions alongside the standard of care (SOC) is needed in order to answer several of the questions raised, ranging from diminishing drug toxicity to including frailty individuals. Therefore, hypothetical tailored clinical studies are presented, aiming to treat all the patients at high-risk of CV events, as well as aged people. 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

Cattle marketed through auction market systems and/or that remain unvaccinated are considered higher risk for BRD, but impacts on host response remain unclear. We sought to identify specific genomic patterns of beef calves vaccinated against BRD viruses or not and commercially marketed or directly transported in a split-plot randomized controlled trial. Forty-one calves who remained clinically healthy from birth through backgrounding were selected (randomly stratified) from a larger cohort of cattle (n = 81). Treatment groups included VAX/DIRECT (n = 12), VAX/AUCTION (n = 11), NOVAX/DIRECT (n = 7), and NOVAX/AUCTION (n = 11). Blood RNA was acquired across five time points, sequenced, and bioinformatically processed via HISAT2 and StringTie2. Significant transcriptional changes (FDR < 0.05) were observed at backgrounding entry (T5) in NOVAX/AUCTION cattle exhibiting 2809 uniquely differentially expressed genes and relative activation of immune, inflammatory, and metabolic pathways with upregulation of interferon-stimulated genes (e.g., IFIT3, MX2, and TRIM25) and downregulation of specialized proresolving mediator (SPM) enzymes (ALOX5 and ALOX15). VAX/AUCTION cattle exhibited modulated immune activation and preserved expression of SPM-associated genes when compared to NOVAX/AUCTION cattle. Both marketing route and vaccination shape the molecular immune landscape during high-stress transitions, with preweaning vaccination potentially modulating this response. This study provides mechanistic insight into how management practices influence immunological resilience and highlights the value of integrating transcriptomics into BRD risk mitigation. Full article

Uterine leiomyoma (uterine fibroids, UF) are benign myometrium tumors that affect up to 70% of the female population and may lead to severe clinical symptoms. Despite the high prevalence, pathogenesis of UF is not understood and involves cytokines, steroid hormones, and growth factors. Additionally, an increased deposition and remodelling of the extracellular matrix is characteristic for UF. Vitamin D seems to play a new role in UF. Interestingly, hypovitaminosis D correlates with a higher prevalence of myomas and the severity of the myomas. Administration of vitamin D in women with insufficiency (serum level <30 ng/mL) restored the vitamin D status and reduced the mild symptoms of myomas. In addition, inflammatory processes may play a role. In the past years, it has become clear that cessation of inflammation is an active process driven by a class of lipid mediator molecules called specialized pro-resolving mediators (SPM). Inadequate resolution of inflammation is related to several chronic inflammatory diseases and several studies have proven the crucial role of SPMs in improving these diseases. In this review, we will give an overview on processes involved in UF growth and will give an overview on the modern view regarding the concept of inflammation and the role of SPMs in resolution of inflammation, especially in chronic inflammatory diseases. Full article

The venom of Bothrops jararaca (BjV) induces intense and prolonged pain, which is not alleviated by antivenom, along with hemorrhage and inflammation. In this study, we investigated the effects of the specialized pro-resolving lipid mediator (SPM) maresin 2 (MaR2) in a murine model of BjV-evoked pain and inflammation. Mice received a single intraperitoneal (i.p.) injection of MaR2 30 min before the intraplantar BjV injection. MaR2 treatment significantly attenuated mechanical (electronic aesthesiometer) and thermal (hot plate) hyperalgesia in a dose-dependent manner. Additionally, MaR2 restored the balance for the hind-paw static weight distribution. When BjV (0.01, 0.1, and 1 μg) stimulus was administered intraperitoneally, pre-treatment with MaR2 (0.3, 1, or 3 ng) ameliorated mechanical and thermal hyperalgesia in a dose-dependent manner. Moreover, MaR2 (3 ng) effectively reduced the levels of myeloperoxidase activity and cytokines (TNF-α, IL-1β, and IL-6) and superoxide anion (O₂^•−) production induced by intraplantar injection of BjV while enhancing total antioxidant levels (ABTS scavenging). For the peritonitis model induced by BjV, MaR2 pretreatment decreased leukocyte recruitment, hemorrhage, nitric oxide (NO), and O₂^•− generation and gp91phox and inducible nitric oxide synthase (iNOS) mRNA expression. In conclusion, this study presents the first evidence that MaR2 effectively mitigated BjV-induced pain, hemorrhage, and inflammation. Full article

