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Kidney360 Jan 2024High-throughput eicosanoid profiling can identify metabolites that may play a protective role in the development of kidney disease. In contrast to many other nonlipid...
KEY POINTS
High-throughput eicosanoid profiling can identify metabolites that may play a protective role in the development of kidney disease. In contrast to many other nonlipid metabolites, eicosanoid levels are minimally related with kidney filtration cross-sectionally.
BACKGROUND
Eicosanoids are derivatives of polyunsaturated fatty acids and participate in the inflammatory response and the maintenance of endothelial function. Specific eicosanoids have been linked to various diseases, including hypertension and asthma, and may also reduce renal blood flow. A systematic investigation of eicosanoid-related metabolites and adverse kidney outcomes could identify key mediators of kidney disease and inform ongoing work in drug development.
METHODS
Profiling of eicosanoid-related metabolites was performed in 9650 participants in the Atherosclerosis Risk in Communities Study (visit 2; mean age, 57 years). The associations between metabolite levels and the development of ESKD was investigated using Cox proportional hazards regression (=256 events; median follow-up, 25.5 years). Metabolites with statistically significant associations with ESKD were evaluated for a potential causal role using bidirectional Mendelian randomization techniques, linking genetic instruments for eicosanoid levels to genomewide association study summary statistics of eGFR.
RESULTS
The 223 eicosanoid-related metabolites that were profiled and passed quality control (QC) were generally uncorrelated with eGFR in cross-sectional analyses (median Spearman correlation, −0.03; IQR, −0.05 to 0.002). In models adjusted for multiple covariates, including baseline eGFR, three metabolites had statistically significant associations with ESKD ( value < 0.05/223). These included a hydroxyoctadecenoic acid, a dihydroxydocosapentaenoic acid, and arachidonic acid, with higher levels of the former two protective against ESKD and higher levels of arachidonic acid having a positive association with risk of ESKD. Mendelian randomization analyses suggested a causal role for the hydroxyoctadecenoic and arachidonic acid in determining eGFR. Spectral analysis identified the former metabolite as either 11-hydroxy-9-octadecenoic acid or 10-hydroxy-11-octadecenoic acid.
CONCLUSIONS
High-throughput eicosanoid profiling can identify metabolites that may play a protective role in the development of kidney disease.
Topics: Humans; Kidney Failure, Chronic; Renal Insufficiency, Chronic; Eicosanoids
PubMed: 38047655
DOI: 10.34067/KID.0000000000000334 -
Experimental Eye Research Oct 2023Docosahexaenoic acid (DHA; 22:6) plays a key role in vision and is the precursor for very-long-chain polyunsaturated fatty acids (VLC-PUFAs). The release of 32- and...
Docosahexaenoic acid (DHA; 22:6) plays a key role in vision and is the precursor for very-long-chain polyunsaturated fatty acids (VLC-PUFAs). The release of 32- and 34-carbon VLC-PUFAs and DHA from sn-1 and sn-2 of phosphatidylcholine (PC) leads to the synthesis of cell-survival mediators, the elovanoids (ELVs) and neuroprotectin D1 (NPD1), respectively. Macula and periphery from age-related macular degeneration (AMD) donor retinas were assessed for the availability of DHA-related lipids by LC-MS/MS-based lipidomic analysis and MALDI-molecular imaging. We found reduced retina DHA and VLC-PUFA pathways to synthesize omega-3 ELVs from precursors that likely resulted in altered disks and photoreceptor loss. Additionally, we compared omega-3 (n-3) fatty acid with DHA (22:6) and omega-6 (n-6) fatty acid with arachidonic acid (AA; 20:4) pathways. n-3 PC(22:6/22:6, 44:12) and n-6 PC(20:4/20:4, 40:8) showed differences among male/female, macula/periphery, and normal/AMD retinas. Periphery of AMD retina males increased 44:12 abundance, while normal females increased 40:8 (all macula had an upward 40:8 tendency). We also showed that female AMD switched from n-3 to n-6 fatty acids; most changes in AMD occurred in the periphery of female AMD retinas. DHA and VLC-PUFA release from PCs leads to conversion in pro-survival NPD1 and ELVs. The loss of the neuroprotective precursors of ELVs in the retina periphery from AMD facilitates uncompensated stress and cell loss. In AMD, the female retina loses peripheral rods VLC-PUFAs to about 33% less than in males limiting ELV formation and its protective bioactivity.
Topics: Female; Male; Humans; Down-Regulation; Chromatography, Liquid; Tandem Mass Spectrometry; Fatty Acids, Omega-3; Macular Degeneration
PubMed: 37659709
DOI: 10.1016/j.exer.2023.109639 -
Viruses Jul 2023Fatty acids (FAs) are important regulators of immune responses and innate defense mechanisms. We hypothesized that disturbed FA metabolism could contribute to the...
