Omega-3 Fatty Acids and Arrhythmias.

The pro- and antiarrhythmic effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been extensively studied in preclinical and human trials. Despite early evidence of an antiarrhythmic role of n-3 PUFA in the prevention of sudden cardiac death and postoperative and persistent atrial fibrillation (AF), subsequent well-designed randomized trials have largely not shown an antiarrhythmic benefit. Two trials that tested moderate and high-dose n-3 PUFA demonstrated a reduction in sudden cardiac death, but these findings have not been widely replicated, and the potential of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to reduce arrhythmic death in combination, or as monotherapy, remains uncertain. The accumulated clinical evidence does not support supplementation of n-3 PUFA for postoperative AF or secondary prevention of AF. Several large, contemporary, randomized controlled trials of high-dose n-3 PUFA for primary or secondary cardiovascular prevention have demonstrated a small, significant, dose-dependent increased risk of incident AF compared with mineral oil or corn oil comparator. These findings were reproduced with both icosapent ethyl monotherapy and a mixed EPA+DHA formulation. The proarrhythmic mechanism of increased AF in contemporary cohorts exposed to high-dose n-3 PUFA is unknown. EPA and DHA and their metabolites have pleiotropic cardiometabolic and pro- and antiarrhythmic effects, including modification of the lipid raft microenvironment; alteration of cell membrane structure and fluidity; modulation of sodium, potassium, and calcium currents; and regulation of gene transcription, cell proliferation, and inflammation. Further characterization of the complex association between EPA, EPA+DHA, and DHA and AF is needed. Which formulations, dose ranges, and patient subgroups are at highest risk, remain unclear.

Eicosapentaenoic Acid Improves Endothelial Nitric Oxide Bioavailability Via Changes in Protein Expression During Inflammation.

BACKGROUND: Endothelial cell (EC) dysfunction involves reduced nitric oxide (NO) bioavailability due to NO synthase uncoupling linked to increased oxidation and reduced cofactor availability. Loss of endothelial function and NO bioavailability are associated with inflammation, including leukocyte activation. Eicosapentaenoic acid (EPA) administered as icosapent ethyl reduced cardiovascular events in REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) in relation to on-treatment EPA blood levels. The mechanisms of cardiovascular protection for EPA remain incompletely elucidated but likely involve direct effects on the endothelium. METHODS AND RESULTS: In this study, human ECs were treated with EPA and challenged with the cytokine IL-6 (interleukin-6). Proinflammatory responses in the ECs were confirmed by ELISA capture of sICAM-1 (soluble intercellular adhesion molecule-1) and TNF-α (tumor necrosis factor-α). Global protein expression was determined using liquid chromatography-mass spectrometry tandem mass tag. Release kinetics of NO and peroxynitrite were monitored using porphyrinic nanosensors. IL-6 challenge induced proinflammatory responses from the ECs as evidenced by increased release of sICAM-1 and TNF-α, which correlated with a loss of NO bioavailability. ECs pretreated with EPA modulated expression of 327 proteins by >1-fold (P<0.05), compared with IL-6 alone. EPA augmented expression of proteins involved in NO production, including heme oxygenase-1 and dimethylarginine dimethylaminohydrolase-1, and 34 proteins annotated as associated with neutrophil degranulation. EPA reversed the endothelial NO synthase uncoupling induced by IL-6 as evidenced by an increased [NO]/[peroxynitrite] release ratio (P<0.05). CONCLUSIONS: These direct actions of EPA on EC functions during inflammation may contribute to its distinct cardiovascular benefits.

Efficient Expression and Application of a Modified Rhizomucor miehei Lipase for Simultaneous Production of Biodiesel and Eicosapentaenoic Acid Ethyl Ester from Nannochloropsis Oil.

