Severe acute respiratory syndrome coronavirus 2 is responsible for coronavirus disease 2019 (COVID‐19). While COVID‐19 is often benign, a subset of patients develops severe multilobar pneumonia that ...can progress to an acute respiratory distress syndrome. There is no cure for severe COVID‐19 and few treatments significantly improved clinical outcome. Dexamethasone and possibly aspirin, which directly/indirectly target the biosynthesis/effects of numerous lipid mediators are among those options. Our objective was to define if severe COVID‐19 patients were characterized by increased bioactive lipids modulating lung inflammation. A targeted lipidomic analysis of bronchoalveolar lavages (BALs) by tandem mass spectrometry was done on 25 healthy controls and 33 COVID‐19 patients requiring mechanical ventilation. BALs from severe COVID‐19 patients were characterized by increased fatty acids and inflammatory lipid mediators. There was a predominance of thromboxane and prostaglandins. Leukotrienes were also increased, notably LTB4, LTE4, and eoxin E4. Monohydroxylated 15‐lipoxygenase metabolites derived from linoleate, arachidonate, eicosapentaenoate, and docosahexaenoate were also increased. Finally yet importantly, specialized pro‐resolving mediators, notably lipoxin A4 and the D‐series resolvins, were also increased, underscoring that the lipid mediator storm occurring in severe COVID‐19 involves pro‐ and anti‐inflammatory lipids. Our data unmask the lipid mediator storm occurring in the lungs of patients afflicted with severe COVID‐19. We discuss which clinically available drugs could be helpful at modulating the lipidome we observed in the hope of minimizing the deleterious effects of pro‐inflammatory lipids and enhancing the effects of anti‐inflammatory and/or pro‐resolving lipid mediators.
The gut microbiota is a unique ecosystem of microorganisms interacting with the host through several biochemical mechanisms. The endocannabinoidome (eCBome), a complex signaling system including the ...endocannabinoid system, approximately 50 receptors and metabolic enzymes, and more than 20 lipid mediators with important physiopathologic functions, modulates gastrointestinal tract function and may mediate host cell-microbe communications there. Germ-free (GF) mice, which lack an intestinal microbiome and so differ drastically from conventionally raised (CR) mice, offer a unique opportunity to explore the eCBome in a microbe-free model and in the presence of a reintroduced functional gut microbiome through fecal microbiota transplant (FMT). We aimed to gain direct evidence for a link between the microbiome and eCBome systems by investigating eCBome alterations in the gut in GF mice before and after FMT. Basal eCBome gene expression and lipid profiles were measured in various segments of the intestine of GF and CR mice at juvenile and adult ages using targeted quantitative PCR transcriptomics and LC-MS/MS lipidomics. GF mice exhibited age-dependent modifications in intestinal eCBome gene expression and lipid mediator levels. FMT from CR donor mice to age-matched GF male mice reversed several of these alterations, particularly in the ileum and jejunum, after only 1 week, demonstrating that the gut microbiome directly impacts the host eCBome and providing a cause-effect relationship between the presence or absence of intestinal microbes and eCBome signaling. These results open the way to new studies investigating the mechanisms through which intestinal microorganisms exploit eCBome signaling to exert some of their physiopathologic functions.
The urgency of climate change has led several countries to develop renewable energy in order to reduce CO2 emissions, through the means of various subsidies. In the electricity sector, one drawback ...of such policies is the negative impact on electricity prices, known as the merit-order effect. This paper aims at assessing how intermittent renewable production depresses electricity prices in Germany, which has experienced a significant increase of its renewable capacity over the last two decades. To do so, we use a two-regime Markov switching model, that enables to disentangle the impact of wind and solar generation, depending on the price being high or low. We find as expected that renewable production induces a negative marginal effect, which is stronger in regimes of relatively high prices. In addition, we show that both wind and solar productions have a significant impact on the distribution of prices, and in particular on the frequency and expected duration of each regime. This has implications in terms of market design, security of supply, and support mechanisms for renewables.
•Renewable production depresses electricity prices (merit-order effect).•The merit-order effect is more important during high-price periods.•Renewable production also induces more frequent and longer episodes of low prices.•The profitability of all producing units and security of supply are put at risk.•Policy implications include market design and support mechanisms.
