Succinate is produced by both host and microbiota, with a key role in the interplay of immunity and metabolism and an emerging role as a biomarker for inflammatory and metabolic disorders in ...middle-aged adults. The relationship between plasma succinate levels and cardiovascular disease (CVD) risk in young adults is unknown.
Cross-sectional study in 100 (65% women) individuals aged 18-25 years from the ACTIvating Brown Adipose Tissue through Exercise (ACTIBATE) study cohort. CVD risk factors, body composition, dietary intake, basal metabolic rate, and cardiorespiratory fitness were assessed by routine methods. Plasma succinate was measured with an enzyme-based assay. Brown adipose tissue (BAT) was evaluated by positron emission tomography, and circulating oxylipins were assessed by targeted metabolomics. Fecal microbiota composition was analyzed in a sub-sample.
Individuals with higher succinate levels had higher levels of visceral adipose tissue (VAT) mass (+ 42.5%), triglycerides (+ 63.9%), C-reactive protein (+ 124.2%), diastolic blood pressure (+ 5.5%), and pro-inflammatory omega-6 oxylipins than individuals with lower succinate levels. Succinate levels were also higher in metabolically unhealthy individuals than in healthy overweight/obese peers. Succinate levels were not associated with BAT volume or activity or with fecal microbiota composition and diversity.
Plasma succinate levels are linked to a specific pro-inflammatory omega-6 signature pattern and higher VAT levels, and seem to reflect the cardiovascular status of young adults.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Monoacylglycerol lipase (MAGL) regulates endocannabinoid 2-arachidonoylglycerol (2-AG) and eicosanoid signalling. MAGL inhibition provides therapeutic opportunities but clinical potential is limited ...by central nervous system (CNS)-mediated side effects. Here, we report the discovery of LEI-515, a peripherally restricted, reversible MAGL inhibitor, using high throughput screening and a medicinal chemistry programme. LEI-515 increased 2-AG levels in peripheral organs, but not mouse brain. LEI-515 attenuated liver necrosis, oxidative stress and inflammation in a CCl
-induced acute liver injury model. LEI-515 suppressed chemotherapy-induced neuropathic nociception in mice without inducing cardinal signs of CB
activation. Antinociceptive efficacy of LEI-515 was blocked by CB
, but not CB
, antagonists. The CB
antagonist rimonabant precipitated signs of physical dependence in mice treated chronically with a global MAGL inhibitor (JZL184), and an orthosteric cannabinoid agonist (WIN55,212-2), but not with LEI-515. Our data support targeting peripheral MAGL as a promising therapeutic strategy for developing safe and effective anti-inflammatory and analgesic agents.
Pre-clinical studies suggest that circulating oxylipins, i.e., the oxidation products of polyunsaturated fatty acids (PUFAs), modulate gut microbiota composition in mice, but there is no information ...available in humans. Therefore, this study aimed to investigate the relationship between omega-3 and omega-6 derived oxylipins plasma levels and fecal microbiota composition in a cohort of young adults. 80 young adults (74% women; 21.9 ± 2.2 years old) were included in this cross-sectional study. Plasma levels of oxylipins were measured using liquid chromatography-tandem mass spectrometry. Fecal microbiota composition was analyzed by V3-V4 16S rRNA gene sequencing. We observed that plasma levels of omega-3 derived oxylipins were positively associated with the relative abundance of
genus (
phylum; rho ≥ 0.415,
≤ 0.009) and negatively associated with the relative abundance of
genus (Proteobacteria phylum; rho ≥ -0.270,
≤ 0.041), respectively. Moreover, plasma levels of omega-6 derived oxylipins were negatively associated with the relative abundance of
and
genera (
phylum; all rho ≥ -0.263,
≤ 0.024), as well as
,
, and
genera (
phylum; all rho ≥ -0.263,
≤ 0.024). Lastly, the ratio between omega-6 and omega-3 oxylipins plasma levels was negatively associated with the relative abundance of
cluster IV genus (
phylum; rho = -0.334,
= 0.004) and
genus (
phylum; rho = -0.292,
= 0.014). In conclusion, our results show that the plasma levels of omega-3 and omega-6 derived oxylipins are associated with the relative abundance of specific fecal bacteria genera.
To investigate the association of plasma levels of endocannabinoids with fecal microbiota.
Plasma levels of endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), as well as their ...eleven analogues, and arachidonic acid (AA), were measured using liquid chromatography-tandem mass spectrometry in 92 young adults. DNA extracted from stool samples was analyzed using 16S rRNA gene sequencing. Lipopolysaccharide levels were measured in plasma samples.
