Oxylipins are diverse bioactive signaling molecules, which occur in very low concentrations in complex matrices, posing challenges in achieving consistent and sensitive analysis. UHPLC-MS/MS is the preferred technique to separate and quantify these molecules, often optimized using a time-consuming trial-and-error approach. In this study, we applied the design of experiments (DoE) approach to systematically investigate the ionization properties of multiple oxylipin species. Fractional factorial and central composite designs were employed to detect relevant instrument parameters and optimize signal intensity in ESI-MS/MS analysis. Response surface modeling revealed distinct ionization and fragmentation behaviors between polar and apolar oxylipins, driven by their responses to interface temperature and collision-induced dissociation (CID) gas pressure. Particularly, prostaglandins and lipoxins benefit from higher CID gas pressure and lower temperatures compared to the lipophilic HODEs and HETEs to achieve optimal intensity in multiple reaction monitoring analysis. While global source parameters were optimized, analyte-specific entrance/exit potentials and collision energies required individual adjustments. The final method was applied to analyze seven oxylipin classes including leukotrienes, prostaglandins, lipoxins, resolvins, HETEs, HODES, and HoTrEs. Although improvements in lower limits of quantification were modest (< 1 pg on-column), signal-to-noise ratios increased two-fold for lipoxins and resolvins and three- to four-fold for leukotrienes and HETEs, enhancing detection at trace levels. This DoE-guided strategy provides a powerful tool to improve UHPLC-MS/MS analysis of oxylipins across various instrument vendors, guiding the way towards inter-laboratory comparability.

Previous studies have demonstrated the potent anti-inflammatory effects of RvE1 in various diseases, and recent research has shown that it can also promote macrophage phagocytosis. Given that hematoma clearance is crucial for intracerebral hemorrhage (ICH) treatment, while neuroinflammation significantly influences secondary injury, we hypothesize that RvE1/ChemR23 activation, by modulating the polarization of macrophages/microglia, promotes hematoma resolution and alleviates neuroinflammatory responses after ICH.

A total of 125 WT C57BL/6 and 67 ChemR23-/- male mice were used. Western blot and immunofluorescence staining assessed the temporal and spatial expression of ChemR23 after ICH. T2WI, T2*WI and behavioral tests were obtained to assess the protective effect of the RvE1/ChemR23 pathway in ICH. Additionally, co-staining of M1 (iNOS) or M2 polarization (Arg-1) markers with Iba-1 was used to explore the polarization status of macrophages/microglia in the perihematomal region. Finally, Akt phosphorylation was validated as a downstream mediator of the RvE1/ChemR23 pathway using an Akt inhibitor.

ChemR23 is mainly expressed in activated microglia and infiltrating macrophages, with expression peaking 5-7 days post-ICH. Activation of the RvE1/ChemR23 pathway promotes hematoma resolution, reduces brain edema, and improves neurological deficits in ICH. These effects are likely mediated by promoting M2 polarization of macrophages/microglia after ICH. Furthermore, the use of an Akt inhibitor can counteract the protective effects of RvE1 in ICH.

Our study provides the first evidence of the protective role of RvE1/ChemR23 signaling in ICH. This pathway might offer novel therapeutic targets for the clinical management of ICH.

Sarcopenia is defined by a reduction in both muscle strength and mass. Sarcopenia may be an inevitable component of the aging process, but it may also be accelerated by comorbidities and metabolic derangements. The underlying mechanisms contributing to these pathological changes remain poorly understood. We propose that chronic inflammation-mediated networks and metabolic defects that exacerbate muscle dysfunction are critical factors in sarcopenia and related diseases. Consequently, utilizing specialized pro-resolving mediators (SPMs) that function through specific G-protein coupled receptors (GPCRs) may offer effective therapeutic options for these disorders. However, challenges such as a limited understanding of SPM/receptor signaling pathways, rapid inactivation of SPMs, and the complexities of SPM synthesis impede their practical application. In this context, stable small-molecule SPM mimetics and receptor agonists present promising alternatives. Moreover, the aged adipose-skeletal axis may contribute to this process. Activating non-SPM GPCRs on adipocytes, immune cells, and muscle cells under conditions of systemic, chronic, low-grade inflammation (SCLGI) could help alleviate inflammation and metabolic dysfunction. Recent preclinical studies indicate that both SPM GPCRs and non-SPM GPCRs can mitigate symptoms of aging-related diseases such as obesity and diabetes, which are driven by chronic inflammation and metabolic disturbances. These findings suggest that targeting these receptors could provide a novel strategy for addressing various chronic inflammatory conditions, including sarcopenia.

Oxidative stress and chronic inflammation are important drivers in the pathogenesis and progression of many chronic diseases, such as cancers of the breast, kidney, lung, and others, autoimmune diseases (rheumatoid arthritis), cardiovascular diseases (hypertension, atherosclerosis, arrhythmia), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), mental disorders (depression, schizophrenia, bipolar disorder), gastrointestinal disorders (inflammatory bowel disease, colorectal cancer), and other disorders. With the increasing demand for less toxic and more tolerable therapies, flavonoids have the potential to effectively modulate the responsiveness to conventional therapy and radiotherapy. Flavonoids are polyphenolic compounds found in fruits, vegetables, grains, and plant-derived beverages. Six of the twelve structurally different flavonoid subgroups are of dietary significance and include anthocyanidins (e.g. pelargonidin, cyanidin), flavan-3-ols (e.g. epicatechin, epigallocatechin), flavonols (e.g. quercetin, kaempferol), flavones (e.g. luteolin, baicalein), flavanones (e.g. hesperetin, naringenin), and isoflavones (daidzein, genistein). The health benefits of flavonoids are related to their structural characteristics, such as the number and position of hydroxyl groups and the presence of C2=C3 double bonds, which predetermine their ability to chelate metal ions, terminate ROS (e.g. hydroxyl radicals formed by the Fenton reaction), and interact with biological targets to trigger a biological response. Based on these structural characteristics, flavonoids can exert both antioxidant or prooxidant properties, modulate the activity of ROS-scavenging enzymes and the expression and activation of proinflammatory cytokines (e.g., interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)), induce apoptosis and autophagy, and target key signaling pathways, such as the nuclear factor erythroid 2-related factor 2 (Nrf2) and Bcl-2 family of proteins. This review aims to briefly discuss the mutually interconnected aspects of oxidative and inflammatory mechanisms, such as lipid peroxidation, protein oxidation, DNA damage, and the mechanism and resolution of inflammation. The major part of this article discusses the role of flavonoids in alleviating oxidative stress and inflammation, two common components of many human diseases. The results of epidemiological studies on flavonoids are also presented.

