Lipid Mediators Research Articles

Leukotriene B4 receptor 1 (BLT1) activation by leukotriene B4 (LTB4) and E resolvins (RvE1 and RvE2)

Leukotriene B4 (LTB4) is a lipid inflammatory mediator derived from arachidonic acid (AA). Leukotriene B4 receptor 1 (BLT1), a G protein-coupled receptor (GPCR), is a receptor of LTB4. Nonetheless, the resolution of inflammation is driven by specialized pro-resolving lipid mediators (SPMs) such as resolvins E1 (RvE1) and E2 (RvE2). Both resolvins are derived from omega-3 fatty acid eicosapentaenoic acid (EPA). Here, long-term molecular dynamics simulations (MD) were performed to investigate the activation of the BLT1 receptor using two pro-resolution agonists (RvE1 and RvE2) and an inflammatory agonist (LTB4). We have analyzed the receptor's activation state, electrostatic interactions, and the binding affinity the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) approach. The results showed that LTB4 and RvE1 have kept the receptor in an active state by higher simulation time. MD showed that the ligand-receptor interactions occurred mainly through residues H94, R156, and R267. The MMPBSA calculations showed residues R156 and R267 were the two mainly hotspots. Our MMPBSA results were compatible with experimental results from other studies. Overall, the results from this study provide new insights into the activation mechanisms of the BLT1 receptor, reinforcing the role of critical residues and interactions in the binding of pro-resolution and pro-inflammatory agonists.

Phospholipids, Sphingolipids, and Cholesterol-Derived Lipid Mediators and Their Role in Neurological Disorders.

Neural membranes are composed of phospholipids, sphingolipids, cholesterol, and proteins. In response to cell stimulation or injury, the metabolism of lipids generates various lipid mediators, which perform many cellular functions. Thus, phospholipids release arachidonic acid or docosahexaenoic acid from the sn-2 position of the glycerol moiety by the action of phospholipases A2. Arachidonic acid is a precursor for prostaglandins, leukotrienes, thromboxane, and lipoxins. Among these mediators, prostaglandins, leukotrienes, and thromboxane produce neuroinflammation. In contrast, lipoxins produce anti-inflammatory and pro-resolving effects. Prostaglandins, leukotrienes, and thromboxane are also involved in cell proliferation, differentiation, blood clotting, and blood vessel permeability. In contrast, DHA-derived lipid mediators are called specialized pro-resolving lipid metabolites (SPMs). They include resolvins, protectins, and maresins. These mediators regulate immune function by producing anti-inflammatory, pro-resolving, and cell protective effects. Sphingolipid-derived metabolites are ceramide, ceramide1-phosphate, sphingosine, and sphingosine 1 phosphate. They regulate many cellular processes, including enzyme activities, cell migration and adhesion, inflammation, and immunity. Cholesterol is metabolized into hydroxycholesterols and 7-ketocholesterol, which not only disrupts membrane fluidity, but also promotes inflammation, oxidative stress, and apoptosis. These processes lead to cellular damage.

Association of polymorphisms in CYP2C8 and CYP2C9 with susceptibility to type 2 diabetes mellitus in a Chinese population

AimsCYP2C8 and CYP2C9 are cytochrome P450 epoxygenases responsible for metabolizing arachidonic acid into epoxyeicosatrienoic acids (EETs). These EETs play a crucial role as lipid mediators with numerous beneficial effects in type 2 diabetes mellitus (T2DM). In this study, we aimed to investigate the association of CYP2C8 and CYP2C9 genetic variants with T2DM in a Chinese population. MethodsWe conducted genotyping for 9 tag single nucleotide polymorphisms (SNPs) in CYP2C8 and 10 tag SNPs in CYP2C9 based on HapMap Chinese and Japanese data. Subsequently, we genotyped these SNPs in a Chinese cohort comprising 3410 individuals with T2DM and 3401 healthy controls. Statistical analyses were performed to assess the association between these SNPs and T2DM. ResultsIn our study population, we observed that rs1819173, located within the CYP2C9 gene region, was significantly associated with T2DM. Notably, the presence of the A allele was found to be protective against T2DM, as indicated by an odds ratio of 0.840 (95 % confidence interval: 0.780–0.904, P = 3.04 × 10−6). Furthermore, specific haplotypes (GT and AT) involving rs2071426 and rs6583967 in CYP2C8 exhibited associations with T2DM (P = 0.049 and 0.038, respectively). Subsequently, we conducted an analysis of the association between rs1819173 and non-alcoholic fatty liver disease (NAFLD), revealing a significant correlation (OR = 0.764, 95 % CI: 0.629–0.928, P = 0.007). ConclusionOur research identified a genetic variants rs1819173 within CYP2C8 are significantly associated with T2DM susceptibility in the Chinese population.