Fatty acids (FAs) are important regulators of immune responses and innate defense mechanisms. We hypothesized that disturbed FA metabolism could contribute to the progression of HIV infection. Plasma levels of 45 FAs were analyzed with gas chromatography in healthy controls and HIV-infected patients with regard to Mycobacterium avium complex (MAC) infection. In vitro, we assessed MAC-PPD-induced release of inflammatory cytokines in peripheral and bone marrow mononuclear cells (PBMC and BMMC) according to levels of n-6 polyunsaturated fatty acids (PUFAs). While plasma saturated FAs were higher in HIV infection, PUFAs, and in particular the n-6 PUFA arachidonic acid (AA), were lower in patients with advanced disease. The ratio between AA and precursor dihomo-γ-linolenic acid, reflecting Δ5-desaturase activity, was markedly lower and inversely correlated with plasma HIV RNA levels in these patients. Depletion of AA was observed prior to MAC infection, and MAC-PPD-induced release of TNF and IL-6 in PBMC and BMMC was lower in patients with low plasma AA. Our findings suggest that dysregulated metabolism of n-6 PUFAs may play a role in the progression of HIV infection. While high AA may contribute to chronic inflammation in asymptomatic HIV-infected patients, low AA seems to increase the susceptibility to MAC infection in patients with advanced disease.
Topics: Humans; Fatty Acids, Omega-6; Fatty Acids; HIV Infections; Leukocytes, Mononuclear; Fatty Acids, Unsaturated; Arachidonic Acid; Disease Progression
PubMed: 37515299
DOI: 10.3390/v15071613 -
Development (Cambridge, England) Oct 2023Lipid droplets (LDs), crucial regulators of lipid metabolism, accumulate during oocyte development. However, their roles in fertility remain largely unknown. During...
Lipid droplets (LDs), crucial regulators of lipid metabolism, accumulate during oocyte development. However, their roles in fertility remain largely unknown. During Drosophila oogenesis, LD accumulation coincides with the actin remodeling necessary for follicle development. Loss of the LD-associated Adipose Triglyceride Lipase (ATGL) disrupts both actin bundle formation and cortical actin integrity, an unusual phenotype also seen when the prostaglandin (PG) synthase Pxt is missing. Dominant genetic interactions and PG treatment of follicles indicate that ATGL acts upstream of Pxt to regulate actin remodeling. Our data suggest that ATGL releases arachidonic acid (AA) from LDs to serve as the substrate for PG synthesis. Lipidomic analysis detects AA-containing triglycerides in ovaries, and these are increased when ATGL is lost. High levels of exogenous AA block follicle development; this is enhanced by impairing LD formation and suppressed by reducing ATGL. Together, these data support the model that AA stored in LD triglycerides is released by ATGL to drive the production of PGs, which promote the actin remodeling necessary for follicle development. We speculate that this pathway is conserved across organisms to regulate oocyte development and promote fertility.
Topics: Animals; Prostaglandins; Lipid Droplets; Actins; Adipogenesis; Drosophila; Lipase; Peroxidases; Drosophila Proteins
PubMed: 37306387
DOI: 10.1242/dev.201516 -
Cell Reports Mar 2024Prostaglandin F (PGF) and thromboxane A (TXA) are endogenous arachidonic acid metabolites, modulating diverse physiological processes including inflammation and...
Prostaglandin F (PGF) and thromboxane A (TXA) are endogenous arachidonic acid metabolites, modulating diverse physiological processes including inflammation and cardiovascular homeostasis through activating PGF receptor (FP) and TXA receptor (TP). Ligands targeting FP and TP have demonstrated efficacy in treating conditions like glaucoma and cardiovascular diseases in humans, as well as reproductive-related diseases in animals. Here, we present five cryoelectron microscopy structures illustrating FP and TP in complex with G and bound to PGF (endogenous ligand), latanoprost acid (a clinical drug), and two other synthetic agonists. Combined with mutational and functional studies, these structures reveal not only structural features for the specific recognition of endogenous ligands and attainment of receptor selectivity of FP and TP but also the common mechanisms of receptor activation and G protein coupling. The findings may enrich our knowledge of ligand recognition and signal transduction of the prostanoid receptor family and facilitate rational ligand design toward these two receptors.
Topics: Humans; Animals; Ligands; Cryoelectron Microscopy; Receptors, Prostaglandin; Signal Transduction; Prostaglandins
PubMed: 38446662
DOI: 10.1016/j.celrep.2024.113893 -
EJC Paediatric Oncology Dec 2023Retinoblastoma is rare but nevertheless the most common pediatric eye cancer that occurs in children under age 5. High-resolution metabolomics (HRM) is a powerful...