Uncontrolled hyperactivation of the immune system is the central mechanism underlying the pathogenesis of autoimmune diseases. Timely control of the inflammatory response is essential to prevent inflammation progression and organ damage. Specialized pro-resolving lipid mediators (SPMs) are autacoid molecules derived from essential polyunsaturated fatty acids during acute inflammatory responses. They promote the resolution of inflammation and orchestrate endogenous reparative responses. The SPM superfamily includes lipoxins, resolvins, protectins, and maresins, as well as novel conjugates involved in tissue regeneration. Much work has been done focusing on the actions of SPMs in autoimmunity and has identified their deficiencies and therapeutic effects in autoimmune diseases. In this review, we provide a brief introduction of SPMs, summarize their effects on key cells involved in innate and adaptive immunity, and highlight their role and therapeutic potential in autoimmune diseases.

Traumatic brain injury (TBI) leads to major membrane lipid breakdown. We investigated plasma lipids over 3 days post-TBI, to identify a signature of acute human TBI and assess its correlation with neuronal injury and inflammation. Plasma from patients with TBI (Abbreviated Injury Scale (AIS)3 - serious injury, n = 5; AIS4 - severe injury, n = 8), and controls (n = 13) was analysed for lipidomic profile, neurofilament light (NFL) and cytokines, and the omega-3 index was measured in red blood cells. A lipid signature separated TBI from controls, at 24 and 72 h. Major species driving the separation were: lysophosphatidylcholine (LPC), phosphatidylcholine (PC) and hexosylceramide (HexCer). Docosahexaenoic acid (DHA, 22:6) and LPC (0:0/22:6) decreased post-injury. NFL levels were increased at 24 and 72 h post-injury in AIS4 TBI vs. controls. Interleukin (IL-)6, IL-2 and IL-13 were elevated at 24 h in AIS4 patients vs. controls. NFL and IL-6 were negatively correlated with several lipids. The omega-3 index at admission was low in all patients (controls: 4.3 ± 1.1% and TBI: 4.0 ± 1.1%) and did not change significantly over 3 days post-injury. We have identified specific lipid changes, correlated with markers of injury and inflammation in acute TBI. These observations could inform future lipid-based therapeutic approaches.

We test whether the specialized pro-resolving molecule Maresin 1 (MaR1) attenuates nociceptive behaviors in mice with osteoarthritis-like pain.

Osteoarthritis (OA)-like pain behavior was induced by intra-articular injection of monosodium iodoacetate (MIA) and treated with MaR1 (N=6) or vehicle (N=5) by intraperitoneal injection 8 weeks after injury. Mice without MIA injection were used as control (N=6). Nociceptive behaviors were examined by von Frey and dynamic weight bearing measurements. Calcitonin gene-related peptide (CGRP) expression and activated macrophages in the dorsal root ganglion (DRG) were examined by immunofluorescence staining. The inflammatory profile in circulation was assessed by cytokine array. Calcium imaging was performed to assess the in vitro functional response of DRG neurons from animals with OA-like pain behavior to MaR1 with or without RAR Related Orphan Receptor A (RORA) inverse agonist SR3335.

MaR1 attenuated knee pain behavior in treated mice (N=6) compared to non-treated mice (N=5) as shown by increased paw withdrawal threshold with a mean difference of 112.2% (95% CI [49.79, 174.6], p=0.0784) at 4 h and 150.9% (95% CI [104.2, 197.5], p=0.0001) at 4 days post-MaR1 treatment, and increased weight bearing with a mean difference of 20.08% (95% CI [2.798, 37.37], p=0.0277) at 1 day post-MaR1 treatment. CGRP expression and activated macrophages were decreased in the DRG, and inflammatory cytokine levels in the circulation were attenuated. Calcium imaging showed MaR1 reduced the functional response of DRG neurons through RORA.

Our results show that MaR1 reduces OA-like pain behavior in mice and could be a potential treatment for OA pain.

The global rise in diabetes prevalence has significantly contributed to the increasing burden of atherosclerotic cardiovascular disease (ASCVD), a leading cause of morbidity and mortality in this population. Diabetes accelerates atherosclerosis through mechanisms such as hyperglycemia, oxidative stress, chronic inflammation, and epigenetic dysregulation, leading to unstable plaques and an elevated risk of cardiovascular events. Despite advancements in controlling traditional risk factors like dyslipidemia and hypertension, a considerable residual cardiovascular risk persists, highlighting the need for innovative therapeutic approaches. Emerging treatments, including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, epigenetic modulators, and RNA-based therapies, are showing promise in addressing the unique challenges of diabetes-associated ASCVD. Precision medicine strategies, such as nanoparticle-based drug delivery and cell-specific therapies, offer further potential for mitigating cardiovascular complications. Advances in multiomics and systems biology continue to deepen our understanding of the molecular mechanisms driving diabetes-associated atherosclerosis. This review synthesizes recent advances in understanding the pathophysiology and treatment of diabetes-related atherosclerosis, offering a roadmap for future research and precision medicine approaches to mitigate cardiovascular risk in this growing population.

Inflammatory bowel disease (IBD) is a multifactorial disease, and patients frequently experience extraintestinal manifestations affecting multiple sites. Causes of systemic inflammation remain poorly understood, but molecules originating from the intestine likely play a role, with microbial and host small molecules polarizing host immune cells towards a pro- or anti-inflammatory phenotype. Using the dextran sodium sulfate (DSS) mouse model, which mimics the disrupted barrier function, microbial dysbiosis, and immune cell dysregulation of IBD, we investigated metabolomic and phenotypic changes at intestinal and systemic sites. Using spatial biology approaches, we mapped the distribution and relative abundance of molecules and cell types across a range of tissues, revealing significant changes in DSS-treated mice. Molecules identified as contributing to the statistical separation of treated from control mice were spatially localized within organs to determine their effects on cellular phenotypes through imaging mass cytometry. This spatial approach identified both intestinal and systemic molecular drivers of inflammation, including several not previously implicated in inflammation linked to IBD or the systemic effects of intestinal inflammation. Metabolic and inflammatory pathway interplay underpins systemic disease, and determining drivers at the molecular level may aid the development of new targeted therapies.

Blood vessels supply oxygen, nutrients and provide gateways for immune surveillance. Since this network nourishes all tissues, vessel abnormalities contribute to many diseases, such as cancer. One of the potential targets for Docosahexaenoic Acid (DHA) in cancer is suppressing angiogenesis, a process of new blood vessel formation within tumors. In addition, aspirin (ASA) has antineoplastic effects that may be mediated, at least in part, by metabolites derived from acetylated COX-2. We aimed at determining the effect of DHA as well as its metabolites in angiogenesis, using in vitro as well as in vivo models.