Rapid Lipid Mediator Profiling by Convergence Chromatography-MS/MS.

Bioactive lipid mediators derived from arachidonic acid constitute an attractive pool of metabolites that reflect cellular function and signaling, as well as potential biomarkers that may respond quantitatively to disease progression or pharmacological treatment. Their quantitative measurement in biological samples is complicated by the number of isomers that share common structural features, which are not easily distinguished by immunoassays or reverse phase chromatography-tandem mass spectrometry. Here, we present a method that enables the rapid analysis of a panel of over 25 biologically important eicosanoids in a 96-well format for cell culture supernatants, plasma, and organ tissues using convergence chromatography-tandem mass spectrometry to resolve these analytes of interest.

9-HODE associates with thalamic atrophy and predicts white matter damage in multiple sclerosis

BackgroundMultiple sclerosis (MS) is characterized by extensive tissue damage leading to a range of complex symptoms, including physical disability and cognitive dysfunction. Recent work has indicated the clinical relevance of bioactive lipid mediators (LMs), which are known to orchestrate inflammation and its resolution and are deregulated in MS. However, it is unknown whether LM profiles relate to white matter (WM) damage. ObjectivesTo investigate the potential association between plasma-derived LMs and MRI-quantified WM damage using fractional anisotropy (FA) and grey matter (GM) atrophy in dimethyl fumarate-treated relapsing remitting MS (RRMS) patients. MethodsSeverity of FA-based WM damage and GM atrophy was determined in RRMS patients (n=28) compared to age- and sex-matched controls (n=31) at treatment initiation (baseline) and after 6 months. Plasma LMs were assessed using HPLC-MS/MS and baseline LMs were correlated to changes in FA and brain volumes. ResultsWe observed significant WM damage in RRMS patients (mean age 41.4 [SD 9.1]) at baseline and follow-up (z-score=-0.33 and 0.31, respectively) compared to controls (mean age 41.9 [SD 9.5]; p<0.001 for both comparisons). Patients with severe WM damage showed a decline of thalamic volume (p=0.02), and this decline correlated (r=0.51, p<0.001) with lower baseline levels of 9-HODE. This LM also predicted FA worsening (beta=0.14, p<0.001) over time at 6 months. ConclusionDespite the relatively small sample size, lower baseline levels of the LM 9-HODE correlated with more thalamic atrophy and predicted subsequent worsening of WM damage in RRMS patients.

Reexamining the Role of Pulmonary Lipids in the Pathogenesis of Pulmonary Fibrosis.

Pulmonary fibrosis (PF) can be idiopathic or driven by a specific insult, genetic susceptibility, or disease process. Inflammation plays a role in the pathophysiology, the extent of which remains a longstanding topic of debate. More recently, there has been increasing interest in a potential inciting role for aberrant lipid metabolism. Lipids are essential for the structure and function of all cell membranes, but specifically in the lung for surfactant composition, intra- and intercellular lipid mediators, and lipofibroblasts. Clinically, there is evidence of increased lipid deposition in the subpleural space and at a whole-lung tissue level in PF. There is evidence of increased parenchymal lipid deposition and abnormal mediastinal fat shape on chest computed tomography. A protective role for cholesterol-lowering drugs, including statins and ezetimibe, has been described in PF. At a cellular level, fatty acid, phospholipid, and glucose metabolism are disordered, as is the production of lipid mediators. Here we put forward the argument that there is substantive clinical and biological evidence to support a role for aberrant lipid metabolism and lipid mediators in the pathogenesis of PF.

