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Lack of dystrophin causes muscle degeneration, which is exacerbated by chronic inflammation and reduced regenerative capacity of muscle stem cells in Duchenne Muscular Dystrophy (DMD). To date, glucocorticoids remain the gold standard for the treatment of DMD. These drugs are able to slow down the progression of the disease and increase lifespan by dampening the chronic and excessive inflammatory process; however, they also have numerous harmful side effects that hamper their therapeutic potential. Here, we investigated Resolvin-D2 as a new therapeutic alternative having the potential to target multiple key features contributing to the disease progression. Our in vitro findings showed that Resolvin-D2 promotes the switch of macrophages toward their anti-inflammatory phenotype and increases their secretion of pro-myogenic factors. Moreover, Resolvin-D2 directly targets myogenic cells and promotes their differentiation and the expansion of the pool of myogenic progenitor cells leading to increased myogenesis. These effects are ablated when the receptor Gpr18 is knocked-out, knocked-down, or blocked by the pharmacological antagonist O-1918. Using different mouse models of DMD, we showed that Resolvin-D2 targets both inflammation and myogenesis leading to enhanced muscle function compared to glucocorticoids. Overall, this preclinical study has identified a new therapeutic approach that is more potent than the gold-standard treatment for DMD. Glucocorticoids delay muscle wasting in Duchenne Muscular Dystrophy by reducing inflammation; but also have harmful side effects. Here, the authors show that Resolvin-D2 is more effective than glucocorticoids in mitigating muscular dystrophy in mouse models, due to its ability to dampen inflammation and target myogenic cells to improve muscle regeneration.

PurposeComplexities surrounding the manufacture and quality control of nanomedicines become increasingly apparent. This research article offers a case study to investigate how, at the laboratory scale, various stages of liposome and nanoparticle synthesis affect the amount of residual solvent found in the formulations. The objective is to bring insights on the reliability of each of these processes to provide final products which meet regulatory standards and facilitate identifying possible bottleneck early during the development process.MethodsThe residual solvent at various stages of preparation and purification was measured by headspace gas chromatography. Liposomes were prepared by two different methods with and without solvent. Polymer nanoparticles prepared via nanoprecipitation and purified by ultrafiltration were studied. The effects of purification by size exclusion chromatography and dialysis were also investigated.ResultsThe complete removal of residual solvent requires processes which go beyond usual preparation methods.ConclusionsThis work might prove valuable as a reference for scientists of different fields to compare their own practices and streamline the translation of nanomedicines into efficacious and safe drug products.

The muscle stem cell niche is well-described as influencing myogenic cell fate decision; however, the intrinsic mechanisms driving muscle stem cell progression during myogenesis are not yet fully elucidated. Here, we demonstrate that bioactive lipid class switching, an auto-regulatory mechanism originally described during the inflammatory process, is conserved during myogenesis. During the transition from proliferation to differentiation, myogenic cells shift from pro-inflammatory to pro-resolution pathways, a process partially mediated by 15Δ-PGJ 2 that promotes the expression of the prostaglandin inactivation enzyme 15-hydroxyprostaglandin dehydrogenase. Using pharmacological inhibitors and knockout models of the pro-resolution enzyme 15-lipoxygenase, we show that blocking the bioactive lipid class switching impairs myoblast differentiation in vitro and muscle regeneration in vivo. Administration of the pro-resolving mediator Protectin-D1 restores myogenesis, enhances muscle regeneration post-injury and improves muscle phenotype in a dystrophic mouse model. Overall, these findings provide a better comprehension of the mechanisms regulating myogenic progression, which opens new therapeutic avenues for muscle regeneration and dystrophies. Here they show that myogenic cells shift their bioactive lipid profile from pro-inflammatory to pro-resolving during myogenesis. Disrupting this transition impairs differentiation, whereas Protectin-D1 restores fusion and improves muscle phenotype in a dystrophic model.

Statin-associated muscle symptoms (SAMS) are frequently reported. Nevertheless, few data on objective measures of muscle function are available. Recent data suggesting an important nocebo effect with statin use could confound such effects. The objective was to assess if subjective and objective measures of muscle function improve after drug withdrawal in SAMS reporters. Patients (59 men, 33 women, 50.3±9.6 yrs.) in primary cardiovascular prevention composed three cohorts: statin users with (SAMS, n = 61) or without symptoms (No SAMS, n = 15), and controls (n = 16) (registered at clinicaltrials.gov, NCT01493648). Force (F), endurance (E) and power (P) of the leg extensors (ext) and flexors (fle) and handgrip strength (Fhg) were measured using isokinetic and handheld dynamometers, respectively. A 10-point visual analogue scale (VAS) was used to self-assess SAMS intensity. Measures were taken before and after two months of withdrawal. Following withdrawal, repeated-measures analyses show improvements for the entire cohort in Eext, Efle, Ffle, Pext and Pfle (range +7.2 to +13.3%, all p≤0.02). Post-hoc analyses show these changes to occur notably in SAMS (+8.8 to +16.6%), concurrent with a decrease in subjective perception of effects in SAMS (VAS, from 5.09 to 1.85). Fhg was also improved in SAMS (+4.0 to +6.2%) when compared to No SAMS (-1.7 to -4.2%) (all p = 0.02). Whether suffering from \"true\" SAMS or nocebo, those who reported SAMS had modest but relevant improvements in muscle function concurrent with a decrease in subjective symptoms intensity after drug withdrawal. Greater attention by clinicians to muscle function in frail statin users appears warranted. This study is registered in clinicaltrials.gov (NCT01493648).