Endothelial cell (EC) proliferation, motility and capillary-like tube formation were determined by MTT, wound healing, Boyden and Matrigel assays, respectively. In vivo angiogenesis was measured by the Matrigel sponge model in mice. The biosynthesis of proresolving lipid mediators by ECs was determined by LC-MS-MS.

DHA, but not arachidonic acid (AA), at concentrations consistent with those reached in blood after fish oil supplementation, decreased EC migration in a time- and concentration-dependent manner. Pretreatment with ASA modulated cell migration already after 24 h, while both DHA and ASA decreased migration at longer incubation times without affecting viability. 17-hydroxy-DHA was detected upon incubation with DHA, and increased amounts were observed upon combined treatment with DHA and ASA, an increase that was associated to a synergic effect on EC migration. 17(R)-hydroxy-DHA (17R-HDHA), the metabolite resulting from acetylated COX-2 activity of DHA, reduced EC migration in a concentration-dependent manner. DHA in the presence of ASA, as well as 17R-HDHA, also reduced EC tube formation. These results were confirmed in vivo where both 17R-HDHA or its downstream metabolite 17RResolvinD1 were able to decrease microvessels density in a Matrigel sponge model. Overall, we demonstrated that DHA in the presence of ASA-dependent acetylation of COX-2 showed increased antiangiogenic effects, possibly resulting from its conversion to its hydroxylated derivatives.

Normothermic ex situ heart perfusion (ESHP) has emerged as a valid modality for advanced cardiac allograft preservation and conditioning prior to transplantation though myocardial function declines gradually during ESHP thus limiting its potential for expanding the donor pool. Recently, the utilization of dialysis has been shown to preserve myocardial and coronary vasomotor function. Herein, we sought to determine the changes in myocardial metabolism that could support this improvement.

Male Yorkshire porcine hearts were subjected to ESHP for 8 h with or without dialysis. Alterations in metabolism were studied with an innovative in vivo solid-phase microextraction (SPME) technology coupled with global metabolite profiling at 15 min, 1.5, 4, and 8 h of perfusion. Bio-SPME sampling was performed by inserting SPME fibres coated with a PAN-based extraction phase containing mixed-mode (C8+benzenesulfonic acid) functionalities into the myocardium to a depth of their entire 8 mm coating or immersing them in the perfusate, followed by a 20-min extraction period for the analytes of interest. Dialyzed hearts demonstrated improved bioenergetics as evidenced by accelerated purine metabolism and less pronounced accumulation of intermediates of fatty acid β/ω-oxidation. Metabolic waste accumulation such as pro-inflammatory lipid mediators (e.g., leukotrienes) was mitigated thereby supporting the process of resolution of inflammation through excretion of specialized pro-resolving mediators (resolvins D1/D2, E2, protecin D1).

Through implementing the unique analytical pipeline we demonstrated that the addition of dialysis may preserve cardiac metabolism allowing for prolonged ESHP. This strategy has the potential to facilitate high-risk donor organs' reconditioning prior to transplantation.

Our goal was to probe the potential transcriptomic basis for the relationship between plasma levels of the specialized pro-resolving precursor, 17-hydroxy-docosahexaenoic acid (17-HDHA) and chronic pain. Participants with osteoarthritis (average age of 62.3, 60% were female, n = 30) were stratified by levels of 17-HDHA and self-reported pain scores. RNAs from CD14++/CD16-/CD66b-/HLA-DR+ (classical) monocytes were sequenced and differentially expressed mRNAs were identified with DESeq2. QIAGEN ingenuity pathway analysis identified the top ranked canonical biological pathway to be eukaryotic initiation factor 2 (EIF2) signaling (lower activation level in the low 17-HDHA-high pain group compared to the high 17-HDHA-low pain group (Z score -3)), followed by EIF4 and P70S6K signaling pathways and mTOR signaling. Our approach provides insight into the biological pathways contributing to the association between 17-HDHA and chronic osteoarthritis (OA) pain, identifying EIF2 signaling, with known roles in osteoclast differentiation, OA pathology, and pain, as a potential downstream target.

Occupational exposure to engineered nanomaterials (ENMs) is increasing in the workplace and can impact human health. Amorphous silicon dioxide nanoparticles (SiO2 NPs) are widely produced respirable ENMs used in commercial products. We have investigated their impact on lung inflammation resolution and bacterial defense. Mice exposed to SiO2 NPs, followed by bacteria, exhibited increased lung inflammation, bacterial proliferation, and lung damage compared to mice not exposed to NPs. SiO2 NPs increased human macrophage production of pro-inflammatory mediators and disrupted phagocytosis of bacteria and efferocytosis of apoptotic neutrophils - pivotal responses for host defense and inflammation resolution. A pro-resolving mediator, resolvin D5 (RvD5), restored macrophage phagocytosis of bacteria and partially controlled excess lung inflammation after SiO2 NPs. These findings demonstrate that SiO2 NPs disrupt endogenous resolution processes to give rise to heightened lung inflammation and infection. RvD5 reduced inflammation and partially restored endogenous resolution cellular processes, suggesting that RvD5 can reduce ENP disruption of resolution.

The arachidonic acid (AA) pathway promotes tumor progression by modulating the complex interactions between cancer and immune cells within the microenvironment. In this Review, we summarize the knowledge acquired thus far concerning the intricate mechanisms through which eicosanoids either promote or suppress the antitumor immune response. In addition, we will discuss the impact of eicosanoids on immune cells and how they affect responsiveness to immunotherapy, as well as potential strategies for manipulating the AA pathway to improve anticancer immunotherapy. Understanding the molecular pathways and mechanisms underlying the role played by AA and its metabolites in tumor progression may contribute to the development of more effective anticancer immunotherapies.

Celiac disease (CD) is a chronic autoimmune disorder driven by both genetic and environmental factors, with the HLA DQ2/DQ8 genotypes playing a central role in its development. Despite the genetic predisposition, only a small percentage of individuals carrying these genotypes develop the disease. Gluten, a protein found in wheat, rye, and barley, is the primary environmental trigger, but other factors, such as the intestinal microbiota, may also contribute to disease progression. While the gluten-free diet (GFD) remains the cornerstone of treatment, many CD patients experience persistent inflammation and gut dysbiosis, leading to ongoing symptoms and complications. This chronic inflammation, which impairs nutrient absorption, increases the risk of malnutrition, anemia, and other autoimmune disorders. Recent studies have identified an altered gut microbiota in CD patients, both on and off the GFD, highlighting the potential role of the microbiota in disease pathogenesis. An emerging area of interest is the supplementation of n-3 polyunsaturated fatty acids (PUFAs), known for their anti-inflammatory properties, as a potential therapeutic strategy. n-3 PUFAs, found in fish oil and certain plant oils, modulate the immune cell function and cytokine production, making them a promising intervention for controlling chronic inflammation in CD. This review explores the current understanding of n-3 PUFAs' effects on the gut microbiota's composition and inflammation in CD, with the goal of identifying new avenues for complementary treatments to improve disease management.