Machine learning and biological validation identify sphingolipids as potential mediators of paclitaxel-induced neuropathy in cancer patients

Background:Chemotherapy-induced peripheral neuropathy (CIPN) is a serious therapy-limiting side effect of commonly used anticancer drugs. Previous studies suggest that lipids may play a role in CIPN. Therefore, the present study aimed to identify the particular types of lipids that are regulated as a consequence of paclitaxel administration and may be associated with the occurrence of post-therapeutic neuropathy.Methods:High-resolution mass spectrometry lipidomics was applied to quantify d=255 different lipid mediators in the blood of n=31 patients drawn before and after paclitaxel therapy for breast cancer treatment. A variety of supervised statistical and machine-learning methods was applied to identify lipids that were regulated during paclitaxel therapy or differed among patients with and without post-therapeutic neuropathy.Results:Twenty-seven lipids were identified that carried relevant information to train machine learning algorithms to identify, in new cases, whether a blood sample was drawn before or after paclitaxel therapy with a median balanced accuracy of up to 90%. One of the top hits, sphinganine-1-phosphate (SA1P), was found to induce calcium transients in sensory neurons via the transient receptor potential vanilloid 1 (TRPV1) channel and sphingosine-1-phosphate receptors.SA1P also showed different blood concentrations between patients with and without neuropathy.Conclusions:Present findings suggest a role for sphinganine-1-phosphate in paclitaxel-induced biological changes associated with neuropathic side effects. The identified SA1P, through its receptors, may provide a potential drug target for co-therapy with paclitaxel to reduce one of its major and therapy-limiting side effects.Funding:This work was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG, Grants SFB1039 A09 and Z01) and by the Fraunhofer Foundation Project: Neuropathic Pain as well as the Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD). This work was also supported by the Leistungszentrum Innovative Therapeutics (TheraNova) funded by the Fraunhofer Society and the Hessian Ministry of Science and Arts. Jörn Lötsch was supported by the Deutsche Forschungsgemeinschaft (DFG LO 612/16-1).

Machine learning and biological validation identify sphingolipids as potential mediators of paclitaxel-induced neuropathy in cancer patients.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious therapy-limiting side effect of commonly used anticancer drugs. Previous studies suggest that lipids may play a role in CIPN. Therefore, the present study aimed to identify the particular types of lipids that are regulated as a consequence of paclitaxel administration and may be associated with the occurrence of post-therapeutic neuropathy. High-resolution mass spectrometry lipidomics was applied to quantify d=255 different lipid mediators in the blood of n=31 patients drawn before and after paclitaxel therapy for breast cancer treatment. A variety of supervised statistical and machine-learning methods was applied to identify lipids that were regulated during paclitaxel therapy or differed among patients with and without post-therapeutic neuropathy. Twenty-seven lipids were identified that carried relevant information to train machine learning algorithms to identify, in new cases, whether a blood sample was drawn before or after paclitaxel therapy with a median balanced accuracy of up to 90%. One of the top hits, sphinganine-1-phosphate (SA1P), was found to induce calcium transients in sensory neurons via the transient receptor potential vanilloid 1 (TRPV1) channel and sphingosine-1-phosphate receptors.SA1P also showed different blood concentrations between patients with and without neuropathy. Present findings suggest a role for sphinganine-1-phosphate in paclitaxel-induced biological changes associated with neuropathic side effects. The identified SA1P, through its receptors, may provide a potential drug target for co-therapy with paclitaxel to reduce one of its major and therapy-limiting side effects. This work was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG, Grants SFB1039 A09 and Z01) and by the Fraunhofer Foundation Project: Neuropathic Pain as well as the Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD). This work was also supported by the Leistungszentrum Innovative Therapeutics (TheraNova) funded by the Fraunhofer Society and the Hessian Ministry of Science and Arts. Jörn Lötsch was supported by the Deutsche Forschungsgemeinschaft (DFG LO 612/16-1).

Pro-Resolving Inflammatory Effects of a Marine Oil Enriched in Specialized Pro-Resolving Mediators (SPMs) Supplement and Its Implication in Patients with Post-COVID Syndrome (PCS).