Oxylipins are derived from enzymatic and non-enzymatic oxidation of n -3 and n -6 long-chain polyunsaturated fatty acids. They are known to be involved in inflammatory processes. The aim of this study was to describe the breast milk oxylipin profile following a docosahexaenoic acid (DHA) supplementation of mothers of preterm infants. We examined the oxylipins profile in breast milk collected at day 14 post-delivery, of 40 mothers who delivered before 29 weeks of gestation and who were supplemented with either DHA-rich algae oil (S-DHA) or a placebo (PL). These mothers were selected from the MOBYDIck cohort (NCT02371460 registered on 25/05/2015 in ClinicalTrials.gov) according to the supplementation received (S-DHA vs. PL) and the DHA content quartiles as measured in breast milk (Low vs. High) to generate four study groups. Milk oxylipins, as ng/mL of milk, were analyzed by LC-MS/MS. Ten oxylipins derived from DHA were higher in the S-DHA-High group than the other three groups (P < 0.001). The 18-HEPE, was also higher in the S-DHA-High group (0.11 ± 0.01) compared to the other groups (P = 0.0001). Compared to the PL-Low group, there was a reduction in pro-inflammatory prostaglandins found in the S-DHA-High group with lower levels of prostaglandins PGF 2α (0.21 ± 0.45 in the S-DHA-High group vs. 1.87 ± 0.44 in the PL-Low group, P = 0.03) and of PGE 2 (0.33 ± 0.26 in the S-DHA-High group vs. 1.28 ± 0.25 in the PL-Low group, P = 0.04).In sum, the DHA supplementation was linked with a predominance of anti-inflammatory oxylipins in breast milk of mothers who delivered very preterm, like 17(S)-HDHA and 18-HEPE, precursors of D and E resolvins respectively. This was also accompanied with a lower level of pro-inflammatory prostaglandins.

Epidemiological investigations consistently demonstrate an overrepresentation of the elderly in COVID-19 hospitalizations and fatalities, making the advanced age as a major predictor of disease severity. Despite this, a comprehensive understanding of the cellular and molecular mechanisms explaining how old age represents a major risk factor remain elusive. To investigate this, we compared SARS-CoV-2 infection outcomes in young adults (2 months) and geriatric (15–22 months) mice. Both groups of K18-ACE2 mice were intranasally infected with 500 TCID 50 of SARS-CoV-2 Delta variant with analyses performed on days 3, 5, and 7 post-infection (DPI). Analyses included pulmonary cytokines, lung RNA-seq, viral loads, lipidomic profiles, and histological assessments, with a concurrent evaluation of the percentage of mice reaching humane endpoints. The findings unveiled notable differences, with aged mice exhibiting impaired viral clearance, reduced survival, and failure to recover weight loss due to infection. RNA-seq data suggested greater lung damage and reduced respiratory function in infected aged mice. Additionally, elderly-infected mice exhibited a deficient antiviral response characterized by reduced Th1-associated mediators (IFNγ, CCL2, CCL3, CXCL9) and diminished number of macrophages, NK cells, and T cells. Furthermore, mass-spectrometry analysis of the lung lipidome indicated altered expression of several lipids with immunomodulatory and pro-resolution effects in aged mice such as Resolvin, HOTrEs, and NeuroP, but also DiHOMEs-related ARDS. These findings indicate that aging affects antiviral immunity, leading to prolonged infection, greater lung damage, and poorer clinical outcomes. This underscores the potential efficacy of immunomodulatory treatments for elderly subjects experiencing symptoms of severe COVID-19.