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.

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.

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.

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.

It is increasingly appreciated that the expression of immunoregulatory molecules within tumors have potential to shape a microenvironment that promotes local immunoevasion and immunoregulation. However, little is known about tissue-intrinsic immunomodulatory mechanisms following transplantation. We propose that differences in the phenotype of microvascular endothelial cells impact the alloantigenicity of the graft and its potential to promote immunoregulation following transplantation. We focus this review on the concept that graft-dependent immunoregulation may evolve post-transplantation, and that it is dependent on the phenotype of select subsets of intragraft endothelial cells. We also discuss evidence that long-term graft survival is critically dependent on adaptive interactions among immune cells and endothelial cells within the transplanted tissue microenvironment.

Wound healing is a complex and iterative process involving myriad cellular and biologic processes that are highly regulated to allow satisfactory repair and regeneration of damaged tissues. This review is intended to be an introductory chapter in a volume focusing on the use of platelet concentrates for tissue regeneration. In order to fully appreciate the clinical utility of these preparations, a sound understanding of the processes and factors involved in soft and hard tissue healing. This encompasses an appreciation of the cellular and biological mediators of both soft and hard tissues in general as well as specific consideration of the periodontal tissues. In light of good advances in this basic knowledge, there have been improvements in clinical strategies and therapeutic management of wound repair and regeneration. The use of platelet concentrates for tissue regeneration offers one such strategy and is based on the principles of cellular and biologic principles of wound repair discussed in this review.

A proposed contributor to Alzheimer's disease (AD) pathology is the induction of neuroinflammation due to tau and beta-amyloid protein accumulation causing neuronal injury and dysfunction. Dysregulation of lipid mediators derived from polyunsaturated fatty acids may contribute to this inflammatory response in the brain of patients with AD, yet the literature has not yet been systematically reviewed. A systematic search was conducted in Medline, Embase and PsychINFO for articles published up to April 22, 2024. Papers were included if they measured levels of lipid mediators and/or enzymes involved in their production in post-mortem brain samples from patients with AD and control without neurological disease. A total of 50 relevant studies were identified. Despite heterogeneity in the results, pro-inflammatory lipid mediators, including 5-, 11-, 12- and 15-hydroxyeicosatetraenoic acid oxylipins and prostaglandin D2, were significantly higher, while anti-inflammatory lipoxin A4 and DHA-derived docosanoids were significantly lower in brains of patients with AD compared to control (16 studies). Thirty-seven articles reported on enzymes, with 32 reporting values for enzyme level changes between AD and controls. Among the 32 articles, the majority reported on levels of cyclooxygenase (COX) (18/32), with fewer studies reporting on phospholipase (8/32), lipoxygenase (LOX) (4/32) and prostaglandin E synthase (4/32). Enzyme levels also exhibited variability in the literature, with a trend towards elevated expression of enzymes involved in the pro-inflammatory response, including COX and LOX enzymes. Overall, these results are consistent with the involvement of neuroinflammation in the pathogenesis of AD measured by lipid mediators. However, the specific contribution of each lipid metabolite and enzymes to either the progression or persistence of AD remains unclear, and more research is required.

Ambient concentrations of the air pollutant, ozone, are rising with increasing global temperatures. Ozone is known to increase incidence and exacerbation of chronic lung diseases, which will increase as ambient ozone levels rise. Studies have identified diet as a variable that is able to modulate the pulmonary health effects associated with ozone exposure. Eicosapentaenoic acid (EPA) is an n-3 (ω-3) PUFA consumed through diet, which lowers inflammation through conversion to oxylipins including hydroxy-eicosapentaenoic acids (HEPEs). However, the role of dietary EPA in ozone-induced pulmonary inflammation is unknown.

Therefore, we hypothesized increasing dietary EPA will decrease ozone-induced pulmonary inflammation and injury through the production of HEPEs.

To test this, male C57BL/6J mice were fed a purified control diet or EPA-supplemented diet for 4 wk and then exposed to filtered air or 1 part per million ozone for 3 h. 24 or 48 h after exposure, bronchoalveolar lavage fluid was collected to assess airspace inflammation/injury and lung tissue was collected for targeted liquid chromatography-mass spectrometry lipidomics.

Following ozone exposure, EPA supplementation did not alter markers of lung injury but decreased ozone-induced airspace neutrophilia. Targeted liquid chromatography-mass spectrometry lipidomics revealed dietary EPA supplementation increased pulmonary EPA-derived metabolites including 5-HEPE and 12-HEPE. Additionally, EPA supplementation decreased pulmonary amounts of proinflammatory arachidonic acid-derived metabolites. To evaluate whether dietary EPA reduces ozone-induced pulmonary inflammation through increased pulmonary HEPEs, C57BL/6J mice were administered 5-HEPEs and 12-HEPEs systemically before filtered air or ozone exposure. Pretreatment with 5-HEPEs and 12-HEPEs reduced ozone-driven increases in airspace macrophages.

Together, these data indicate that an EPA-supplemented diet protects against ozone-induced airspace inflammation which is, in part, due to increasing pulmonary amounts of 5-HEPEs and 12-HEPEs. These findings suggest that dietary EPA and/or increasing EPA-derived metabolites in the lung can reduce ozone-driven incidences and exacerbations of chronic pulmonary diseases.

Lung inflammation, infection, and injury can lead to critical illness and death. The current means to pharmacologically treat excessive uncontrolled lung inflammation needs improvement because many treatments are or will become immunosuppressive. The inflammatory response evolved to protect the host from microbes, injury, and environmental insults. This response brings phagocytes from the bloodstream to the tissue site to phagocytize and neutralize bacterial invaders and enables airway antimicrobial functions. This physiologic response is ideally self-limited with initiation and resolution phases. Polyunsaturated essential fatty acids are precursors to potent molecules that govern both phases. In the initiation phase, arachidonic acid is converted to prostaglandins and leukotrienes that activate leukocytes to transmigrate from postcapillary venules. The omega-3 fatty acids (e.g., DHA and EPA) are precursors to resolvins, protectins, and maresins, which are families of chemically distinct mediators with potent functions in resolution of acute and chronic inflammation in the respiratory system.