Few reports exist on one-step enzymatic methods for the simultaneous production of biodiesel and eicosapentaenoic acid ethyl ester (EPA-EE), a high-value pharmaceutical compound. This study aimed to efficiently express Rhizomucor miehei lipase (pRML) in Pichia pastoris X-33 via propeptide mutation and high-copy strain screening. The mutated enzyme was then used to simultaneously catalyze the production of both biodiesel and EPA-EE. The P46N mutation in the propeptide (P46N-pRML) significantly boosted its production, with the four-copy strain increasing enzyme yield by 3.7-fold, reaching 3425 U/mL. Meanwhile, its optimal temperature increased to 45-50 °C, pH expanded to 7.0-8.0, specific activity doubled, Km reduced to one-third, and kcat/Km increased 7-fold. Notably, P46N-pRML efficiently converts Nannochloropsis gaditana oil's eicosapentaenoic acid (EPA). Under optimal conditions, it achieves up to 93% biodiesel and 92% EPA-EE yields in 9 h. Our study introduces a novel, efficient one-step green method to produce both biodiesel and EPA-EE using this advanced enzyme.

15-epi-lipoxin A5 promotes neutrophil exit from exudates for clearance by splenic macrophages.

Specialized proresolving mediators (SPMs) promote local macrophage efferocytosis but excess leukocytes early in inflammation require additional leukocyte clearance mechanism for resolution. Here, neutrophil clearance mechanisms from localized acute inflammation were investigated in mouse dorsal air pouches. 15-HEPE (15-hydroxy-5Z,8Z,11Z,13E,17Z-eicosapentaenoic acid) levels were increased in the exudates. Activated human neutrophils converted 15-HEPE to lipoxin A5 (5S,6R,15S-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), 15-epi-lipoxin A5 (5S,6R,15R-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), and resolvin E4 (RvE4; 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid). Exogenous 15-epi-lipoxin A5, 15-epi-lipoxin A4 and a structural lipoxin mimetic significantly decreased exudate neutrophils and increased local tissue macrophage efferocytosis, with comparison to naproxen. 15-epi-lipoxin A5 also cleared exudate neutrophils faster than the apparent local capacity for stimulated macrophage efferocytosis, so the fate of exudate neutrophils was tracked with CD45.1 variant neutrophils. 15-epi-lipoxin A5 augmented the exit of adoptively transferred neutrophils from the pouch exudate to the spleen, and significantly increased splenic SIRPa+ and MARCO+ macrophage efferocytosis. Together, these findings demonstrate new systemic resolution mechanisms for 15-epi-lipoxin A5 and RvE4 in localized tissue inflammation, which distally engage the spleen to activate macrophage efferocytosis for the clearance of tissue exudate neutrophils.

Carrageenan-ferrocene-eicosapentaenoic acid composite hydrogel induce ferroptosis and apoptosis for anti-tumor recurrence and metastasis.

The immune-suppressive microenvironment of solid tumors is a key factor limiting the effectiveness of immunotherapy, which seriously threatens human life and health. Ferroptosis and apoptosis are key cell-death pathways implicated in cancers, which can synergistically activate tumor immune responses. Here, we developed a multifunctional composite hydrogel (CE-Fc-Gel) based on the self-assembly of poloxamer 407, cystamine-linked ιota-carrageenan (CA)-eicosapentaenoic acid (EPA), and ferrocene (Fc). CE-Fc-Gel improved targeting in tumor microenvironment due to its disulfide bonds. Moreover, CE-Fc-Gel promoted lipid peroxidation, enhanced reactive oxygen species (ROS) production, and decreased glutathione peroxidase 4 (GPX4), inducing ferroptosis by the synergistic effect of Fc and EPA. CE-Fc-Gel induced apoptosis and immunogenic cell death (ICD), thereby promoting dendritic cells (DCs) maturation and T cell infiltration. As a result, CE-Fc-Gel significantly inhibited primary and metastatic tumors in vivo. Our findings provide a novel strategy for enhancing tumor immunotherapy by combining apoptosis, ferroptosis, and ICD.

Impact of Resolvin-E1 and Maresin-1 on Bone Marrow Stem Cell Osteogenesis under Inflammatory Stress.