BACKGROUND
Retinoblastoma is rare but nevertheless the most common pediatric eye cancer that occurs in children under age 5. High-resolution metabolomics (HRM) is a powerful analytical approach to profile metabolic features and pathways or identify metabolite biomarkers. To date, no studies have used pre-diagnosis blood samples from retinoblastoma cases and compared them to healthy controls to elucidate early perturbations in tumor pathways.
OBJECTIVES
Here, we report on metabolic profiles of neonatal blood comparing cases later in childhood diagnosed with retinoblastoma and controls.
METHODS
We employed untargeted metabolomics analysis using neonatal dried blood spots for 1327 children (474 retinoblastoma cases and 853 healthy controls) born in California from 1983 to 2011. Cases were selected from the California Cancer Registry and controls, frequency matched to cases by birth year, from California birth rolls. We performed high-resolution metabolomics to extract metabolic features, partial least squares discriminant analysis (PLS-DA) and logistic regression to identify features associated with disease, and Mummichog pathway analysis to characterize enriched biological pathways.
RESULTS
PLS-DA identified 1917 discriminative features associated with retinoblastoma and Mummichog identified 14 retinoblastoma-related enriched pathways including linoleate metabolism, pentose phosphate pathway, pyrimidine metabolism, fructose and mannose metabolism, vitamin A metabolism, as well as fatty acid and lipid metabolism.
INTERPRETATION
Our findings linked a retinoblastoma diagnosis in early life to newborn blood metabolome perturbations indicating alterations in inflammatory pathways and energy metabolism. Neonatal blood spots may provide a venue for early detection for this or potentially other childhood cancers.
PubMed: 38130370
DOI: 10.1016/j.ejcped.2023.100123 -
International Journal of Molecular... Aug 2023The resolution of inflammation is a complex process that is critical for removing inflammatory cells and restoring tissue function. The dysregulation of these mechanisms...
The resolution of inflammation is a complex process that is critical for removing inflammatory cells and restoring tissue function. The dysregulation of these mechanisms leads to chronic inflammatory disorders. Platelets, essential cells for preserving homeostasis, are thought to play a role in inflammation as they are a source of immunomodulatory factors. Our aim was to identify key metabolites carried by platelet-derived extracellular vesicles (PL-EVs) in a model of allergic inflammation. PL-EVs were isolated by serial ultracentrifugation using platelet-rich plasma samples obtained from platelet apheresis from severely ( = 6) and mildly ( = 6) allergic patients and non-allergic individuals used as controls ( = 8). PL-EVs were analysed by a multiplatform approach using liquid and gas chromatography coupled to mass spectrometry (LC-MS and GC-MS, respectively). PL-EVs obtained from severely and mildly allergic patients and control individuals presented comparable particle concentrations and sizes with similar protein concentrations. Strikingly, PL-EVs differed in their lipid and metabolic content according to the severity of inflammation. L-carnitine, ceramide (Cer (d18:0/24:0)), and several triglycerides, all of which seem to be involved in apoptosis and regulatory T functions, were higher in PL-EVs from patients with mild allergic inflammation than in those with severe inflammation. In contrast, PL-EVs obtained from patients with severe allergic inflammation showed an alteration in the arachidonic acid pathway. This study demonstrates that PL-EVs carry specific lipids and metabolites according to the degree of inflammation in allergic patients and propose novel perspectives for characterising the progression of allergic inflammation.
Topics: Humans; Blood Platelets; Gas Chromatography-Mass Spectrometry; Extracellular Vesicles; Arachidonic Acid; Inflammation
PubMed: 37628895
DOI: 10.3390/ijms241612714 -
American Journal of Translational... 2023Plant-based natural antioxidants have a wide variety of biological activities with significant therapeutic value. has been used traditionally to treat a variety of...
OBJECTIVE
Plant-based natural antioxidants have a wide variety of biological activities with significant therapeutic value. has been used traditionally to treat a variety of ailments in animals and human, but little is defined about its biological or pharmacological effects. Therefore, the objective of the present study was to evaluate phytochemical, antioxidant, antipyretic and anti-inflammatory activities of aqueous-methanolic leaf extract of .
METHODS
To investigate the possible impact of aqueous-methanolic leaf extract of on oxidative stress, inflammation, and pyrexia, we used a combined in vitro and in vivo series of experiments on laboratory animals.