This study aimed to investigate the innate immune response of human macrophages to Porphyromonas gingivalis W83 using a novel in vitro infection model. The growth kinetics of P. gingivalis W83 were analyzed, revealing an exponential growth phase at 8 h (optical density = 0.70). To establish a reliable macrophage model, the differentiation of THP-1 monocytes into macrophages was optimized using low concentrations of phorbol 12-myristate 13-acetate (PMA). This approach induced enhanced adherence and morphological changes, with full differentiation achieved after 48 h of PMA treatment followed by 24 h of rest. Polarization towards the pro-inflammatory M1 phenotype was successfully induced with interferon-γ (IFN-γ) and lipopolysaccharide (LPS), as confirmed using cytokine profiling. Cytokine analysis using Luminex® technology demonstrated significant increases in interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and IL-6, indicating the effective activation of macrophages towards a pro-inflammatory phenotype. Building upon this macrophage model, this study investigated the interactions between macrophages and P. gingivalis W83 during its exponential growth phase. After a one-hour infection period, bacterial DNA quantification in supernatants and lysed macrophages revealed minimal levels of internalized or adherent bacteria, supporting the hypothesis that P. gingivalis effectively evades immune detection. These findings emphasize the utility of this model in uncovering the sophisticated immune evasion strategies employed by P. gingivalis, with significant implications for the development of targeted therapeutic interventions.

Lipids form energy storage depots, cellular barriers and signaling molecules. They are generated and metabolized by enzymes under the influence of biotic and abiotic factors, and some-the long-chain polyunsaturated ω3 and ω6 fatty acids and cholesterol-are essential for optimal health in marine organisms. In addition, lipids have direct and indirect roles in the control of buoyancy in marine fauna ranging from copepods to whales. Phytoplankton account for about half of the planet's carbon fixation, and about half of that carbon goes into lipids. Lipids are an important component of the ocean's ability to sequester carbon away from the atmosphere through sinking and especially after transfer to zooplankton. Phytoplankton are the main suppliers of ω3 polyunsaturated fatty acids (PUFAs) in the marine environment. They also supply cholesterol and many phytosterols to ocean ecosystems; however, genomics is indicating that members of the Cnidaria, Rotifera, Annelida, and Mollusca phyla also have the endogenous capacity for the de novo synthesis of ω3 PUFAs as well as phytosterols. It has been predicted that ω3 long-chain PUFAs will decrease in marine organisms with climate change, with implications for human consumption and for carbon sequestration; however, the responses of ω3 PUFA supply to future conditions are likely to be quite diverse.

Neuroinflammation impacts on the progression of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. Specialized pro-resolving mediators trigger the resolution of inflammation. We investigate the specialized pro-resolving mediator blood profile and their receptors' expression in peripheral blood mononuclear cells in relation to survival in ALS. People living with ALS (pwALS) were stratified based on bulbar versus limb onset and on key progression metrics using a latent class model, to separate faster progressing from slower progressing ALS. Specialized pro-resolving mediator blood concentrations were measured at baseline and in one additional visit in 20 pwALS and 10 non-neurological controls (Cohort 1). Flow cytometry was used to study the GPR32 and GPR18 resolvin receptors' expression in peripheral blood mononuclear cells from 40 pwALS and 20 non-neurological controls (Cohort 2) at baseline and in two additional visits in 17 pwALS. Survival analysis was performed using Cox proportional hazards models, including known clinical predictors and GPR32 and GPR18 mononuclear cell expression. Differential expression and linear discriminant analyses showed that plasma resolvins were able to distinguish phenotypic variants of ALS from non-neurological controls. RvE3 was elevated in blood from pwALS, whilst RvD1, RvE3, RvT4 and RvD1n-3 DPA were upregulated in A-S and RvD2 in A-F. Compared to non-neurological controls, GPR32 was upregulated in monocytes expressing the active inflammation-suppressing CD11b+ integrin from fast-progressing pwALS, including those with bulbar onset disease (P < 0.0024), whilst GPR32 and GPR18 were downregulated in most B and T cell subtypes. Only GPR18 was upregulated in naïve double positive Tregs, memory cytotoxic Tregs, senescent late memory B cells and late senescent CD8+ T cells from pwALS compared to non-neurological controls (P < 0.0431). Higher GPR32 and GPR18 median expression in blood mononuclear cells was associated with longer survival, with GPR32 expression in classical monocytes (hazard ratio: 0.11, P = 0.003) and unswitched memory B cells (hazard ratio: 0.44, P = 0.008) showing the most significant association, along with known clinical predictors. Low levels of resolvins and downregulation of their membrane receptors in blood mononuclear cells are linked to a faster progression of ALS. Higher mononuclear cell expression of resolvin receptors is a predictor of longer survival. These findings suggest a lipid-mediated neuroprotective response that could be harnessed to develop novel therapeutic strategies and biomarkers for ALS.

Acute myocardial infarction (AMI) causes ischemic damage and cardiac remodeling that ultimately progresses into ischemic cardiomyopathy (ICM). Coronary revascularization reduces morbidity and mortality from an MI, however, reperfusion also induces oxidative stress that drives cardiac myocyte (CM) dysfunction and ICM. Oxidative stress in CMs leads to reactive oxygen species (ROS) production and mitochondrial damage. Free fatty acid receptor 4 (Ffar4) is a GPCR for long chain fatty acids (FA) that is expressed in multiple cell types including CMs. We have recently shown that CM-specific overexpression of Ffar4 protects the heart from systolic dysfunction in the context of ischemic injury. Mechanistically, in CMs, Ffar4 increases the levels of 18-hydroxyeicosapentaenoic acid (18-HEPE), an eicosapentaenoic acid (EPA)-derived, cardioprotective oxylipin (oxidatively modified FA). 18-HEPE is the precursor for resolvin E1 (RvE1), a cardioprotective, specialized pro-resolving mediator (SPM) that activates the GPCR ChemR23. We hypothesize Ffar4 in CMs protects the heart from oxidative stress and ischemic injury through activation of a CM-autonomous, Ffar4-ChemR23 cardioprotective signaling pathway. Here, we developed an in vitro hypoxia reoxygenation (H/R) model (3 hours of hypoxia, 17 hours of reoxygenation) in adult CMs as a model for ischemic injury. In adult CMs subjected to H/R, TUG-891, an Ffar4 agonist, attenuated ROS generation and TUG-891, 18-HEPE, and RvE1 protected CMs from H/R-induced cell death. More importantly, we found that the ChemR23 antagonist α-NETA prevented TUG-891 cytoprotection in adult CMs subjected to H/R, demonstrating that ChemR23 is required for Ffar4 cardioprotection. In summary, our data demonstrate co-expression of Ffar4 and ChemR23 in the same CM, that Ffar4, 18-HEPE, and RvE1 attenuate H/R-induced CM death, and that ChemR23 is required for Ffar4 cardioprotection in H/R support a CM-autonomous Ffar4-ChemR23 cardioprotective signaling pathway.