Periodontal disease is characterized by inflammation and bone loss. Central to its pathogenesis is the dysregulated inflammatory response, complicating regenerative therapies. Mesenchymal stem cells (MSCs) hold significant promise in tissue repair and regeneration. This study investigated the effects of specialized pro-resolving mediators (SPMs), Resolvin E1 (RvE1) and Maresin 1 (MaR1), on the osteogenic differentiation of human bone marrow-derived MSCs under inflammatory conditions. The stem cells were treated with SPMs in the presence of lipopolysaccharide (LPS) to simulate an inflammatory environment. Osteogenic differentiation was assessed through alkaline phosphatase activity and alizarin red staining. Proteomic analysis was conducted to characterize the protein expression profile changes, focusing on proteins related to osteogenesis and osteoclastogenesis. Treatment with RvE1 and MaR1, both individually and in combination, significantly enhanced calcified deposit formation. Proteomic analysis revealed the differential expression of proteins associated with osteogenesis and osteoclastogenesis, highlighting the modulatory impact of SPMs on bone metabolism. RvE1 and MaR1 promote osteogenic differentiation of hBMMSCs in an inflammatory environment, with their combined application yielding synergistic effects. This study provides insights into the therapeutic potential of SPMs in enhancing bone regeneration, suggesting a promising avenue for developing regenerative therapies for periodontal disease and other conditions characterized by inflammation-induced bone loss.

Specialized pro-resolution mediators in the bladder: effects of resolvin E1 on diabetic bladder dysfunction in the type 1 diabetic male Akita mouse model.

BACKGROUND: One of the most common, but least studied, diabetic complication is diabetic bladder dysfunction. Current therapies include glucose control and symptom-based interventions. However, efficacy of these therapies is mixed and often have undesirable side effects. Diabetes is now known to be a chronic inflammatory disease. Specialized pro-resolving mediators are a class of compounds that promote the resolution of inflammation and have been shown to be effective in treating chronic inflammatory conditions. In this study we examine the ability of resolvin E1 to improve signs of diabetic bladder dysfunction. METHODS: Male Akita mice (Type 1 diabetic) develop hyperglycemia at 4 weeks and signs of bladder underactivity by 15 weeks. Starting at 15 weeks, mice were given one or two weeks of daily resolvin E1 and compared to age-matched wild type and untreated Akita mice. RESULTS: Resolvin E1 did not affect diabetic blood glucose after one week, although there was a slight decrease after two weeks. Diabetes decreased body weight and increased bladder weights and this was not affected by resolvin E1. Evan's blue dye extravasation (an indirect index of inflammation) was dramatically suppressed after one week of resolvin E1 treatment, but, surprisingly, had returned to diabetic levels after two weeks of treatment. Using cystometry, untreated Akita mice showed signs of underactivity (increased void volumes and intercontraction intervals). One week of resolvin E1treatment restored these cystometric findings back to control levels. After two weeks of treatment, cystometric changes were changed from controls but still significantly different from untreated levels, indicating a durable treatment effect even in the presence of increased inflammation at 2 weeks. CONCLUSIONS: Resolvin E1 has a beneficial effect on diabetic bladder dysfunction in the type 1 diabetic male Akita mouse model.

The sphingosine-1-phosphate receptor 1 mediates the atheroprotective effect of eicosapentaenoic acid.

