Search Results (137)

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

Background: Lung ischemia reperfusion injury (LIRI) is a severe complication after lung transplantation (LT). Ferroptosis contributes to the pathogenesis of LIRI. Maresin1 (MaR1) is an endogenous pro-resolving lipid mediator that exerts protective effects against multiorgan diseases. However, the role and mechanism of MaR1 in the ferroptosis of LIRI after LT need to be further investigated. Methods: A mouse LT model and a pulmonary vascular endothelial cell line after hypoxia reoxygenation (H/R) culture were established in our study. Histological morphology and inflammatory cytokine levels predicted the severity of LIRI. Cell viability and cell injury were determined by CCK-8 and LDH assays. Ferroptosis biomarkers, including Fe²⁺, MDA, 4-HNE, and GSH, were assessed by relevant assay kits. Transferrin receptor (TFRC) and Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) protein levels were examined by western blotting. In vitro, lipid peroxide levels were detected by DCFH-DA staining and flow cytometry analysis. The ultrastructure of mitochondria was imaged using transmission electron microscopy. Furthermore, the potential mechanism by which MaR1 regulates ferroptosis was explored and verified with signaling pathway inhibitors using Western blotting. Results: MaR1 protected mice from LIRI after LTx, which was reversed by the ferroptosis agonist Sorafenib in vivo. MaR1 administration decreased Fe²⁺, MDA, 4-HNE, TFRC, and ACSL4 contents, increased GSH levels, and ameliorated mitochondrial ultrastructural injury after LTx. In vitro, Sorafenib resulted in lower cell viability and worsened cell injury and enhanced the hallmarks of ferroptosis after H/R culture, which was rescued by MaR1 treatment. Mechanistically, the protein kinase A and YAP inhibitors partly blocked the effects of MaR1 on ferroptosis inhibition and LIRI protection. Conclusions: This study revealed that MaR1 alleviates LIRI and represses ischemia reperfusion-induced ferroptosis via the PKA-Hippo-YAP signaling pathway, which may offer a promising theoretical basis for the clinical application of organ protection after LTx. Full article

Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that severely impacts patients’ quality of life. Although current therapies have improved symptom management, they often fail to alter disease progression and are associated with immunosuppressive side effects. This study evaluated the immunomodulatory potential of resolvin D2 (RvD2), a pro-resolving lipid mediator, using a murine model of colitis and the ex vivo treatment of intestinal mucosal biopsies from CD patients, comparing its effects to those of conventional anti-TNFα therapy. To determine the optimal concentration of RvD2 for application in human tissue explant cultures, an initial in vitro assay was conducted using intestinal biopsies from mice with experimentally induced colitis. The explants were treated in vitro with varying concentrations of RvD2, and 0.1 μM emerged as an effective dose. This concentration significantly reduced the transcriptional levels of TNF-α (p = 0.004) and IL-6 (p = 0.026). Intestinal mucosal biopsies from fifteen patients with CD and seven control individuals were analyzed to validate RNA-sequencing data, which revealed dysregulation in the RvD2 biosynthetic and signaling pathways. The real-time PCR confirmed an increased expression of PLA2G7 (p = 0.02) and ALOX15 (p = 0.02), while the immunohistochemical analysis demonstrated the reduced expression of the RvD2 receptor GPR18 (p = 0.04) in intestinal tissues from CD patients. Subsequently, samples from eight patients with active Crohn’s disease, eight patients in remission, and six healthy controls were used for the serum analysis of RvD2 by ELISA, in vitro treatment of intestinal biopsies with RvD2 or anti-TNF, followed by transcriptional analysis, and a multiplex assay of the explant culture supernatants. The serum analysis demonstrated elevated RvD2 levels in CD patients both with active disease (p = 0.02) and in remission (p = 0.002) compared to healthy controls. The ex vivo treatment of intestinal biopsies with RvD2 decreased IL1β (p = 0.04) and TNFα (p = 0.02) transcriptional levels, comparable to anti-TNFα therapy. Additionally, multiplex cytokine profiling confirmed a reduction in pro-inflammatory cytokines, including IL-6 (p = 0.01), IL-21 (p = 0.04), and IL-22 (p = 0.009), in the supernatant of samples treated with RvD2. Altogether, these findings suggest that RvD2 promotes the resolution of inflammation in CD and supports its potential as a promising therapeutic strategy. Full article