So far, it has been proven that benign prostatic hyperplasia (BPH) is strongly associated with inflammation resulting from, i.a. the presence of infectious agent, autoimmune disease, aging process and lipid disorders associated with metabolic syndrome (MetS). We analyzed the association between serum eicosanoides (HETE, HODE, lipoxins, prostaglandin, and leucotrien) in aging man with benign prostatic hyperplasia (BPH) and healthy controls. The study involved 219 men (with BPH, n = 144; healthy controls, n = 75). We assessed the content arachidonic and linoleic acid derivatives in the serum samples of the study participants using liquid chromatography (HPLC). The levels of: RvE1 (p < 0.001); LXA4 5S,6R,15R (p = 0.001); 10S,17R-DiDHA (p < 0.001); MaR1 (p = 0.002); 9S-HODE (p < 0.05); 15S-HETE (p < 0.05); 12S-HETE (p < 0.001); 5-oxoETE (p < 0.05) and 5-HETE (p < 0.001) were significantly higher in patients with BPH than in the control group. PGE2 (p = 0.007), LTB4 (p < 0.001), and 18RS-HEPE (p < 0.001) were significantly higher in control group. We also analyzed the relationship between LXA4 5S,6R,15R serum levels of oxidative stress markers and concomitance of MetS. We noticed a relationship between levels and MetS (F1216 = 6.114965, p = 0.01). Our research results suggest that pro-inflammatory mediators and suppressors of inflammation are involved in the development of BPH, but their exact contribution has yet to be investigated.

The immune system plays a pivotal role in maintaining physiological homeostasis and influencing disease processes. Dysregulated immune responses drive chronic inflammation, which in turn results in a range of diseases that are among the leading causes of death globally. Traditional immune interventions, which aim to regulate either insufficient or excessive inflammation, frequently entail lifelong comorbidities and the risk of severe side effects. In this context, intrinsic immunomodulatory hydrogels, designed to precisely control the local immune microenvironment, have recently attracted increasing attention. In particular, these advanced hydrogels not only function as delivery mechanisms but also actively engage in immune modulation, optimizing interactions with the immune system for enhanced tissue repair, thereby providing a sophisticated strategy for managing chronic inflammation. In this tutorial review, we outline key elements of chronic inflammation and subsequently explore the strategic design principles of intrinsic immunomodulatory hydrogels based on these elements. Finally, we examine the challenges and prospects of such immunomodulatory hydrogels, which are expected to inspire further preclinical research and clinical translation in addressing chronic inflammation.

This review summarizes findings presented at the 19th World Congress of Basic & Clinical Pharmacology 2023 (Glasgow, Scotland, July 3rd to 7th, 2023) from 8 speakers in the field of resolution of inflammation, resolution pharmacology and resolution biology. It is now accepted that the acute inflammatory response is protective to defend the host against infection or tissue injury. Acute inflammation is self-limited and programmed to be limited in space and time: this is achieved through endogenous resolution processes that ensure return to homeostasis. Resolution is brought about by agonist mediators that include specialized pro-resolving lipid mediators (SPMs) and pro-resolving proteins and peptides such as annexin A1 and angiotensin-(1-7), all acting to initiate anti-inflammatory and pro-resolving processes. If the inflammatory reaction remains unchecked through dysfunctional resolution mechanism, it can become chronic and contribute to a plethora of human diseases, including respiratory, cardiovascular, metabolic, allergic diseases, and arthritis. Herein, we discuss how non-resolving inflammation plays a role in the pathogenesis of these diseases. In addition to SPMs, we highlight the discovery, biosynthesis, biofunctions, and latest research updates on innovative therapeutics (including annexin-A1 peptide-mimetic RTP-026, small molecule FPR2 agonist BM-986235/LAR-1219, biased agonist for FPR1/FPR2 Cmpd17b, lipoxin mimetics AT-01-KG and AT-02-CT, melanocortin receptor agonist AP1189, gold nanoparticles, angiotensin-(1-7), and CD300a) that can promote resolution of inflammation directly or through modulation of SPMs production. Drug development strategies based on the biology of the resolution of inflammation can offer novel therapeutic means and/or add-on therapies for the treatment of chronic diseases.

Octadecanoids are a subset of oxylipins derived from 18-carbon fatty acids. These compounds have historically been understudied but have more recently attracted attention to their purported biological activity. One obstacle to the study of octadecanoids has been a lack of specific analytical methods for their measurement. A particular limitation has been the need for chiral-based methods that enable separation and quantification of individual stereoisomers. The use of chirality provides an additional dimension for distinguishing analytes produced enzymatically from those formed through autoxidation. In this chapter, we describe a comprehensive method using chiral supercritical fluid chromatography-tandem mass spectrometry (SFC-MS/MS) for the quantification of octadecanoids in human plasma. This method stands as an effective approach for quantifying octadecanoids and is applicable to diverse research applications including clinical research.

Acute respiratory distress syndrome (ARDS) is a pulmonary inflammatory process primarily caused by sepsis. The resolution of inflammation is an active process involving the endogenous biosynthesis of specialized pro-resolving mediators, including resolvin D1 (RvD1). Resident alveolar macrophages (RAMs) maintain pulmonary homeostasis and play a key role in the resolution phase. However, the role of RAMs in promoting the resolution of inflammation by RvD1 is unclear.

Here, we investigated the mechanisms of RvD1 on regulating RAMs to promote the resolution of ARDS.

Mice were administered lipopolysaccharide and/or Escherichia coli via aerosol inhalation to establish a self-limited ARDS model. Then, RvD1 was administered at the peak inflammatory response. RAMs self-renewal was measured by flow cytometry, RAM phagocytosis was measured by two-photon fluorescence imaging. In addition, plasma was collected from intensive care unit patients on days 0-2, 3-5, and 6-9 to measure RvD1 and S100A8/A9 levels using triple quadrupole/linear ion trap mass spectrometry.

RAMs were found to play a pivotal role in resolving inflammation during ARDS, and RvD1 enhanced RAM proliferation and phagocytosis, which was abrogated by a lipoxin A4 receptor (ALX, RvD1 receptor) inhibitor. Both primary RAMs transfected with rS100A8/A9 and/or S100A8/A9 siRNA and S100A9-/- mice (also deficient in S100A8 function) showed higher turnover and phagocytic function, indicating that RvD1 exerted its effects on RAMs by inhibiting S100A8/A9 production in the resolution phase. RvD1 reduced S100A8/A9 and its upstream MAPK14 levels in vivo and in vitro. Finally, in the patients, RvD1 levels were lower, but S100A8/A9 levels were higher.