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have been associated with potential cardiovascular benefits, partly attributed to their bioactive metabolites. However, the underlying mechanisms responsible for these advantages are not fully understood. We previously reported that metabolites of the cytochrome P450 pathway derived from eicosapentaenoic acid (EPA) mediated the atheroprotective effect of ω-3 PUFAs. Here, we show that 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and its receptor, sphingosine-1-phosphate receptor 1 (S1PR1), in endothelial cells (ECs) can inhibit oscillatory shear stress- or tumor necrosis factor-α-induced endothelial activation in cultured human ECs. Notably, the atheroprotective effect of 17,18-EEQ and purified EPA is circumvented in male mice with endothelial S1PR1 deficiency. Mechanistically, the anti-inflammatory effect of 17,18-EEQ relies on calcium release-mediated endothelial nitric oxide synthase (eNOS) activation, which is abolished upon inhibition of S1PR1 or Gq signaling. Furthermore, 17,18-EEQ allosterically regulates the conformation of S1PR1 through a polar interaction with Lys34Nter. Finally, we show that Vascepa, a prescription drug containing highly purified and stable EPA ethyl ester, exerts its cardiovascular protective effect through the 17,18-EEQ-S1PR1 pathway in male and female mice. Collectively, our findings indicate that the anti-inflammatory effect of 17,18-EEQ involves the activation of the S1PR1-Gq-Ca2+-eNOS axis in ECs, offering a potential therapeutic target against atherosclerosis.

[Resolvin E1 as a potential lead for the treatment of depression].

Typical monoamine-based antidepressants have significant limitations, including a time lag for therapeutic response and low efficacy (more than one-third of depressed patients fail to respond to multiple antidepressant medications and are considered treatment-resistant). Conversely, ketamine, an N-methyl-D-aspartate receptor antagonist, exhibits rapid and sustained antidepressant actions in patients with treatment-resistant depression. However, clinical use of ketamine is limited due to its serious side effects. Thus, there is a significant need to develop novel ketamine-like antidepressants with fewer side effects. We previously demonstrated that intracerebroventricular infusion of resolvins (RvD1, RvD2, RvE1, RvE2, and RvE3), specialized pro-resolving lipid mediators derived from docosahexaenoic and eicosapentaenoic acids, produce antidepressant-like effects in mouse models of depression. Among resolvins, RvE1 produces the most potent antidepressant-like effects likely via ChemR23 in several mouse models of depression. Local infusion of RvE1 into the medial prefrontal cortex (mPFC) or dorsal hippocampal dentate gyrus (DG) also produces antidepressant-like effects, suggesting that these brain regions are sites of action of RvE1. Additionally, intranasal (i.n.) administration of RvE1 produces antidepressant-like effects through mechanisms similar to ketamine: activity-dependent release of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and subsequent mechanistic target of rapamycin complex 1 (mTORC1) activation in the mPFC play a crucial role in the rapid and sustained antidepressant-like actions of i.n. RvE1. Moreover, the antidepressant-like effects of i.n. RvE1 require BDNF and VEGF release, but not mTORC1 activation, in the dorsal DG. These findings suggest that RvE1 can be a promising lead for a novel rapid-acting antidepressant.

Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid (RESPECT-EPA).

BACKGROUND: Low plasma levels of eicosapentaenoic acid (EPA) are associated with cardiovascular events. This trial aimed to assess the clinical benefits of icosapent ethyl in patients with coronary artery disease, a low EPA/arachidonic acid (AA) ratio, and statin treatment. METHODS: In this prospective, multicenter, randomized, open-label, blinded end-point study, patients with stable coronary artery disease and a low EPA/AA ratio (<0.4) were randomized to EPA (1800 of icosapent ethyl administered daily) or control group. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina pectoris, and coronary revascularization. The secondary composite end points of coronary events included sudden cardiac death, fatal and nonfatal myocardial infarction, unstable angina requiring emergency hospitalization and coronary revascularization, or coronary revascularization. RESULTS: Overall, 3884 patients were enrolled at 95 sites in Japan. Among them, 2506 patients had a low EPA/AA ratio, and 1249 and 1257 patients were randomized to the EPA and control group, respectively. The median EPA/AA ratio was 0.243 (interquartile range, 0.180-0.314) and 0.235 (interquartile range, 0.163-0.310) in the EPA and control group, respectively. Over a median period of 5 years, the primary end point occurred in 112 of 1225 patients (9.1%) and 155 of 1235 patients (12.6%) in the EPA and control group, respectively (hazard ratio, 0.79 [95% CI, 0.62-1.00]; P=0.055). Meanwhile, the secondary composite end point of coronary events in the EPA group was significantly lower (81/1225 [6.6%] versus 120/1235 [9.7%] patients; hazard ratio, 0.73 [95% CI, 0.55-0.97]). Adverse events did not differ between the groups, but the rate of new-onset atrial fibrillation was significantly higher in the EPA group (3.1% versus 1.6%; P=0.017). CONCLUSIONS: Icosapent ethyl treatment resulted in a numerically lower risk of cardiovascular events that did not reach statistical significance in patients with chronic coronary artery disease, a low EPA/AA ratio, and statin treatment. REGISTRATION: URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000012069.