Introduction: Type 2 diabetes (T2D) risk factors are associated with gut microbiota dysregulation that can alter circulating metabolite levels such as bile acids (BAs) and short-chain fatty acids (SCFAs). The objective was to investigate how the high dairy (HD) (≥4 servings/day) product intake compared to adequate dairy (AD) (≤2 servings/day) intake influences the correlations between Roseburia, Faecalibacterium, Flavonifractor, as well as Verrucomicrobia and circulating BAs and SCFAs in subjects at risk of T2D. Methods: In a randomized crossover trial, 10 hyperinsulinemic adults were randomized to HD or AD for 6 weeks separated by a 6-week washout period. Gut microbiota were measured with 16S rRNA-based high-throughput sequencing. BA profiling in plasma was performed by high-performance liquid chromatography-tandem mass spectrometry. Serum SCFAs were determined using headspace gas chromatography. Results: No significant differences were observed in mean circulating BA or SCFA levels between AD and HD consumption. Verrucomicrobia and Flavonifractor showed positive correlations with secondary BAs following HD and AD intake, respectively. Additionally, Flavonifractor correlated positively with acetic and propionic acids after HD intake. Roseburia correlated positively with primary BAs, propionate, and butyrate after HD intake. Faecalibacterium was positively correlated with cholic acid after AD intake and with hexanoic acid after HD intake. Conclusion: These findings suggest that HD intake may modulate microbiota-metabolite interactions without altering circulating metabolite concentrations, highlighting a potential role for dietary patterns in shaping gut-derived metabolic signals in individuals at risk of T2D.

Secretory phospholipase A 2 -IIA (sPLA 2 -IIA) is a bactericidal enzyme that hydrolyzes membrane phospholipids, releasing lipid metabolites that can affect inflammation. sPLA 2 -IIA exhibits poor activity toward eukaryotic cells but preferentially targets gram-positive bacterial membranes. While sPLA 2 -IIA is constitutively expressed in the intestine and upregulated by inflammation in various bodily fluids, its precise physiological substrates remain debated. Intriguingly, sPLA 2 -IIA can modulate the intestinal lipidome without altering the microbiota composition. Here, we investigated whether sPLA 2 -IIA could use membranes from bacterial extracellular vesicles (bEVs) as alternative substrates to modulate immune signaling. We found that bEVs from both Staphylococcus aureus and Escherichia coli could mitigate the bactericidal effects of sPLA 2 -IIA on gram-positive bacteria. Enzymatic hydrolysis of bacteria, bEVs and fecal extracellular vesicles released distinct lipid metabolites and differentially impacted Toll-like receptor activation. These findings suggest that sPLA 2 -IIA can use bEVs as substrates and modulate inflammatory signaling through the generation of pathogen-associated molecular patterns, thus linking bacterial lipid metabolism to host immune response. Secretory phospholipase A2-IIA, a bactericidal enzyme whose main expression is in the intestine, uses bacterial extracellular vesicles as substrates to release lipid metabolites and affect immune pathways.

Indigenous peoples have traditionally relied on foods hunted and gathered from their immediate environment. The Eastern James Bay Cree people consume wild game and birds, and these are believed to provide health as well as cultural benefits. To determine the fatty acid (FA) composition of traditional game and bird meats hunted in the Eastern James Bay area. Harvested traditional game and birds were analysed for FA composition. A total of 52 samples from six wildlife species were collected in the areas of Chisasibi, Waswanipi and Mistissini, of which 35 were from birds (white partridge and Canada goose) and 17 were from land animals (beaver, moose, caribou and black bear). Alpha-linolenic acid (ALA) was the most common n-3 polyunsaturated fatty acid (PUFA) in all samples except for the black bear flesh, in which it was docosapentaenoic acid (DPAn-3). In white partridge, beaver and caribou flesh, PUFAs (mainly n-6) were the most common category of fats while in goose, moose and black bear flesh, monounsaturated fatty acids (MUFAs) predominated. In all species, saturated fatty acids (SFAs) were the second most important FAs. It would appear that in the land animals and birds that were analysed, the SFA content was lower and the PUFA content was higher than store-bought meats giving them a more heart-healthy profile. These results showed that the FA composition of game species consumed by the James Bay Cree population is consistent with a beneficial diet and that traditional foods should continue to be promoted among the Cree people to provide better physical health as well as social and spiritual benefits.

Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder that accelerates atherosclerosis and leads to premature cardiovascular diseases (CVD). Whole food, plant-based diets (WFPB) are recommended worldwide for their cardioprotective properties but evidence regarding their effects in HeFH management remains unavailable. This study aims to evaluate the impact of a WFPB, in place of a standard American diet (SAD), on LDL-cholesterol (LDL-C) (primary outcome) and other CVD risk factors among adults with HeFH. In this randomized, two-period, two-treatment, crossover, controlled feeding trial, 50 adults with genetically confirmed HeFH, free of cholesterol-lowering medication, consumed a WFPB and a SAD for 4 weeks each in a random order, under fully controlled, isocaloric feeding conditions. The diets were separated by a two- to four-week washout period. LDL-C and other CVD risk factors were measured at the end of each diet. The WFPB induced a clinically significant reduction in LDL-C relative to the SAD ( − 17.9%, 95% CI: −21.7%, −14.3%; P < 0.0001). The study demonstrates the clinical significance of diet therapy in HeFH and supports its re-establishment as a cornerstone in clinical guidelines (clinicaltrials.gov registration: NCT05181553; funding: Canadian Institutes of Health Research).