Plasma levels of endocannabinoids and their analogues were not related to beta or alpha diversity indexes. Plasma levels of AEA and related N-acylethanolamines correlated positively with the relative abundance of
genus (all rho ≥ 0.26,
≤ 0.012) and
genus (all rho ≥ 0.22,
≤ 0.036), and negatively with the relative abundance of
genus (all rho ≤ -0.23,
≤ 0.031). Moreover, plasma levels of 2-AG and other acylglycerols correlated positively with the relative abundance of
(all rho ≥ 0.24,
≤ 0.020) and
genera (all rho ≥ 0.27,
≤ 0.011), and negatively with the relative abundance of
genus (all rho ≤ -0.24,
≤ 0.023). In participants with high lipopolysaccharide values, the plasma levels of AEA and related N-acylethanolamines, as well as AA and 2-AG, were negatively correlated with plasma levels of lipopolysaccharide (all rho ≤ -0.24,
≤ 0.020).
Plasma levels of endocannabinoids and their analogues are correlated to specific fecal bacterial genera involved in maintaining gut barrier integrity in young adults. This suggests that plasma levels of endocannabinoids and their analogues may play a role in the gut barrier integrity in young adults.
The endocannabinoid 2-arachidonoylglycerol (2-AG) is involved in neuronal differentiation. This study aimed to identify the biosynthetic enzymes responsible for 2-AG production during retinoic acid ...(RA)-induced neurite outgrowth of Neuro-2a cells. First, we confirmed that RA stimulation of Neuro-2a cells increases 2-AG production and neurite outgrowth. The diacylglycerol lipase (DAGL) inhibitor DH376 blocked 2-AG production and reduced neuronal differentiation. Surprisingly, CRISPR/Cas9-mediated knockdown of DAGLα and DAGLβ in Neuro-2a cells did not reduce 2-AG levels, suggesting another enzyme capable of producing 2-AG in this cell line. Chemical proteomics revealed DAGLβ and α,β-hydrolase domain containing protein (ABHD6) as the only targets of DH376 in Neuro-2a cells. Biochemical, genetic and lipidomic studies demonstrated that ABHD6 possesses DAGL activity in conjunction with its previously reported monoacylglycerol lipase activity. RA treatment of Neuro-2a cells increased by three-fold the amount of active ABHD6. Our study shows that ABHD6 exhibits significant DAG lipase activity in Neuro-2a cells in addition to its known MAG lipase activity and suggest it is involved in neuronal differentiation.
Signaling lipids (SLs) play a crucial role in various signaling pathways, featuring diverse lipid backbone structures. Emerging evidence showing the biological significance and biomedical values of ...SLs has strongly spurred the advancement of analytical approaches aimed at profiling SLs. Nevertheless, the dramatic differences in endogenous abundances across lipid classes as well as multiple isomers within the same lipid class makes the development of a generic analytical method challenging. A better analytical method that combines comprehensive coverage and high sensitivity is needed to enable us to gain a deeper understanding of the biochemistry of these molecules in health and disease. In this study, we developed a fast and comprehensive targeted ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) method for profiling SLs. The platform enables analyses of 260 metabolites covering oxylipins (isoprostanes, prostaglandins and other oxidized lipids), free fatty acids, lysophospholipids, sphingoid bases (C16, C18), platelet activating factors (C16, C18), endocannabinoids and bile acids. Various validation parameters including linearity, limit of detection, limit of quantification, extraction recovery, matrix effect, intra-day and inter-day precision were used to characterize this method. Metabolite quantitation was successfully achieved in both NIST Standard Reference Material for human plasma (NIST SRM 1950) and pooled human plasma, with 109 and 144 metabolites quantitated. The quantitation results in NIST SRM 1950 plasma demonstrated good correlations with certified or previously reported values in published literature. This study introduced quantitative data for 37 SLs for the first time. Metabolite concentrations measured in NIST SRM 1950 will serve as essential reference data for facilitating interlaboratory comparisons. The methodology established here will be the cornerstone for in-depth profiling of signaling lipids across diverse biological samples and contexts.
Display omitted
•Optimization of sample preparation strategy enabling fast and simultaneous extraction of polar lipids.•Tailored chromatographic separation of diverse signaling lipid classes.•A comprehensive UHPLC-MS/MS method targeting 261 signaling lipids.•Significant sensitivity improvement for prostanoids, leukotrienes and specialized pro-resolving mediators.•Metabolite quantitation in NIST Standard Reference Material for human plasma (NIST SRM 1950).
Objective
Omega‐6 and omega‐3 oxylipins are known to play a role in inflammation and cardiometabolic diseases in preclinical models. The associations between plasma levels of omega‐6 and omega‐3 ...polyunsaturated fatty acid–derived oxylipins and body composition and cardiometabolic risk factors in young adults were assessed.
Methods
Body composition, brown adipose tissue, traditional serum cardiometabolic risk factors, inflammatory markers, and a panel of 83 oxylipins were analyzed in 133 young adults (age 22.1SD 2.2 years, 67% women).