Structural characteristics and emulsifying properties of linear dextrin/eicosapentaenoic acid composites: Effect of the degree of polymerization.

This work aimed at building functional emulsions based on the linear dextrins (LDs) emulsion system. The gradient polyethylene glycol (PEG) precipitaion method was used to fractionate LDs into fractions with different degrees of polymerization (DP). A package, and co-precipitation procedure of LDs, and eicosapentaenoic acid (EPA) was used to fabricate LDs-EPA composites. The gas chromatograph, Fourier transform infrared spectroscopy, X-ray diffraction and differential scanning calorimetry analyses affirmed the formation of the LDs-EPA composites. The sizes of these composites were 38.55 nm, 59.14 nm to 80.62 nm, respectively, and they had good amphiphilicity. Compared with LDs, these LDs-EPA composites stabilized Pickering emulsion had higher stability and antioxidant capacity. Their emulsifying ability was positively correlated with the DP values of LDs. Furthermore, the oxidation stability results showed that LDsF10-EPA emulsion had the lowest lipid hydroperoxide (LHs) content, malondioxide (MDA) content and hexal concentration, which were 138.75 mmol kg-1 oil, 15.50 mmol kg-1 oil and 3.83 µmol kg-1 oil, respectively. The study provided a new idea and application values for the application of LDs in emulsion.

Resolvin E1 improves efferocytosis and rescues severe aplastic anemia in mice.

Severe aplastic anemia (SAA) is a rare, fatal disease characterized by severe cytopenias and loss of hematopoietic stem cells (HSCs). Immune-mediated destruction and inflammation are known drivers of SAA, however, the underlying mechanisms driving persistent inflammation are unknown. Current treatments for SAA rely on immunosuppressive therapies or HSC transplantation, however, these treatments are not always effective. Using an established mouse model of SAA, we observed a significant increase in apoptotic cells within the bone marrow (BM) and impaired efferocytosis in SAA mice, relative to radiation controls. Single-cell transcriptomic analysis revealed heterogeneity among BM monocytes and unique populations emerged during SAA characterized by increased inflammatory signatures and significantly increased expression of Sirpa and Cd47. CD47, a "don't eat me" signal, was increased on both live and apoptotic BM cells, concurrent with markedly increased expression of signal regulatory protein alpha (SIRPα) on monocytes. Functionally, SIRPα blockade improved cell clearance and reduced accumulation of CD47-positive apoptotic cells. Lipidomic analysis revealed a reduction in the precursors of specialized pro-resolving lipid mediators (SPMs) and increased prostaglandins in the BM during SAA, indicative of impaired inflammation resolution. Specifically, 18-HEPE, a precursor of E-series resolvins, was significantly reduced in SAA-induced mice relative to radiation controls. Treatment of SAA mice with Resolvin E1 (RvE1) improved efferocytic function, BM cellularity, platelet output, and survival. Our data suggest that impaired efferocytosis and inflammation resolution contributes to SAA progression and demonstrate that SPMs, such as RvE1, offer new and/or complementary treatments for SAA that do not rely on immune suppression.

Icosapent ethyl modulates circulating vascular regenerative cell content: The IPE-PREVENTION CardioLink-14 trial.