This study aimed to evaluate the eicosanoid and pro-resolutive parameters in patients with Post-COVID Syndrome (PCS) during a 12-week supplementation with a marine oil enriched in specialized pro-resolving mediators (SPMs). This study was conducted on 53 adult patients with PCS. The subjects included must have had a positive COVID-19 test (PCR, fast antigen test, or serologic test) and persistent symptoms related to COVID-19 at least 12 weeks before their enrolment in the study. The following parameters were evaluated: polyunsaturated fatty acids EPA, DHA, ARA, and DPA; specialized pro-resolving mediators (SPMs), 17-HDHA, 18-HEPE, 14-HDHA, resolvins, maresins, protectins, and lipoxins. The eicosanoids group included prostaglandins, thromboxanes, and leukotrienes. The development of the clinical symptoms of fatigue and dyspnea were evaluated using the Fatigue Severity Scale (FSS) and the Modified Medical Research Council (mMRC) Dyspnea Scale. Three groups with different intake amounts were evaluated (daily use of 500 mg, 1500 mg, and 3000 mg) and compared to a control group not using the product. In the serum from patients with PCS, an increase in 17-HDHA, 18-HEPE, and 14-HDHA could be observed, and a decrease in the ratio between the pro-inflammatory and pro-resolutive lipid mediators was detected; both differences were significant (p < 0.05). There were no differences found between the three treatment groups. Fatigue and dyspnea showed a trend of improvement after supplementation in all groups. A clear enrichment in the serum of the three monohydroxylated SPMs could be observed at a dosage of 500 mg per day. Similarly, a clear improvement in fatigue and dyspnea was observed with this dosage.

Re-evaluation of the canonical PAF pathway in cutaneous anaphylaxis

Platelet-activating factor (PAF) is a potent classical lipid mediator that plays a critical role in various diseases such as allergy and nervous system disorders. In the realm of allergy, previous studies suggested that PAF is generated in response to extracellular stimuli and contributes to allergic reactions via PAF receptor (PAFR). However, the sources of endogenous PAF and its pathophysiological dynamics remain largely elusive in vivo. Here, we report that rapid and local PAF generation completely depends on lysophospholipid acyltransferase 9 (LPLAT9, also known as LPCAT2) expressed in mast cells in IgE-mediated passive cutaneous anaphylaxis. However, we found that LPLAT9 knockout (KO) mice did not display attenuated vascular leakage. Additionally, decreased vascular leakage was observed in PAFR KO mice, but not in endothelial cell-specific mice in this model. These divergences highlight a yet unsolved complexity of the biological functions of PAF and PAFR in a pathophysiological process.

Structural basis for the access and binding of resolvin D1 (RvD1) to formyl peptide receptor 2 (FPR2/ALX), a class A GPCR.

Inflammation is essential to the body's defense against tissue injury and microbial invasion. However, uncontrolled inflammation is highly detrimental and can result in chronic inflammatory diseases such as asthma, cancer, obesity, and diabetes. An increasing body of evidence suggests that specialized pro-resolving lipid mediators (SPMs), such as resolvins, are actively involved in critical cellular events that drive the resolution of inflammation and a return to homeostasis. An imbalance caused by insufficient SPMs can result in the unsuccessful resolution of inflammation. The D-series resolvins (metabolites of docosahexaenoic acid), such as resolvin D1 (RvD1) and resolvin D2 (RvD2), carry out their pro-resolving functions by directly binding to class A G protein-coupled receptors FPR2/ALXR and GPR32, and GPR18, respectively. We recently demonstrated that RvD1 and RvD2 preferentially partition and accumulate at the polar headgroup regions of the membrane. However, the mechanistic detail of how RvD1 gains access to the FPR2 binding site from a surrounding membrane environment remains unknown. In this study, we used classical MD and well-tempered metadynamics simulations to examine the structural basis for the access and binding of RvD1 to its target receptor from aqueous and membrane environments. The results offer valuable insights into the access path, potential binding pose, and key residue interactions essential for the access and binding of RvD1 to FPR2/ALXR and may help in identifying small molecule therapeutics as a possible treatment for inflammatory disorders.

Resolvin D2/GPR18 signaling enhances monocytic myeloid-derived suppressor cell function to mitigate abdominal aortic aneurysm formation.

Abdominal aortic aneurysm (AAA) formation is a chronic vascular pathology characterized by inflammation, leukocyte infiltration, and vascular remodeling. The aim of this study was to delineate the protective role of Resolvin D2 (RvD2), a bioactive isoform of specialized pro-resolving lipid mediators, via G-protein-coupled receptor 18 (GPR18) receptor signaling in attenuating AAAs. Importantly, RvD2 and GPR18 levels were significantly decreased in aortic tissue of AAA patients compared with controls. Furthermore, using an established murine model of AAA in C57BL/6 (WT) mice, we observed that treatment with RvD2 significantly attenuated aortic diameter, pro-inflammatory cytokine production, immune cell infiltration (neutrophils and macrophages), elastic fiber disruption, and increased smooth muscle cell α-actin expression as well as increased TGF-β2 and IL-10 expressions compared to untreated mice. Moreover, the RvD2-mediated protection from vascular remodeling and AAA formation was blocked when mice were previously treated with siRNA for GPR18 signifying the importance of RvD2/GPR18 signaling in vascular inflammation. Mechanistically, RvD2-mediated protection significantly enhanced infiltration and activation of monocytic myeloid-derived suppressor cells (M-MDSCs) by increasing TGF-β2 and IL-10 secretions in a GPR18-dependent manner to attenuate aortic inflammation and vascular remodeling. Collectively, this study demonstrates that RvD2 treatment induces an expansion of myeloid-lineage committed progenitors, such as M-MDSCs, activates GPR18-dependent signaling to enhance TGF-β2 and IL-10 secretion, and mitigates SMC activation that contributes to resolution of aortic inflammation and remodeling during AAA formation.