We propose that RvD1 improved RAM self-renewal and phagocytosis via the ALX/MAPK14/S100A8/A9 signaling pathway. Plasma RvD1 and S100A8/A9 levels were negatively correlated, and associated with the outcome of sepsis-induced ARDS.

Following cardiopulmonary bypass (CPB) surgery, patients may experience vasoplegic or vasogenic shock syndrome. This condition has a variable incidence, reaching up to 44% in high-risk patients, with mortality rates ranging from 30% to 50%, primarily due to multiple organ failure. This complex condition is characterized by low arterial pressure, unresponsive vascular collapse to high doses of vasopressors, and biochemical signals of cellular oxygen debt. The cardiac output can either be low or abnormally elevated. A fundamental aspect of the pathophysiology of vasogenic syndrome after CPB is related to the dysfunction of vascular smooth muscle cell contraction. This syndrome is often associated with complex cardiac surgery such as reoperations, long periods of bypass and aorta clamping, and excessive blood transfusion. Some potential triggers that might lead to this condition include the preoperative use of antagonists of the renin-angiotensin system, calcium blockers antagonists, and chronic renal disease. Recent literature has advocated treating vasoplegic syndrome after bypass using oxide nitric synthase inhibitors, such as methylene blue and hydroxocobalamin, along with the progressive escalation of potent vasopressors and intravascular volume adjustment.

Dravet syndrome is a severe, intractable epilepsy in which 80 % of patients have a de novo mutation in the gene SCN1A. We recently reported that a high seizure burden increased hippocampal concentrations of an array of pro-inflammatory prostaglandins in the Scn1a+/- mouse model of Dravet syndrome. This raised the possibility that a high seizure burden might also trigger the accumulation of specialized pro-resolving mediators that facilitate the resolution of neuroinflammation and brain repair. The present study therefore aimed to examine whether a high seizure burden increased hippocampal concentrations of various specialized pro-resolving mediators in the Scn1a+/- mouse model of Dravet syndrome.

Scn1a+/- mice at postnatal day 21 (P21) were primed with a single hyperthermia-induced seizure event to induce a high seizure burden. On P24 primed Scn1a+/- mice with a high seizure burden, unprimed naïve Scn1a+/- mice and wild-type (WT) mice were euthanized and hippocampal tissue was collected for analysis of various specialized pro-resolving mediators using liquid chromatography mass spectrometry.

Scn1a+/- mice with a high seizure burden showed increased hippocampal concentrations of the pro-inflammatory leukotrienes B4 and E4. Further, a high seizure burden increased hippocampal concentrations of various special pro-resolving mediators, including the maresins (maresin1), D-series resolvins (RVD1 and RVD4), and protectin (PCTR1). To further characterize these changes, we determined the mRNA expression of lipoxygenase genes, as these synthetic enzymes are common across classes of specialized pro-resolving mediators. However, hippocampal expression of Alox5, Alox12 and Alox15 were not influenced by a high seizure burden.

We report for the first time that a high seizure burden increases the hippocampal concentrations of various specialized pro-resolving mediators in Scn1a+/- mice. This provides a platform for future studies to examine whether modulation of these mediators might be exploited to reduce seizures and facilitate brain repair in intractable epilepsy syndromes.

Cardiovascular disease (CVD), the leading cause of death in the United States and globally, is a chronic inflammatory disease likely caused by an impaired ability to resolve inflammation. Pre-clinical studies have provided strong evidence of the activating role of specialized pro-resolving lipid mediators (SPMs) derived from the omega-3 fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) on the resolution of inflammation. However, there is a dearth of information on the role of SPMs on inflammation in humans. Therefore, the aim of this study was to assess whether plasma concentrations of omega-3 fatty acids and their derived SPMs are associated with inflammatory markers in subjects with low-grade chronic inflammation (C-reactive protein >2 µg/mL). The plasma phospholipid content of omega-3 fatty acids, a marker of dietary intake, plasma concentrations of SPMs, and serum concentrations of inflammatory markers were measured in 21 older men and postmenopausal women (age 53-73 y) at the end of a four-week placebo phase (3 g/day high oleic acid sunflower oil). The phospholipid DHA content was inversely related to interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and IL-10 concentrations. Moreover, MCP-1 was inversely associated with the DHA-derived 14-HDHA and 4-HDHA, and IL-10 was inversely associated with EPA-derived 18-HEPE, 12-HEPE and 5-HEPE, DPA-derived Rv5DPA, and DHA-derived 4-HDHA. These findings support the anti-inflammatory effect of dietary omega-3 fatty and suggest that lipid mediators derived from EPA, DPA, and DHA participate in the regulation of inflammation in subjects with chronic inflammation.

E-cigarette/vaping-associated lung injury (EVALI) is strongly associated with vitamin E acetate and often occurs with concomitant tetrahydrocannabinol (THC) use. To uncover pathways associated with EVALI, we examined cytokines, transcriptomic signatures, and lipidomic profiles in bronchoalveolar lavage fluid (BALF) from THC-EVALI patients. At a single center, we prospectively enrolled mechanically ventilated patients with EVALI from THC-containing products (N = 4) and patients with non-vaping acute lung injury and airway controls (N = 5). BALF samples were analyzed by Luminex multiplex assay, RNA sequencing, and mass spectrometry. After treating BEAS-2B lung epithelial cells with vaping and non-vaping BALF, LDH release was quantified. THC-EVALI BALF had significant increases in IFNγ, CCL2, CXCL5, and MMP2 relative to non-vaping patients. RNA sequencing showed enrichment for biological oxidation, glucuronidation, and fatty acid metabolism pathways. Oleic acid and arachidonic acid metabolites were increased in THC-EVALI, as were oxidized phosphatidylethanolamines (PE) such as PE(38:4). THC-EVALI BALF induced more LDH release compared to BALF from non-vaping patients. Thus, THC-EVALI is characterized by altered phospholipid composition, accumulation of lipid oxidation products, and increased pro-inflammatory mediators that may contribute to epithelial cell death. These findings serve as a framework to study novel oxidized phospholipids implicated in the pathogenesis of EVALI.

Unresolved chronic inflammation, a hallmark of cancer, promotes tumor growth and metastasis in various cancer types. In contrast to blocking inflammation, stimulation of resolution of inflammation is an entirely novel approach to "resolve" inflammation. Resolution of inflammation mechanisms in cancer includes clearance of tumor debris, counter-regulation of pro-inflammatory eicosanoids and cytokines, and suppression of leukocyte infiltration. Conventional cytotoxic chemotherapy, radiation, anti-angiogenic therapy, and immune checkpoint inhibitors directly or indirectly can lead to the generation of pro-tumorigenic cellular debris. Over the past two decades, a potential paradigm shift has emerged in the inflammation field with the discovery of specialized pro-resolving mediators (SPMs), including resolvins, lipoxins, maresins, and protectins. SPMs are structurally distinct families of mediators grouped together by their pro-resolving "debris-clearing" functions. "Pro-resolving" therapies are in clinical development for various inflammation-driven diseases, including cancer. SPMs, as novel cancer therapeutics, have tremendous potential to enhance current cancer therapy. The mechanisms of SPMs as anti-cancer therapeutics are under active investigation by various laboratories worldwide. Here, we explore the current appreciation of the SPMs as innovative potential treatments designed to harness the unique anti-cancer activity of SPMs.