Results
Plasma levels of four omega‐6 oxylipins (15‐HeTrE, 5‐HETE, 14,15‐EpETrE, and the oxidative stress–derived 8,12‐iso‐iPF2α‐VI) correlated positively with adiposity, prevalence of metabolic syndrome, fatty liver index, and homeostatic model assessment of insulin resistance index and lipid parameters. By contrast, the plasma levels of three omega‐3 oxylipins (14,15‐DiHETE, 17,18‐DiHETE, and 19,20‐DiHDPA) were negatively correlated with adiposity, prevalence of metabolic syndrome, fatty liver index, homeostatic model assessment of insulin resistance index, and lipid parameters. The panel of seven oxylipins predicted adiposity better than traditional inflammatory markers such as interferon gamma or tumor necrosis factor‐alpha. Pathway analyses revealed that individuals with obesity had higher plasma levels of omega‐6 and lower plasma levels of omega‐3 oxylipins than normal‐weight individuals.
Conclusion
Plasma levels of seven omega‐6 and omega‐3 oxylipins may have utility as early markers of cardiometabolic risk in young adults.
The endocannabinoid system (ECS) is a signaling system composed of endocannabinoids (eCBs), their receptors, and the enzymes involved in their synthesis and metabolism. Alterations in the ECS are ...linked to the development of cardiometabolic diseases.
Here, we investigated the relationship between plasma levels of eCBs and their analogues with body composition and cardiometabolic risk factors.
The study included 133 young adults (age 22.1 ± 2.2 years, 67% women). Fasting plasma levels of eCBs and their analogues were measured using liquid chromatography-tandem mass spectrometry. Body composition, brown adipose tissue (BAT) volume, glucose uptake, and traditional cardiometabolic risk factors were measured.
Plasma levels of eCBs and several eCB analogues were positively correlated with adiposity and traditional cardiometabolic risk factors (eg, serum insulin and triacylglyceride levels, all r ≥ 0.17 and P ≤ .045). Plasma levels of 2-arachidonoyl glycerol and N-pentadecenoylethanolamine were negatively correlated with BAT volume and glucose uptake (all r ≤ -0.17 and P ≤ .047). We observed that the plasma levels of eCBs and their analogues were higher in metabolically unhealthy overweight-obese participants than in metabolically healthy overweight-obese participants.
Our findings show that the plasma levels of eCBs and their analogues are related to higher levels of adiposity and worse cardiometabolic profile.
A quantitative evaluation method for determining the shape, length and depth of surface defects is proposed for the purpose of non-destructive testing (NDT) and evaluation of metal materials. The ...COMSOL Multiphysics finite element software is used to calculate and analyse the eddy current
magnetic field and the influence of the geometric parameters of defects on the spatial three-dimensional magnetic field distributions are studied. The results show that the shape of the surface defect can be judged from the measurement result of the x-Bx curve. The quantitative
analysis of the crack length is realised according to the corresponding position of the peak (trough) of surface magnetic field Bz . The depth of the crack can be inversely calculated by the quantitative relationship between the trough depth of Bx (or the peak value of
Bz) and the crack depth. Therefore, this method provides convenient and contactless detection technology in which the characteristic quantities corresponding to the defect parameters are independent from each other to improve the accuracy of defect evaluation.
Bile acids (BA) are known for their role in intestinal lipid absorption and can also play a role as signaling molecules to control energy metabolism. Prior evidence suggests that alterations in ...circulating BA levels and in the pool of circulating BA are linked to an increased risk of obesity and a higher incidence of type 2 diabetes in middle-aged adults.
We aimed to investigate the association between plasma levels of BA with cardiometabolic risk factors in a cohort of well-phenotyped, relatively healthy young adults.
Body composition, brown adipose tissue, serum classical cardiometabolic risk factors, and a set of 8 plasma BA (including glyco-conjugated forms) in 136 young adults (age 22.1 ± 2.2 years, 67% women) were measured.
Plasma levels of chenodeoxycholic acid (CDCA) and glycoursodeoxycholic acid (GUDCA) were higher in men than in women, although these differences disappeared after adjusting for body fat percentage. Furthermore, cholic acid (CA), CDCA, deoxycholic acid (DCA), and glycodeoxycholic acid (GDCA) levels were positively, yet weakly associated, with lean body mass (LBM) levels, while GDCA and glycolithocholic acid (GLCA) levels were negatively associated with 18F-fluorodeoxyglucose uptake by brown adipose tissue. Interestingly, glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), and GUDCA were positively associated with glucose and insulin serum levels, HOMA index, low-density lipoprotein cholesterol, tumor necrosis factor alpha, interleukin (IL)-2, and IL-8 levels, but negatively associated with high-density lipoprotein cholesterol, ApoA1, and adiponectin levels, yet these significant correlations partially disappeared after the inclusion of LBM as a confounder.
Our findings indicate that plasma levels of BA might be sex dependent and are associated with cardiometabolic and inflammatory risk factors in young and relatively healthy adults.
PDF