Omega-3 polyunsaturated fatty acids in depression: insights from recent clinical trials

Purpose of review This review examines evidence from recent clinical trials on the therapeutic potential of omega-3 polyunsaturated fatty acids (PUFAs) in major depressive disorder (MDD). We focus on the effects in MDD with comorbidities, younger populations, and high-inflammation presentations. Recent findings PubMed, Cochrane, and Embase databases were systematically searched for studies published between May 2022 and May 2024. The search was conducted on randomized controlled trials using omega-3 PUFAs with participants with a clinical diagnosis of depression. Higher doses of eicosapentaenoic acid (EPA) (&gt;1 g/day) improved measures of depression, particularly in MDD with elevated inflammation markers, comorbid cardiovascular diseases, late-life onset, and children and adolescent populations. Improvements in depressive symptoms were associated with increases in omega-3 PUFA-derived anti-inflammatory and proresolving lipid mediators. As adjuvant treatments, omega-3 PUFAs have potential benefits in mood, cognitive and metabolic functions, kynurenine and serotonin pathways, and alterations in corticolimbic functional connectivity. Summary While evidence suggests promise, particularly for high-dose EPA and in inflammatory MDD subtypes, more research is needed to establish optimal dosing regimens, treatment duration, and patient subgroups most likely to benefit. Future studies should focus on sex differences, long-term effects, and potential synergies with other treatments.

Activation of pro-resolving pathways mediate the therapeutic effects of thymosin beta-4 during Pseudomonas aeruginosa-induced keratitis.

Current treatments for bacterial keratitis fail to address the sight-threatening inflammatory host response. Our recent work elucidating the therapeutic mechanisms of adjunctive thymosin beta-4 (Tβ4) in resolving inflammation and infection in bacterial keratitis revealed modulation of effector cell function and enhanced bacterial killing. The current study builds upon the observed effects on effector cell function by investigating the impact of Tβ4 on specialized pro-resolving lipid mediator (SPM) pathways as they play a significant role in inflammation resolution. Using a well-established in vivo model of Pseudomonas aeruginosa-induced bacterial keratitis, we assessed key enzymes (5-LOX and 12/15-LOX) involved in SPM pathway activation, SPM end products (lipoxins, resolvins), and receptor levels for these mediators. In vitro validation using LPS-stimulated murine monocyte/MΦ-like RAW 264.7 cells and siRNA to inhibit Tβ4 and LOX enzymes was carried out to complement our in vivo findings. Findings from our in vivo and in vitro investigations demonstrated that adjunctive Tβ4 treatment significantly influences enzymes and receptors involved in SPM pathways. Further, Tβ4 alone enhances the generation of SPM end products in the cornea. Our in vitro assessments confirmed that Tβ4-enhanced phagocytosis is directly mediated by SPM pathway activation. Whereas Tβ4-enhanced efferocytosis appeared to be indirect. Collectively, these findings suggest that the therapeutic effect of Tβ4 resolves inflammation through the activation of SPM pathways, thereby enhancing host defense and tissue repair. Our research contributes to understanding the potential mechanisms behind Tβ4 immunoregulatory function, pointing to its promising ability as a comprehensive adjunctive treatment for bacterial keratitis.

Proresolving Lipid Mediators in the Respiratory System.

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.