Preterm birth is a major cause of perinatal complications and neonatal deaths. Furthermore, in the field of obstetrics many clinical entities like uterine contractions or the occurrence of pre- eclampsia remain to be serious complications during pregnancy and represent a major psychological, financial, and economic burden for society. Several published guidelines, studies and recommendations have highlighted the importance of supplementation of omega-3 long chain polyunsaturated fatty acids (PUFAs) during pregnancy. This narrative review aims at giving an overview on the modern perception of inflammatory processes and the role of specialized pro-resolving mediators (SPMs) in their resolution, especially in obstetrics. Additionally, we highlight the possible role of SPMs in the prevention of obstetric complications through oral supplementation using enriched marine oil nutritional's. The intake of PUFAs may result in an overall improvement of pregnancy outcomes by contributing to fetal brain growth and neurological development but more importantly though modulation of inflammation-associated pathologies. Especially the use of SPMs represents a promising approach for the management of obstetric and perinatal complications. SPMs are monohydroxylates derived from enriched marine oil nutritional's that involve certain pro-resolutive metabolites of omega-3 long chains PUFAs and may contribute to an attenuation of inflammatory diseases. This may be obtained through various mechanisms necessary for a proper resolution of inflammation such as the termination of neutrophil tissue infiltration, initiation of phagocytosis, downregulation of pro-inflammatory cytokines or tissue regeneration. In this way, acute and chronic inflammatory diseases associated with serious obstetrical complications can be modulated, which might contribute to an improved pregnancy outcome.

As identified in 1936 by Hans Selye, stress is shaping diseases through the induction of inflammation. But inflammation display some yin yang properties. On one hand inflammation is merging with the innate immune response aimed to fight infectious or sterile insults, on the other hand inflammation favors chronic physical or psychological disorders. Nature has equipped the cells, the organs, and the individuals with mediators and mechanisms that allow them to deal with stress, and even a good stress (eustress) has been associated with homeostasis. Likewise, societies and the planet are exposed to stressful settings, but wars and global warming suggest that the regulatory mechanisms are poorly efficient. In this review we list some inducers of the physiological stress, psychologic stress, societal stress, and planetary stress, and mention some of the great number of parameters which affect and modulate the response to stress and render it different from an individual to another, from the cellular level to the societal one. The cell, the organ, the individual, the society, and the planet share many stressors of which the consequences are extremely interconnected ending in the domino effect and the butterfly effect.

Agriculture dust contains many organic immunogenic compounds, and organic dust exposure is strongly associated with the development of immune-mediated chronic pulmonary diseases such as chronic obstructive pulmonary disease (COPD). Chronic organic dust exposure from agriculture sources induces chronic lung inflammatory diseases and organic dust exposure has recently been linked to an increased risk of developing dementia. The cytokine interleukin-22 (IL-22) has been established as an important mediator in the resolution and repair of lung tissues. The omega-3 fatty acid metabolite aspirin-triggered Resolvin D1 (AT-RvD1) has shown efficacy in modulating the immune response in both pulmonary and neurological inflammation but has not been explored as a therapeutic in organic dust exposure-induced neuroinflammation. Investigating the link between IL-22 and AT-RvD1 may help in developing effective therapies for these immune-mediated diseases. We aimed to investigate the link between organic dust exposure and neuroinflammation, the role of IL-22 in the pulmonary and neurological immune response to organic dust exposure, and the immune-modulating therapeutic applications of AT-RvD1 in an IL-22 knock-out mouse model of organic dust exposure. C57BL/6J (WT) and IL-22 knock-out (KO) mice were repetitively exposed to aqueous agriculture organic dust extract (DE) 5 days per week for 3 weeks (15 total instillations) and treated with AT-RvD1 either once per week (3 total injections) or 5 times per week (15 total injections) for 3 weeks and allowed to recover for 3 days. We observed a significant pulmonary and neurological immune response to DE characterized by the development of inducible bronchus associated lymphoid tissue in the lung and gliosis in the frontal areas of the brain. We also observed that IL-22 knock-out increased pulmonary and neurological inflammation severity. Animals exposed to DE and treated with AT-RvD1 displayed reduced lung pathology severity and gliosis. Our data demonstrate that DE exposure contributes to neurological inflammation and that IL-22 is crucial to effective tissue repair processes. Our data further suggest that AT-RvD1 may have potential as a novel therapeutic for organic dust exposure-induced, immune-mediated pulmonary and neurological inflammation, improving outcomes of those with these diseases.

Background: Prostaglandins are naturally occurring local mediators that can participate in the modulation of the cardiovascular system through their interaction with Gs/Gi-coupled receptors in different tissues and cells, including platelets. Thrombin is one of the most important factors that regulates platelet reactivity and coagulation. Clinical trials have consistently shown that omega-3 fatty acid supplementation lowers the risk for cardiovascular mortality and morbidity. Since omega-3 fatty acids are the main precursors of PGE3 in vivo, it would be relevant to investigate the effects of PGE3 on Thrombin Receptor Activating Peptide (TRAP-6)-induced platelet reactivity to determine the receptors and possible mechanisms of action of these compounds. Methods: We have measured platelet aggregation, P-selectin expression, and vasodilator-stimulated phosphoprotein (VASP) phosphorylation to evaluate platelet reactivity induced by TRAP-6 to determine the effects of PGE3 on platelet function. Results: We assessed the ability of DG-041, a selective prostanoid EP3 receptor antagonist, and of ONO-AE3-208, a selective prostanoid EP4 receptor antagonist, to modify the effects of PGE3. PGE3 inhibited TRAP-6-induced platelet aggregation and activation. This inhibition was enhanced in the presence of a Gi-coupled EP3 receptor antagonist and abolished in the presence of a Gs-coupled EP4 receptor antagonist. The effects of PGE3 were directly related to changes in cAMP, assessed by VASP phosphorylation. Conclusions: The general effects of PGE3 on human platelet reactivity are the consequence of a balance between activatory and inhibitory effects at receptors that have contrary effects on adenylate cyclase. These results indicate a potential mechanism by which omega-3 fatty acids underlie cardioprotective effects.