BACKGROUND: REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) showed that icosapent ethyl (IPE) reduced major adverse cardiovascular events by 25%. Since the underlying mechanisms for these benefits are not fully understood, the IPE-PREVENTION CardioLink-14 trial (ClinicalTrials.gov: NCT04562467) sought to determine if IPE regulates vascular regenerative (VR) cell content in people with mild to moderate hypertriglyceridemia. METHODS: Seventy statin-treated individuals with triglycerides ≥1.50 and <5.6 mmol/L and either atherosclerotic cardiovascular disease or type 2 diabetes with additional cardiovascular risk factors were randomized to IPE (4 g/day) or usual care. VR cells with high aldehyde dehydrogenase activity (ALDHhi) were isolated from blood collected at the baseline and 3-month visits and characterized with lineage-specific cell surface markers. The primary endpoint was the change in frequency of pro-vascular ALDHhiside scatter (SSC)lowCD133+ progenitor cells. Change in frequencies of ALDHhiSSCmid monocyte and ALDHhiSSChi granulocyte precursor subsets, reactive oxygen species production, serum biomarkers, and omega-3 levels were also evaluated. FINDINGS: Baseline characteristics, cardiovascular risk factors, and medications were balanced between the groups. Compared to usual care, IPE increased the mean frequency of ALDHhiSSClowCD133+ cells (-1.00% ± 2.45% vs. +7.79% ± 1.70%; p = 0.02), despite decreasing overall ALDHhiSSClow cell frequency. IPE assignment also reduced oxidative stress in ALDHhiSSClow progenitors and increased ALDHhiSSChi granulocyte precursor cell content. CONCLUSIONS: IPE-PREVENTION CardioLink-14 provides the first translational evidence that IPE can modulate VR cell content and suggests a novel mechanism that may underlie the cardioprotective effects observed with IPE in REDUCE-IT. FUNDING: HLS Therapeutics provided the IPE in kind and had no role in the study design, conduct, analyses, or interpretation.

Lipoprotein(a) Blood Levels and Cardiovascular Risk Reduction With Icosapent Ethyl.

BACKGROUND: Elevated lipoprotein(a) (Lp[a]) concentrations are associated with increased cardiovascular event risk even in the presence of well-controlled low-density lipoprotein cholesterol levels, but few treatments are documented to reduce this residual risk. OBJECTIVES: The aim of this post hoc analysis of REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) was to explore the cardiovascular benefit of icosapent ethyl (IPE) across a range of Lp(a) levels. METHODS: A total of 8,179 participants receiving statin therapy with established cardiovascular disease or age ≥50 years with diabetes and ≥1 additional risk factor, fasting triglyceride 1.69 to 5.63 mmol/L, and low-density lipoprotein cholesterol 1.06 to 2.59 mmol/L were randomized to receive 2 g twice daily of IPE or matching placebo. Relationships between continuous baseline Lp(a) mass concentration and risk for first and total (first and subsequent) major adverse cardiovascular events (MACE) were analyzed, along with the effects of IPE on first MACE among those with Lp(a) concentrations ≥50 or <50 mg/dL. RESULTS: Among 7,026 participants (86% of those randomized) with baseline Lp(a) assessments, the median concentration was 11.6 mg/dL (Q1-Q3: 5.0-37.4 mg/dL). Lp(a) had significant relationships with first and total MACE (P < 0.0001), while event reductions with IPE did not vary across the range of Lp(a) (interaction P > 0.10). IPE significantly reduced first MACE in subgroups with concentrations ≥50 and <50 mg/dL. CONCLUSIONS: Baseline Lp(a) concentration was prognostic for MACE among participants with elevated triglyceride levels receiving statin therapy. Importantly, IPE consistently reduced MACE across a range of Lp(a) levels, including among those with clinically relevant elevations.

Adiposity associates with lower plasma resolvin E1 (Rve1): a population study.