Low-dose pro-resolving mediators temporally reset the resolution response to microbial inflammation

BackgroundSpecialized pro-resolving mediators (SPMs) promote resolution of inflammation, clear infections and stimulate tissue regeneration. These include resolvins, protectins, and maresins. During self-resolving acute inflammation, SPMs are produced and have key functions activating endogenous resolution response for returning to homeostasis. Herein, we addressed whether infections initiated with ongoing inflammation alter resolution programs, and if low-dose repetitive SPM regimen re-programs the resolution response.MethodsInflammation was initiated with zymosan (1 mg/mouse) followed by E. coli (105 CFU/mouse) infections carried out in murine peritonitis, and exudates collected at 4-72 h. Leukocytes were enumerated using light microscopy, percentages of PMN, monocytes and macrophages were determined using flow cytometry, and resolution indices calculated. Lipid mediators and SPM profiles were established using mass spectrometry-based metabololipidomics. Repetitive dosing with a SPM panel consisting of RvD1, RvD2, RvD5, MaR1 and RvE2 (0.1 ng/mouse each, i.p.) was given to mice, followed by zymosan challenge. Leukocyte composition, resolution indices and RNA-sequencing were carried out for the repetitive SPM treatments.ResultsE. coli infections initiated acute inflammation-resolution programs with temporal SPM production in the infectious exudates. Zymosan-induced inflammation prior to E. coli peritonitis shifted exudate resolution indices and delayed E. coli clearance. Lipid mediator metabololipidomics demonstrated that E. coli infection with ongoing zymosan-induced inflammation shifted the time course of exudate SPMs, activating a SPM cluster that included RvD1, RvD5 and MaR1 during the initiation phase of infectious inflammation (0-4 h); RvD5 and MaR1 were present also in the resolution phase (24-48 h). To emulate daily SPM regimens used in humans, a repetitive subthreshold dosing of the SPM panel RvD1, RvD2, RvD5, MaR1 and RvE2 each at 0.1 ng per mouse was administered. This low-dose SPM regimen accelerated exudate PMN clearance following zymosan-induced inflammation, and shortened the resolution interval by > 70%. These low-dose SPMs regulated genes and pathways related to immune response, chemokine clearance and tissue repair, as demonstrated by using RNA-sequencing.ConclusionsInfections encountered during ongoing inflammation in mice reset the resolution mechanisms of inflammation via SPM clusters. Low-dose SPMs activate innate immune responses and pathways towards the resolution response that can be reprogrammed.

Continuous infusion of resolvin D2 in combination with Angiotensin-II show contrary effects on blood pressure and intracardiac artery remodeling

Specialized pro-resolving mediators (SPMs) are key effectors of resolution of inflammation. This is highly relevant for cardiac and vessel remodeling, where the net inflammatory response contributes to determine disease outcome. Herein, we used a mice model of angiotensin (Ang)–II–induced hypertension to study the effect of the SPM Resolvin D2 (RvD2), on hypertension and cardiac remodeling. By using subcutaneous osmotic minipumps, mice were treated with PBS or Ang-II in combination with or without RvD2 for two weeks. Mice receiving RvD2 gained less blood pressure increase compared to Ang-II alone. Surprisingly, however, examination of intracardiac arteries revealed that RvD2 treatment in combination with Ang-II exacerbated Ang–II–induced fibrosis. Measures of vascular smooth muscle cell dedifferentiation correlated with the level of vascular remodeling, indicating that this dedifferentiation, including increased proliferation and migration, is a contributing factor. RNA sequencing of left ventricle cardiac tissue supported these findings as pathways related to cell proliferation and cell differentiation were upregulated in mice treated with Ang-II in combination with RvD2. Additionally, the RNA sequencing also showed upregulation of pathways related to SPM metabolism. In line with this, Mass spectrometry analysis of lipid mediators showed reduced cardiac levels of the arachidonic acid derived metabolite leukotriene E4 in RvD2 treated mice. Our study suggests that continuous infusion through osmotic minipumps should not be the recommended route of RvD2 administration in future studies.

Aspergillus fumigatus-derived gliotoxin impacts innate immune cell activation through modulating lipid mediator production in macrophages.

Gliotoxin (GT), a secondary metabolite and virulence factor of the fungal pathogen Aspergillus fumigatus, suppresses innate immunity and supports the suppression of host immune responses. Recently, we revealed that GT blocks the formation of the chemotactic lipid mediator leukotriene (LT)B4 in activated human neutrophils and monocytes, and in rodents in vivo, by directly inhibiting LTA4 hydrolase. Here, we elucidated the impact of GT on LTB4 biosynthesis and the entire lipid mediator networks in human M1- and M2-like monocyte-derived macrophages (MDMs) and in human tissue-resident alveolar macrophages. In activated M1-MDMs with high capacities to generate LTs, the formation of LTB4 was effectively suppressed by GT, connected to attenuated macrophage phagocytic activity as well as human neutrophil movement and migration. In resting macrophages, especially in M1-MDMs, GT elicited strong formation of prostaglandins, while bacterial exotoxins from Staphylococcus aureus evoked a broad spectrum of lipid mediator biosynthesis in both MDM phenotypes. We conclude that GT impairs functions of activated innate immune cells through selective suppression of LTB4 biosynthesis, while GT may also prime the immune system by provoking prostaglandin formation in macrophages.