Inflammation is a complicated physiological process that contributes to a variety of disorders including osteoarthritis (OA) and rheumatoid arthritis (RA). Endocannabinoids and the endocannabinoid system (ECS) play a pivotal role in the physiological response to pain and inflammation. A clinical study to investigate the role of the endocannabinoid system and related lipids in pain and inflammation in OA and RA was performed. In total, 80 subjects, namely, 25 patients with RA, 18 with OA, and 37 healthy participants, were included. Sixteen endocannabinoids and congeners, as well as 129 oxylipins, were quantified in plasma using specific, quantitative LC-MS/MS assays. The endocannabinoid analysis revealed significantly lower levels of 2-arachidonoylglycerol (2-AG) in RA and OA patients compared to healthy participants. In contrast, the EC levels of the ethanolamide group (anandamide, docosahexaenoyl-EA, palmitoleoyl-EA, and other ethanolamides) were higher in the RA study cohort and to a lesser extent also in the OA cohort. This analysis of oxylipins revealed lower levels of the pro-resolving lipid 9-oxo-octadecadienoic acid (9-oxoODE) and the ω-3 fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) in RA compared to all other study cohorts. 2-AG is a key regulator of nociception and inflammation, and its relatively low levels might be a mechanistic contributor to residual pain and inflammation in RA and OA. Several changes in pro- and anti-inflammatory lipid mediators were detected, including lower levels of EPA and DHA in RA, which might reveal the potential for nutritional supplementation with these anti-inflammatory fatty acids. Full article

Lipids play important roles in maintaining pulmonary structure, performing physiological functions and controlling the immune status of the lung. There is increasing evidence that lipid metabolism and immune activity are closely linked and that dysfunction in lipid metabolism contributes to the development and progression of chronic respiratory diseases such as COPD and asthma. These diseases are characterized by metabolic and immune dysregulation, with lipid mediators playing a key role in both the development and resolution of inflammation. In this regard, lipid metabolic pathways are attracting increasing attention as promising targets for biomarker detection and therapeutic intervention. 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

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. Full article

Background/Objectives: Constant inflammation can be a detrimental response in bone regeneration. To regulate of the inflammatory response and synchronically promote rapid tissue regeneration is a vital clinical challenge. The urinary bladder matrix (UBM) and small intestinal submucosa (SIS) composite are commonly used extracellular matrix (ECM) materials. We designed a novel drug-loaded membrane by integrating the biological matrix (BM) composed of UBM and SIS composites with Resolvin D1 (RvD1), an endogenous pro-resolving lipid mediator, using the lyophilization process. This membrane is referred to as BRL, an acronym for BM-RvD1-Lyophilization. Methods: In this study, the physicochemical properties of the membranes were characterized. Fluorescence staining and the CCK8 assay kit were utilized to assess biocompatibility. To evaluate the inflammatory resolution properties and osteogenic ability of osteoblasts, real-time quantitative PCR and ELISA were conducted. Results: BRL exhibited a more pronounced three-dimensional pore structure, demonstrating excellent physicochemical properties and enabling the slow release of RvD1. This approach improved the viability of MG63 osteoblast-like cells, reduced LPS-induced inflammation, and upregulated osteogenesis-related genes significantly. Conclusions: By integrating inflammation control capabilities into tissue regeneration materials, BRL effectively regulates the tissue regeneration microenvironment, thereby enhancing regeneration efficiency and positioning itself as an exceptional candidate for future tissue regeneration membranes. Full article