The study investigated the relationship between short sprint performance and mechanical parameters obtained during the acceleration and deceleration tasks with the change of direction (COD) ...performance in female and male soccer players. The acceleration and deceleration ability were compared in the “High/Fast”
versus
“Low/Slow” COD performance group based on a median split analysis in each sex group. One hundred three French soccer players were assessed for the sprinting Force-Velocity (F-V) profile (i.e., theoretical maximal force F0, velocity V0, power Pmax), 10 m performance, linear deceleration test (maximal braking force HBF
max
, braking power BP
max
, deceleration Dec
max
), and COD performance using 505-test. The 10 m performance was strongly associated with 505-test performance (ES = 0.64 to 0.71), whereas the sprinting F-V profiles parameters were weakly to moderately correlated with 505- performance (ES = -0.47 to -0.38). The BP
max
was also moderately associated with 505-test performance (ES: range = -0.55 to -0.46). In addition, the High/Fast female COD group presented higher F0, Pmax, HBF
max
, and BP
max
than the Low/Slow group, whereas the male groups presented very few mechanical differences. Multiple regression analysis shows that the COD performance of male players was determined by 10 m performance and maximum deceleration power. In contrast, no statistically significant model could be found to determine the change of direction performance in female players. In conclusion, the current finding indicated that the only variable strongly associated with COD performance was the linear 10 m sprint time. In the same way, the mechanical parameters obtained from acceleration and deceleration seemed to play a non-neglectable role in this population.
Neutrophils and eosinophils are important sources of bioactive lipids from the 5- and the 15-lipoxygenase (LO) pathways. Herein, we compared the effectiveness of humans eosinophils and ...eosinophil-depleted neutrophils to synthesize 15-LO metabolites using a cocktail of different 15-LO substrates as well as their sensitivities to eight documented 15-lipoxygenase inhibitors. The treatment of neutrophils and eosinophils with linoleic acid, dihomo-γ-linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid and arachidonyl-ethanolamide, led to the synthesis of 13-HODE, 15-HETrE, 15-HETE, 15-HEPE, 14-HDHA/17-HDHA, and 15-hydroxy-AEA. Neutrophils and eosinophils also metabolized the endocannabinoid 2-arachidonoyl-glycerol into 15-HETE-glycerol, although this required 2-arachidonoyl-glycerol hydrolysis inhibition. Neutrophils and eosinophils differed in regard to dihomo-γ-linolenic acid and linoleic acid utilization with 15-HETrE/13-HODE ratios of 0.014 ± 0.0008 and 0.474 ± 0.114 for neutrophils and eosinophils respectively. 15-LO metabolite synthesis by neutrophils and eosinophils also differed in regard to their relative production of 17-HDHA and 14-HDHA.The synthesis of 15-LO metabolites by neutrophils was concentration-dependent and rapid, reaching a plateau after one minute. While investigating the biosynthetic routes involved, we found that eosinophil-depleted neutrophils express the 15-lipoxygenase-2 but not the 15-LO-1, in contrast to eosinophils which express the 15-LO-1 but not the 15-LO-2. Moreover, 15-LO metabolite synthesis by neutrophils was not inhibited by the 15-LO-1 inhibitors BLX769, BLX3887, and ML351. However, 15-LO product synthesis was partially inhibited by 100 μM NDGA. Altogether, our data indicate that the best 15-LO-1 inhibitors in eosinophils are BLX3887, BLX769, NDGA and ML351 and that the synthesis of 15-LO metabolites by neutrophils does not involve the 15-LO-1 nor the phosphorylation of 5-LO on Ser-663 but is rather the consequence of 15-LO-2 or another unidentified 15-LO.
Omega-3 fatty acids support cardiometabolic health and reduce chronic low-grade inflammation. These fatty acids may impart their health benefits partly by modulating the endocannabinoidome and the ...gut microbiome, both of which are key regulators of metabolism and the inflammatory response. Whole hemp seeds (
Cannabis sativa
) are of exceptional nutritional value, being rich in omega-3 fatty acids. We assessed the effects of dietary substitution (equivalent to about 2 tablespoons of seeds a day for humans) of whole hemp seeds in comparison with whole linseeds in a diet-induced obesity mouse model and determined their effects on obesity and the gut microbiome-endocannabinoidome axis. We show that whole hemp seed substitution did not affect weigh gain, adiposity, or food intake, whereas linseed substitution did, in association with higher fasting glucose levels, greater insulin release during an oral glucose tolerance test, and higher levels of liver triglycerides than controls. Furthermore, hemp seed substitution mitigated diet-induced obesity-associated increases in intestinal permeability and circulating PAI-1 levels, while having no effects on markers of inflammation in epididymal adipose tissue, which were, however, increased in mice fed linseeds. Both hemp seeds and linseeds were able to modify the expression of several endocannabinoidome genes and markedly increased the levels of several omega-3 fatty acid–derived endocannabinoidome bioactive lipids with previously suggested anti-inflammatory actions in a tissue specific manner, despite the relatively low level of seed substitution. While neither diet markedly modified the gut microbiome, mice on the hemp seed diet had higher abundance of
Clostridiaceae 1
and
Rikenellaceae
than mice fed linseed or control diet, respectively. Thus, hemp seed-containing foods might represent a source of healthy fats that are not likely to exacerbate the metabolic consequences of obesogenic diets while producing intestinal permeability protective effects and some anti-inflammatory actions.