7,8‑dihydroxyflavone reduces lipid peroxidation, proinflammatory cytokines, and mediators in chemically induced‑phenylketonuria model.

Phenylketonuria (PKU) stems from a rare genetic metabolic imbalance attributed to an insufficiency in the enzyme phenylalanine hydroxylase. Within the context of PKU, brain‑derived neurotrophic factor (BDNF) plays a pivotal role in brain function. 7,8‑dihydroxyflavone (7,8‑DHF) operates as a tropomyosin receptor kinase B (TrkB) agonist, mimicking the effects of BDNF. This study aimed to examine the effects of administering 7,8‑DHF in chemically‑induced rat models specifically induced to simulate PKU chemically. The rats were subcutaneously injected with phenylalanine and p‑chlorophenylalanine, a phenylalanine hydroxylase inhibitor, along with 7,8‑DHF. The injections began on the 2nd day after birth and continued until the 10th day. Levels of interleukin‑1β (IL‑1β), interleukin‑6 (IL‑6), interleukin‑33 (IL‑33), BDNF, malondialdehyde (MDA), monoamine oxidase (MAO), and superoxide dismutase (SOD) in the brain tissues were quantified using the enzyme‑linked immunosorbent assay (ELISA). Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was performed to assess the gene expressions of inducible nitric oxide synthase (iNOS), nuclear factor kappa beta (NF‑κB), caspase‑3, nuclear factor erythroid 2‑related factor 2 (Nrf2), heme oxygenase‑1 (HO‑1), and BDNF. The results showed a decrease in mRNA levels of iNOS, IL‑1β, IL‑6, and lipid peroxidation in the group that received 7,8‑DHF. These results indicate that administering 7,8‑DHF has the potential to reduce brain damage in PKU by lowering proinflammatory cytokine levels and lipid peroxidation in PKU models. Thus, 7,8‑DHF, as a small molecule, might offer a promising adjunct therapeutic approach for PKU.

Effects of Omega-3 Polyunsaturated Fatty Acids on the Formation of Adipokines, Cytokines, and Oxylipins in Retroperitoneal Adi-Pose Tissue of Mice.

Oxylipins and specialized pro-resolving lipid mediators (SPMs) derived from polyunsaturated fatty acids (PUFAs) are mediators that coordinate an active process of inflammation resolution. While these mediators have potential as circulating biomarkers for several disease states with inflammatory components, the source of plasma oxylipins/SPMs remains a matter of debate but may involve white adipose tissue (WAT). Here, we aimed to investigate to what extent high or low omega (n)-3 PUFA enrichment affects the production of cytokines and adipokines (RT-PCR), as well as oxylipins/SPMs (liquid chromatography-tandem mass spectrometry) in the WAT of mice during lipopolysaccharide (LPS)-induced systemic inflammation (intraperitoneal injection, 2.5 mg/kg, 24 h). For this purpose, n-3 PUFA genetically enriched mice (FAT-1), which endogenously synthesize n-3 PUFAs, were compared to wild-type mice (WT) and combined with n-3 PUFA-sufficient or deficient diets. LPS-induced systemic inflammation resulted in the decreased expression of most adipokines and interleukin-6 in WAT, whereas the n-3-sufficient diet increased them compared to the deficient diet. The n-6 PUFA arachidonic acid was decreased in WAT of FAT-1 mice, while n-3 derived PUFAs (eicosapentaenoic acid, docosahexaenoic acid) and their metabolites (oxylipins/SPMs) were increased in WAT by genetic and nutritional n-3 enrichment. Several oxylipins/SPMs were increased by LPS treatment in WAT compared to PBS-treated controls in genetically n-3 enriched FAT-1 mice. Overall, we show that WAT may significantly contribute to circulating oxylipin production. Moreover, n-3-sufficient or n-3-deficient diets alter adipokine production. The precise interplay between cytokines, adipokines, and oxylipins remains to be further investigated.