RESULTS
Results revealed significant antioxidant potential in 2,2-diphenylpicrylhydrazyl (DPPH) and nitric oxide (NO) scavenging assay, while significant but dose dependent antipyretic potential was documented in typhoid-paratyphoid A and B (TAB) vaccine and prostaglandin E (PGE) induced pyrexia models. Significant anti-inflammatory effects were observed in both acute and chronic inflammatory models of arachidonic acid and formalin. Phytochemical screening and high-performance liquid chromatography (HPLC) analysis of confirmed the presence of mangiferin, quercetin, and isoquercetin. These phytoconstituents likely play a role in the observed biological activities. Our results show that has antioxidant, anti-inflammatory, and antipyretic effects, lending credence to its traditional use and advocating for its utilization as a viable contender in treating oxidative stress-associated ailments.
CONCLUSION
It is concluded that has various properties in the treatment of various diseases.
PubMed: 37560231
DOI: No ID Found -
Scientific Reports Oct 2023Human neutrophil peptides (HNPs) can induce cell proliferation and activation so their growth promoting activities may have potential clinical benefit. This study...
Human neutrophil peptides (HNPs) can induce cell proliferation and activation so their growth promoting activities may have potential clinical benefit. This study investigated the effects of HNPs on human dermal fibroblasts. Differential gene expression in HNP-treated cells and genes involved in regulating intracellular pathways were explored. Dermal fibroblasts were isolated from healthy neonatal foreskin and treated with HNPs in 2D and 3D cell culture systems. The expression of cell proliferation (Ki-67) gene and cell activation (COL1A1) gene plus their proteins was measured. Differential gene expression was determined using RNA-seq, and upregulated and downregulated genes were mapped onto intracellular pathways by KEGG analysis and Gene Ontology databases. HNPs significantly increased cell proliferation without cytotoxicity whilst HNP1 enhanced expression of COL1A1 and type I collagen production in 2D cells and 3D spheroids. RNA-sequencing analysis showed gene clustering with clear separation between HNP1-treated and control groups. A heatmap of top 50 differentially expressed genes was consistent among HNP1-treated samples. Most upregulated genes were associated with cell proliferation and activation as mapped into intracellular pathways whilst most downregulated genes belonged to steroid/arachidonic acid metabolism and inflammatory signaling pathways. HNP1 increased cell proliferation and activation but reduced lipid metabolism and inflammation.
Topics: Infant, Newborn; Humans; Neutrophils; alpha-Defensins; Signal Transduction; Skin; Fibroblasts
PubMed: 37840103
DOI: 10.1038/s41598-023-44889-8 -
Frontiers in Nutrition 2024Depression is associated with greater functional impairment and high societal costs than many other mental disorders. Research on the association between plasma...
BACKGROUND
Depression is associated with greater functional impairment and high societal costs than many other mental disorders. Research on the association between plasma polyunsaturated fatty acids (PUFAs) levels and depression have yielded inconsistent results.
OBJECTIVE
To evaluate whether plasma n-3 and n-6 PUFAs levels are associated with depression in American adults.
METHODS
A cross-sectional study included 2053 adults (aged ≥20 y) in the National Health and Nutrition Examination Survey (NHANES), 2011-2012. The level of plasma n-3 and n-6 PUFAs were obtained for analysis. Self-reported Patient Health Questionnaire-9 (PHQ-9) was used to identify the depression status. Binary logistic regression analysis was performed to evaluate the association between quartiles of plasma n-3 and n-6 PUFAs and depression after adjustments for confounders.
RESULTS
The study of 2053 respondents over 20 years of age with a weighted depression prevalence of 7.29% comprised 1,043 men (weighted proportion, 49.13%) and 1,010 women (weighted, 50.87%), with a weighted mean (SE) age of 47.58 (0.67) years. Significantly increased risks of depression over non-depression were observed in the third quartiles (OR = 1.65, 95% CI = 1.05-2.62) for arachidonic acid (AA; 20:4n-6); the third quartiles (OR = 2.20, 95% CI = 1.20-4.05) for docosatetraenoic acid (DTA; 22:4n-6); the third (OR = 2.33, 95% CI = 1.34-4.07), and highest quartiles (OR = 1.83, 95% CI = 1.03-3.26) for docosapentaenoic acid (DPAn-6; 22:5n-6); and the third (OR = 2.18, 95% CI = 1.18-4.03) and highest quartiles (OR = 2.47, 95% CI = 1.31-4.68) for docosapentaenoic acid (DPAn-3; 22:5n-3); the second (OR = 2.13, 95% CI = 1.24-3.66), third (OR = 2.40, 95% CI = 1.28-4.50), and highest quartiles (OR = 2.24, 95% CI = 1.08-4.69) for AA/docosahexaenoic acid (DHA; 22:6n-3) ratio compared with the lowest quartile after adjusting for confounding factors.
CONCLUSION
Higher plasma levels of AA, DTA, DPAn-6, DPAn-3 PUFAs, and AA/DHA ratio may be potential risk factors for depression in US adults.
PubMed: 38544754
DOI: 10.3389/fnut.2024.1342304