BACKGROUND: Inadequate inflammation resolution may contribute to persistent low-grade inflammation that accompanies many chronic conditions. Resolution of inflammation is an active process driven by Specialized Pro-resolving Mediators (SPM) that derive from long chain n-3 and n-6 fatty acids. This study examined plasma SPM in relation to sex differences, lifestyle and a broad range cardiovascular disease (CVD) risk factors in 978, 27-year olds from the Australian Raine Study. METHODS: Plasma SPM pathway intermediates (18-HEPE, 17-HDHA and 14-HDHA), and SPM (E- and D-series resolvins, PD1, MaR1) and LTB4 were measured by liquid chromatography-tandem mass spectrometry (LCMSMS). Pearson correlations and multiple regression analyses assessed relationships between SPM and CVD risk factors. Unpaired t-tests or ANOVA assessed the effect of sex, smoking, unhealthy alcohol consumption and obesity on SPM. RESULTS: Women had higher 17-HDHA (p = 0.01) and lower RvE1 (p < 0.0001) and RvD1 (p = 0.05) levels compared with men. In univariate analysis, obesity associated with lower RvE1 (p = 0.002), whereas smoking (p < 0.001) and higher alcohol consumption (p < 0.001) associated with increased RvE1. In multiple regression analysis, plasma RvE1 was negatively associated with a range of measures of adiposity including BMI, waist circumference, waist-to-height ratio, abdominal subcutaneous fat volume, and skinfold thicknesses in both men and women. CONCLUSION: This population study suggests that a deficiency in plasma RvE1 may occur in response to increasing adiposity. This observation could be relevant to ongoing inflammation that associates with CVD and other chronic diseases.

Specialized proresolving mediator resolvin E1 corrects the altered cystic fibrosis nasal epithelium cilia beating dynamics.

In cystic fibrosis (CF), impaired mucociliary clearance leads to chronic infection and inflammation. However, cilia beating features in a CF altered environment, consisting of dehydrated airway surface liquid layer and abnormal mucus, have not been fully characterized. Furthermore, acute inflammation is normally followed by an active resolution phase requiring specialized proresolving lipid mediators (SPMs) and allowing return to homeostasis. However, altered SPMs biosynthesis has been reported in CF. Here, we explored cilia beating dynamics in CF airways primary cultures and its response to the SPMs, resolvin E1 (RvE1) and lipoxin B4 (LXB4). Human nasal epithelial cells (hNECs) from CF and non-CF donors were grown at air-liquid interface. The ciliary beat frequency, synchronization, orientation, and density were analyzed from high-speed video microscopy using a multiscale Differential Dynamic Microscopy algorithm and an in-house developed method. Mucins and ASL layer height were studied by qRT-PCR and confocal microscopy. Principal component analysis showed that CF and non-CF hNEC had distinct cilia beating phenotypes, which was mostly explained by differences in cilia beat organization rather than frequency. Exposure to RvE1 (10 nM) and to LXB4 (10 nM) restored a non-CF-like cilia beating phenotype. Furthermore, RvE1 increased the airway surface liquid (ASL) layer height and reduced the mucin MUC5AC thickness. The calcium-activated chloride channel, TMEM16A, was involved in the RvE1 effect on cilia beating, hydration, and mucus. Altogether, our results provide evidence for defective cilia beating in CF airway epithelium and a role of RvE1 and LXB4 to restore the main epithelial functions involved in the mucociliary clearance.

Omega-3 fatty acids for cardiovascular event lowering.

Low-density lipoprotein cholesterol (LDL-C) is the main target for therapeutics aimed at reducing the risk of atherosclerotic cardiovascular disease (ASCVD) and downstream cardiovascular (CV) events. However, multiple studies have demonstrated that high-risk patient populations harbour residual risk despite effective LDL-C lowering. While data support the causal relationship between triglycerides and ASCVD risk, triglyceride-lowering therapies such as omega-3 fatty acids have shown mixed results in CV outcomes trials. Notably, icosapent ethyl, a purified formulation of eicosapentaenoic acid (EPA), has garnered compelling evidence in lowering residual CV risk in patients with hypertriglyceridaemia and treated with statins. In this review, we summarize studies that have investigated omega-3-fatty acids for CV event lowering and discuss the clinical implementation of these agents based on trial data and guidelines.