Background/Objectives: Localized provoked vulvodynia (LPV) is characterized by chronic vulvar pain upon light touch to the vestibule, a specialized ring of tissue immediately surrounding the vaginal opening. LPV affects about 14 million people in the US, yet the etiopathology of the disease is unknown. In LPV, the vestibule expresses elevated levels of the pro-nociceptive pro-inflammatory mediators prostaglandin E₂ (PGE2) and interleukin-6 (IL-6), which corresponds to lower pain thresholds. Previous studies have shown reduced amounts of arachidonic acid (AA)-derived pro-resolving lipid mediators in tissue biopsies from LPV patients that might impede the resolution of inflammation. AA is obtained from dietary linoleic acid, pointing to a defect in the metabolism of dietary polyunsaturated fatty acids in LPV. We aimed to further explore the involvement of AA metabolism in LPV, which appears dysregulated in the vestibule of LPV patients and culminates in chronic inflammation and chronic pain. Methods: Vestibular and vulvar tissue biopsies obtained from LPV and non-LPV patients were used to generate fibroblast strains and assessed for COX/LOX expression using qRT-PCR. Fibroblast strains were treated with inflammatory stimuli, and then COX-1 and COX-2 expression was assessed using Western blot analysis. Pro-inflammatory mediator production was assessed using enzyme-linked immunosorbent assays (ELISAs). ALOX5 and ALOX12 expression was assessed using qRT-PCR. Finally, lipidomic analysis was carried out to screen for 143 lipid metabolites following inflammatory challenge. Results: Tissue and fibroblasts from LPV patients exhibited altered expression of COX/LOX enzymes and production of AA-derived lipid mediators compared to non-LPV patients. Conclusions: Lipid profiles of tissue and vestibular fibroblasts from LPV patients differed from non-LPV patients, and this difference was attributed to differential COX/LOX expression and activity, which metabolizes AA derived from dietary linoleic acid. This dysregulation fosters chronic inflammation and reduced resolution capacity in LPV patients, causing chronic pain. While further work is needed, these findings suggest that dietary modifications could impact the LPV mechanism. Full article

Exercise-induced muscle damage (EIMD) initiates an inflammatory response that is essential for tissue repair. However, when prolonged or excessive, this response can impair recovery and muscular performance. Specialized pro-resolving mediators (SPMs), derived from the metabolism of omega-3 (n-3) polyunsaturated fatty acids (PUFAs), facilitate the resolution of inflammation without causing immunosuppression. Evidence from preclinical studies indicates that SPM administration accelerates muscle repair and functional recovery by enhancing the clearance of apoptotic cells, suppressing pro-inflammatory signaling and modulating macrophage polarization. However, translation to human applications remains limited as commercially available SPM-enriched marine oils do not contain active SPMs but rather their monohydroxylated precursors, including 14-Hydroxy-Docosahexaenoic Acid (14-HDHA), 17-Hydroxy-Docosahexaenoic Acid (17-HDHA), and 18-Hydroxy-Eicosapentaenoic Acid (18-HEPE) in addition to low doses of the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Furthermore, the variable increases in circulating SPM concentrations as a result of dietary intake of EPA and DHA, whether from fish or fish oil supplements, and the wide diversity of SPM molecules (many of which remain under investigation), highlight the complexity of their structural and functional networks. While advances in lipidomics have identified SPMs and their pathway intermediates in human biological samples, further research is needed to determine optimal dosing strategies, delivery mechanisms, and the real impact of SPM-enriched marine oil on athletic performance and recovery. This narrative review examines the biological rationale and current evidence surrounding SPM-enriched marine oil supplementation and its potential to enhance muscle recovery following EIMD. By synthesizing findings from preclinical and human studies, the potential of SPM-enriched supplementation as a novel tool for optimizing performance recovery in athletic populations is reviewed to inform future research directions. Full article