Elderly represents a growing population and cardiovascular diseases (CVD) is one of the leading causes of mortality in this population. Sex differences are involved in CVD with middle-aged males ...being at higher risk than females. After menopause, females are no longer protected by hormones and the role of sex on cardiovascular parameters involved in CVD, such as endothelial function and blood viscosity, is still unclear. The purpose of this study was to investigate the effect of sex on endothelial function, blood viscosity and CVD in elderly. Clinical investigation and blood analyses were performed on 182 (93 females and 89 males) elderly participants (mean age: 75.83 ± 1.22). Health status of participants were classified. Sex differences in endothelial function, blood viscosity, high density lipoprotein (HDL), hematocrit, and red blood cell (RBC) aggregation were assessed. CVD prevalence was higher in males (27.0%) than in females (5.4%) (
< 0.001). Females had higher vasoreactivity (
= 0.014) and HDL (
< 0.001) level than males. Blood viscosity was higher in males than in females at any shear rate (
< 0.001). Hematocrit was greater in males than in females (
< 0.001) while RBC aggregation did not differ between the two populations. To conclude, females have less CVD than age-matched males that might be due to their greater vascular function and lower blood viscosity.
Temporary disruption of the blood-brain barrier (BBB) using pulsed ultrasound leads to the clearance of both amyloid and tau from the brain, increased neurogenesis, and mitigation of cognitive ...decline in pre-clinical models of Alzheimer's disease (AD) while also increasing BBB penetration of therapeutic antibodies. The goal of this pilot clinical trial was to investigate the safety and efficacy of this approach in patients with mild AD using an implantable ultrasound device.
An implantable, 1-MHz ultrasound device (SonoCloud-1) was implanted under local anesthesia in the skull (extradural) of 10 mild AD patients to target the left supra-marginal gyrus. Over 3.5 months, seven ultrasound sessions in combination with intravenous infusion of microbubbles were performed twice per month to temporarily disrupt the BBB.
F-florbetapir and
F-fluorodeoxyglucose positron emission tomography (PET) imaging were performed on a combined PET/MRI scanner at inclusion and at 4 and 8 months after the initiation of sonications to monitor the brain metabolism and amyloid levels along with cognitive evaluations. The evolution of cognitive and neuroimaging features was compared to that of a matched sample of control participants taken from the Alzheimer's Disease Neuroimaging Initiative (ADNI).
A total of 63 BBB opening procedures were performed in nine subjects. The procedure was well-tolerated. A non-significant decrease in amyloid accumulation at 4 months of - 6.6% (SD = 7.2%) on
F-florbetapir PET imaging in the sonicated gray matter targeted by the ultrasound transducer was observed compared to baseline in six subjects that completed treatments and who had evaluable imaging scans. No differences in the longitudinal change in the glucose metabolism were observed compared to the neighboring or contralateral regions or to the change observed in the same region in ADNI participants. No significant effect on cognition evolution was observed in comparison with the ADNI participants as expected due to the small sample size and duration of the trial.
These results demonstrate the safety of ultrasound-based BBB disruption and the potential of this technology to be used as a therapy for AD patients. Research of this technique in a larger clinical trial with a device designed to sonicate larger volumes of tissue and in combination with disease-modifying drugs may further enhance the effects observed.
ClinicalTrials.gov, NCT03119961.