Periodontitis is a chronic inflammatory disease characterized by the destruction of tooth-supporting structures, influenced by immune system dysregulation, oxidative stress, and imbalances in bone metabolism. Given its multifactorial pathogenesis, bioactive compounds such as vitamin D, melatonin, and omega-3 fatty acids have emerged as potential adjuncts to periodontal therapy due to their immunomodulatory, anti-inflammatory, and antioxidative properties. This narrative review explores the role of these three supplements in periodontal health, their potential in synergistic effects, and existing research gaps, providing a foundation for future studies on their clinical applications. Vitamin D is essential for calcium homeostasis, bone remodeling, and immune function. It modulates both innate and adaptive immune responses, enhancing antimicrobial peptide production and reducing inflammatory cytokine expression. Omega-3 fatty acids reduce the production of pro-inflammatory eicosanoids while promoting the synthesis of pro-resolving lipid mediators, contributing to bone preservation and immune balance. Melatonin, known for its antioxidant and osteogenic properties, supports bone remodeling by stimulating osteoblast proliferation and inhibiting osteoclast activity, while also regulating circadian rhythms, which may influence oral health. Although these bioactive compounds show promising effects in preclinical and clinical studies, significant knowledge gaps remain regarding optimal dosages, long-term efficacy, combined use, and standardized treatment protocols. Further clinical trials are necessary to elucidate their therapeutic value in periodontal disease management, especially those focused on their potential synergistic mechanisms. Understanding their synergistic mechanisms may open new avenues for adjunctive strategies in periodontal therapy. 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

Background: Omega-3 polyunsaturated fatty acids (n-3 PUFA) have been used in the treatment of inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS), and their effects are potentiated upon conversion to specialized pro-resolving mediators (SPM). Recent studies indicated that the probiotic bacterial strain Bacillus megaterium DSM 32963 can be used to enhance the production of SPM and its precursors in vivo. Methods: Here, we explored the contribution of Bacillus megaterium DSM 32963 to SPM production in a validated, dynamic model of the upper and lower intestine. The TIM-1 and TIM-2 models were applied, with the TIM-2 model inoculated with the fecal microbiota of healthy individuals and probed with an n-3 PUFA lysine salt with and without Bacillus megaterium DSM 32963 or an SPM-enriched fish oil or placebo. Kinetics of SPM production were assessed by metabololipidomics analysis, and survival and engraftment of the Bacillus megaterium strain was monitored by plate counting and by strain-specific qPCR. Results: Bacillus megaterium DSM 32963 poorly survived TIM-1 conditions but propagated in the TIM-2 model, where it enabled the metabolism of n-3 PUFA to SPM (resolvin E2 and protectin DX) and SPM precursors (e.g., 5-hydroxyeicosapentaenoic acid (5-HEPE), 15-HEPE, 18-HEPE, 4-hydroxydocosahexaenoic acid (4-HDHA), 10-HDHA, and 17-HDHA, among other EPA- and DHA-derived metabolites) with significantly higher levels of lipid mediator production compared to the n-3 PUFA lysine salt alone; esterified n-3 PUFA were hardly converted by the microbiota. Conclusions: These findings reinforce that Bacillus megaterium DSM 32963 facilitates SPM production in situ from bioavailable n-3 PUFA in the large intestine, highlighting its use to complement eukaryotic SPM biosynthesis by the host and its possible therapeutic use for, e.g., IBD and IBS. Full article

Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) is a regulating agent in antioxidant response also involved in controlling inflammation. The impact of varicocele and urogenital infections on sperm PPARγ expression was studied. The PPARγ gene expression was investigated in spermatozoa of 26 normozoospermic men grouped according to their clinical conditions: normal semen parameters (N), normal semen parameters and varicocele (N + V), and normal semen parameters and urogenital infections (N + UI). Sperm PPARγ expression was correlated with F₂-isoprostanes (F₂-IsoPs), as markers of lipid peroxidation, and Resolvin D1 (RvD1), a pro-resolving mediator in inflammation. Sperm PPARγ expression was evaluated through comparative real-time PCR, and F₂-IsoPs and RvD1 were quantified in the seminal plasma via GC/NCI-MS/MS and immunoassay, respectively. PPARγ expression correlates positively with sperm morphology and vitality and negatively with F₂-IsoPs and RvD1. Sperm morphology positively correlates with vitality and negatively with F₂-IsoP and RvD1 levels. Despite the normozoospermia in the three examined groups, sperm morphology and PPARγ expression were significantly reduced in N + V and N + UI groups compared to the N group. Additionally, F₂-IsoP and RvD1 levels were elevated in N + V and N + UI patients. These data suggest that PPARγ expression is compromised by inflammation and lipoperoxidation, providing new insights to further explore new possibilities of targeted treatment of male infertility. Full article