Regulatory B cells (B regs) are immune cells that help suppress excessive inflammatory responses by interacting with other immune components. Among them, B-10 cells are known for their strong immunoregulatory function. This study focused on how B-10 cells influence macrophage phenotype and function through the PD-1 signaling pathway. To investigate this, B-10 cells derived from mouse spleens were co-cultured with bone marrow-derived macrophages (BMDMs) from either wild-type (WT) or PD-1 knockout (PD-1 KO) mice, using both direct contact and Transwell setups. The findings indicated that direct co-culture with B-10 cells significantly promoted the polarization of macrophages towards the anti-inflammatory M2 type, characterized by increased expression of surface markers (F4/80⁺, CD206⁺, CD163⁺), higher levels of PD-1, and upregulation of M2-related genes (IL-1ra, IL-10, Arg-1, IL-6, and CCL1). These macrophages also exhibited enhanced phagocytic activity and greater secretion of specialized pro-resolving mediator (SPMs) like RvD2 and 15-epi LXA4. In contrast, these effects were reduced when B-10 cells were cultured indirectly or when PD-1 was absent. These findings suggest that B-10 cells promote anti-inflammatory macrophage activity primarily through PD-1 signaling, offering insights into potential therapeutic approaches for controlling inflammation. Full article

Brain aging is driven by interconnected processes, including impaired autophagy, chronic inflammation, mitochondrial dysfunction, and cellular senescence, all of which contribute to neurovascular decline and neurodegenerative diseases such as Alzheimer’s disease (AD). Targeting these mechanisms simultaneously offers a promising therapeutic approach. This review explores the rationale for combining metformin, benzimidazole derivatives, phosphodiesterase-5 (PDE5), and acetylsalicylic acid (ASA) as a multi-targeted strategy to restore proteostasis, reduce senescence-associated secretory phenotype (SASP) factors, and enhance mitochondrial and lysosomal function. Metformin activates AMP-activated protein kinase (AMPK) and promotes autophagy initiation and chaperone-mediated autophagy, whilst benzimidazole derivatives enhance lysosomal fusion through JIP4–TRPML1 pathways independently of mTOR signaling; and ASA augments autophagic flux while suppressing NF-κB-driven inflammation and promoting specialized pro-resolving mediator pathways. This combinatorial approach targets both upstream autophagy initiation and downstream autophagosome–lysosome fusion, while concurrently attenuating inflammation and cellular senescence. Patient stratification based on the biomarkers of autophagy impairment, inflammation, and metabolic dysfunction could optimize therapeutic responses. While this strategy shows strong preclinical promise, careful attention to timing, dosing, and cell-specific responses is crucial to maximize benefits and avoid adverse effects. Future studies integrating biomarker-guided precision medicine frameworks are essential to validate the potential of this therapeutic combination in preventing or slowing cognitive decline and promoting healthy brain aging. Full article

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. Full article

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. Full article

The stereoselective total synthesis of an allylic epoxide-containing polyunsaturated fatty acid, in its triethylsilyl (TES) ether and methyl ester form, is described. Key features include a Sharpless enantioselective epoxidation to install the oxirane unit and Wittig coupling reactions to forge critical alkenyl configuration and secure the core carbon skeleton. The deprotected epoxy acid was recently demonstrated to play a central role as the precursor to biologically active resolvins D1, D2, and the cysteinyl conjugate in tissue regeneration (RCTR1) by human leukocytes. These natural products belong to a family of cell signaling molecules termed specialized pro-resolving mediators (SPMs). Full article

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are known to help resolve inflammation through generation of anti-inflammatory eicosanoids and specialized pro-resolving mediators, including resolvins, protectins, and maresins. Through binding to the GPR120/FFAR4 receptor, their beneficial effects result from phospholipid membrane remodeling, impairment of inflammatory signaling molecules clustering, subsequent inhibition of NF-κB and inflammasome activation, and a reduction in oxidative stress. Obesity, a chronic inflammatory disease that contributes to metabolic disorders, is alleviated by n-3 PUFAs. In the adipose tissue (AT) of individuals with obesity, n-3 PUFAs counteract hypoxia, inhibit immune cell infiltration and AT inflammation, improve insulin sensitivity, and reduce fat mass. Beyond AT, n-3 PUFAs also alleviate other metabolic disorders such as metabolic-associated steatotic liver disease (MASLD), gut dysbiosis, and/or renal dysfunction. In cardiovascular disease (CVD), they are mainly recommended as a secondary prevention for patients with coronary heart disease risks. This review provides an in-depth analysis of the benefits of n-3 PUFAs in obesity and related metabolic diseases, examining both the mechanistic and clinical aspects. Additionally, it also explores the effects of n-3 PUFAs in obesity-related chronic inflammatory conditions, including inflammatory bowel disease, psoriasis, rheumatoid arthritis, osteoarthritis, and multiple sclerosis, by targeting specific pathophysiological mechanisms. Clinical applications and limitations of n-3 PUFAs are discussed based on findings from human clinical trials. Full article