2‐Arachidonoyl‐glycerol (2‐AG) is an endocannabinoid with anti‐inflammatory properties. Blocking 2‐AG hydrolysis to enhance CB2 signaling has proven effective in mouse models of inflammation. ...However, the expression of 2‐AG lipases has never been thoroughly investigated in human leukocytes. Herein, we investigated the expression of seven 2‐AG hydrolases by human blood leukocytes and alveolar macrophages (AMs) and found the following protein expression pattern: monoacylglycerol (MAG lipase; eosinophils, AMs, monocytes), carboxylesterase (CES1; monocytes, AMs), palmitoyl‐protein thioesterase (PPT1; AMs), α/β‐hydrolase domain (ABHD6; mainly AMs), ABHD12 (all), ABHD16A (all), and LYPLA2 (lysophospholipase 2; monocytes, lymphocytes, AMs). We next found that all leukocytes could hydrolyze 2‐AG and its metabolites derived from cyclooxygenase‐2 (prostaglandin E2‐glycerol PGE2‐G) and the 15‐lipoxygenase (15‐hydroxy‐eicosatetraenoyl‐glycerol 15‐HETE‐G). Neutrophils and eosinophils were consistently better at hydrolyzing 2‐AG and its metabolites than monocytes and lymphocytes. Moreover, the efficacy of leukocytes to hydrolyze 2‐AG and its metabolites was 2‐AG ≥ 15‐HETE‐G >> PGE2‐G for each leukocyte. Using the inhibitors methylarachidonoyl‐fluorophosphonate (MAFP), 4‐nitrophenyl‐4‐(dibenzod1,3dioxol‐5‐yl(hydroxy)methyl)piperidine‐1‐carboxylate (JZL184), Palmostatin B, 4′‐carbamoylbiphenyl‐4‐yl methyl(3‐(pyridin‐4‐yl)benzyl)carbamate, N‐methyl‐N‐3‐(4‐pyridinyl)phenylmethyl‐4′‐(aminocarbonyl)1,1′‐biphenyl‐4‐yl ester carbamic acid (WWL70), 4′‐methyl3‐(4‐pyridinyl)phenylmethylaminocarbonyloxy‐1,1′‐biphenyl‐4‐carboxylic acid, ethyl ester (WWL113), tetrahydrolipstatin, and ML349, we could not pinpoint a specific hydrolase responsible for the hydrolysis of 2‐AG, PGE2‐G, and 15‐HETE‐G by these leukocytes. Furthermore, JZL184, a selective MAG lipase inhibitor, blocked the hydrolysis of 2‐AG, PGE2‐G, and 15‐HETE‐G by neutrophils and the hydrolysis of PGE2‐G and 15‐HETE‐G by lymphocytes, two cell types with limited/no MAG lipase. Using an activity‐based protein profiling (ABPP) probe to label hydrolases in leukocytes, we found that they express many MAFP‐sensitive hydrolases and an unknown JZL184‐sensitive hydrolase of ∼52 kDa. Altogether, our results indicate that human leukocytes are experts at hydrolyzing 2‐AG and its metabolites via multiple lipases and probably via a yet‐to‐be characterized 52 kDa hydrolase. Blocking 2‐AG hydrolysis in humans will likely abrogate the ability of human leukocytes to degrade 2‐AG and its metabolites and increase their anti‐inflammatory effects in vivo.
Human leukocytes express several 2‐arachidonoyl‐glycerol lipases and efficiently hydrolyze 2‐arachidonoyl‐glycerol and its metabolites from the COX‐2 and 15‐LO pathways.
Chronic hemolysis, enhanced oxidative stress, and decreased nitric oxide (NO) bioavailability promote vasculopathy in sickle cell anemia (SCA). Oxidative stress and NO are known to modulate eryptosis ...in healthy red blood cells (RBCs); however, their role in SCA eryptosis and their impact on the genesis of RBC-derived microparticles (RBC-MPs) remains poorly described. RBC-MPs could play a role in vascular dysfunction in SCA. The aims of this study were to evaluate the roles of oxidative stress and NO in eryptosis and RBC-MPs release, and to determine whether RBC-MPs could be involved in vascular dysfunction in SCA. Markers of eryptosis and oxidative stress, plasma RBC-MPs concentration and arterial stiffness were compared between SCA and healthy (AA) individuals
experiments were performed to test: 1) the effects of oxidative stress (antioxidant: n-acetylcysteine (NAC); pro-oxidant: cumene hydroperoxide) and NO (NO donor: sodium nitroprusside (SNP); NO-synthase inhibitor (L-NIO)) on eryptosis, RBC deformability and RBC-MP genesis; 2) the effects of SCA/AA-RBC-MPs on human aortic endothelial cell (HAEC) inflammatory phenotype and TLR4 pathway. Eryptosis, RBC-MPs, oxidative stress and arterial stiffness were increased in SCA. NAC increased RBC deformability and decreased eryptosis and RBC-MPs release, while cumene did the opposite. SNP increased RBC deformability and limited eryptosis, but had no effect on RBC-MPs. L-NIO did not affect these parameters. Arterial stiffness was correlated with RBC-MPs concentration in SCA. RBC-MPs isolated directly from SCA blood increased adhesion molecules expression and the production of cytokines by HAEC compared to those isolated from AA blood. TLR4 inhibition alleviated these effects. Our data show that oxidative stress could promote eryptosis and the release of RBC-MPs that are potentially involved in macrovascular dysfunction in SCA.
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