Background: Specialized pro-resolving lipid mediators (SPMs), such as maresins and resolvins, play a key role in resolving inflammation and repairing tissues. This study aimed to evaluate whether maresin-1 (MaR1) and resolvin-D1 (RvD1) could serve as serum non-invasive biomarkers for monitoring disease activity in ulcerative colitis (UC). Methods: This cross-sectional study included 60 UC patients (30 active, 30 remission) and 30 healthy controls. Disease activity was assessed using the Mayo Endoscopic Subscore (MES). Inflammatory indices, including the neutrophil–lymphocyte ratio (NLR), monocyte–HDL cholesterol ratio (MHR), platelet–lymphocyte ratio (PLR), CRP–lymphocyte ratio (CLR), CRP–albumin ratio (CAR), systemic inflammation response index (SIRI), and systemic immune-inflammation index (SII), were calculated. Plasma MaR1 and RvD1 levels were measured via enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) analysis was performed to evaluate biomarker accuracy. Results: CRP, NLR, PLR, CLR, CAR, SIRI, and SII were significantly elevated in active UC, whereas MaR1 and RvD1 were lower compared to remission and controls (p < 0.05). MaR1 levels were lower in the remission group than in controls. ROC analysis demonstrated high area under the curve (AUC) values for RvD1 (0.906), CAR (0.872), CLR (0.861), and CRP (0.858) in distinguishing active UC from remission, and for CRP (0.944), CAR (0.939), CLR (0.939), RvD1 (0.928), and MaR1 (0.889) in distinguishing active UC from controls. The specificity for detecting active UC was 60% for MaR1 and 80% for RvD1. Both RvD1 and MaR1 showed a negative correlation with the MES, with RvD1 demonstrating a stronger correlation (r = −0.754, p < 0.001). Conclusions: RvD1 shows a strong negative correlation with disease severity in ulcerative colitis, while low MaR1 levels in remission may indicate subclinical inflammation. Although MaR1 and RvD1 are not disease-specific, their role in inflammation resolution suggests they may complement conventional inflammatory markers for more comprehensive UC monitoring. Full article

Many polyunsaturated fatty acids within cells exhibit diverse physiological functions. Particularly, arachidonic acid is the precursor of highly bioactive prostaglandins and leukotrienes, which are pro-inflammatory mediators. However, polyunsaturated fatty acids, such as arachidonic, docosahexaenoic, and eicosapentaenoic acids, can be metabolized into specialized proresolving mediators (SPMs), which have anti-inflammatory properties. Given that pro-inflammatory mediators and SPMs are produced via similar enzymatic pathways, SPMs can play a crucial role in mitigating excessive tissue damage induced by inflammation. Mast cells are immune cells that are widely distributed and strategically positioned at interfaces with the external environment, such as the skin and mucosa. As immune system sentinels, they respond to harmful pathogens and foreign substances. Upon activation, mast cells release various pro-inflammatory mediators, initiating an inflammatory response. Furthermore, these cells secrete factors that promote tissue repair and inhibit inflammation. This dual function positions mast cells as central regulators, balancing between the body’s defense mechanisms and the need to minimize tissue injury. This review investigates the production of SPMs by mast cells and their subsequent effects on these cells. By elucidating the intricate relationship between mast cells and SPMs, this review aims to provide a comprehensive understanding of the mechanism by which these cells regulate the delicate balance between tissue damage and repair at inflammatory sites, ultimately contributing to the resolution of inflammatory responses. Full article