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Environmental Pollution (Barking, Essex... Nov 2023Excessive amounts of iron (Fe), zinc (Zn), and copper (Cu) can be toxic to neuronal cells, even though these are essential trace elements for animals and humans....
Excessive amounts of iron (Fe), zinc (Zn), and copper (Cu) can be toxic to neuronal cells, even though these are essential trace elements for animals and humans. However, the precise mechanisms underlying the neurotoxicity of exposure to mixtures of Fe, Zn, and Cu are still mostly unclear. The research aimed to investigate the influence of co-exposure to iron, zinc and copper and the related mechanisms in HT22 murine hippocampal neuronal cells. Intracellular metal content, markers of oxidative damage, and biomarkers of ferroptosis were respectively detected. Afterward, metabolomic analyses were performed to obtain a comprehensive understanding of the metal mixtures on metabolism, and the functions of key enzymes on metabolic pathways were validated. The results showed that metal co-exposure resulted in cellular iron overload and increased lipid peroxidation, accompanied by significant pathological damage and mitochondrial abnormalities in HT22 cells. Meanwhile, it was found that GSH depletion, decreased GPX4, and increased expression of the lipid metabolism gene ACSL4 play important roles in ferroptosis induced by metal mixture. Further, metabolomic analysis revealed metal co-exposure induced significant alterations in metabolite levels, especially in the glycerophospholipid metabolism pathway and the arachidonic acid metabolism pathway. The levels of cPLA2 and its metabolite, arachidonic acid, were significantly increased after metal co-exposure. Then, inhibition of cPLA2 decreased the level of arachidonic acid and attenuated ferroptosis in neuronal cells. Collectively, our findings unveiled ferroptosis induced by metal co-exposure associated with crucial molecular changes in neuronal cells, providing a novel perspective on the comprehensive toxicity risk assessment of metal mixtures.
Topics: Humans; Mice; Animals; Zinc; Copper; Ferroptosis; Lipid Metabolism; Arachidonic Acid; Iron; Metals; Lipid Metabolism Disorders; Phospholipases A2, Cytosolic
PubMed: 37625769
DOI: 10.1016/j.envpol.2023.122438 -
Clinical Nutrition (Edinburgh, Scotland) May 2024Clinical trials supplementing the long-chain polyunsaturated fatty acids (LCPUFAs) docosahexaenoic acid (DHA) and arachidonic acid (AA) to preterm infants have shown... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIM
Clinical trials supplementing the long-chain polyunsaturated fatty acids (LCPUFAs) docosahexaenoic acid (DHA) and arachidonic acid (AA) to preterm infants have shown positive effects on inflammation-related morbidities, but the molecular mechanisms underlying these effects are not fully elucidated. This study aimed to determine associations between DHA, AA, and inflammation-related proteins during the neonatal period in extremely preterm infants.
METHODS
A retrospective exploratory study of infants (n = 183) born below 28 weeks gestation from the Mega Donna Mega trial, a randomized multicenter trial designed to study the effect of DHA and AA on retinopathy of prematurity. Serial serum samples were collected after birth until postnatal day 100 (median 7 samples per infant) and analyzed for phospholipid fatty acids and proteins using targeted proteomics covering 538 proteins. Associations over time between LCPUFAs and proteins were explored using mixed effect modeling with splines, including an interaction term for time, and adjusted for gestational age, sex, and center.
RESULTS
On postnatal day one, 55 proteins correlated with DHA levels and 10 proteins with AA levels. Five proteins were related to both fatty acids, all with a positive correlation. Over the first 100 days after birth, we identified 57 proteins to be associated with DHA and/or AA. Of these proteins, 41 (72%) related to inflammation. Thirty-eight proteins were associated with both fatty acids and the overall direction of association did not differ between DHA and AA, indicating that both LCPUFAs similarly contribute to up- and down-regulation of the preterm neonate inflammatory proteome. Primary examples of this were the inflammation-modulating cytokines IL-6 and CCL7, both being negatively related to levels of DHA and AA in the postnatal period.
CONCLUSIONS
This study supports postnatal non-antagonistic and potentially synergistic effects of DHA and AA on the inflammation proteome in preterm infants, indicating that supplementation with both fatty acids may contribute to limiting the disease burden in this vulnerable population.
CLINICAL REGISTRATION NUMBER
ClinicalTrials.gov (NCT03201588).
Topics: Humans; Docosahexaenoic Acids; Arachidonic Acid; Infant, Extremely Premature; Infant, Newborn; Female; Retrospective Studies; Male; Inflammation; Proteome
PubMed: 38603973
DOI: 10.1016/j.clnu.2024.03.031 -
Pediatric Research Apr 2024Very preterm infants are at high risk of growth failure. Poor weight gain is a prominent risk factor for retinopathy of prematurity (ROP) and optimizing nutrition could... (Review)
Review
Very preterm infants are at high risk of growth failure. Poor weight gain is a prominent risk factor for retinopathy of prematurity (ROP) and optimizing nutrition could potentially promote growth and reduce ROP. Most infants at risk of ROP need parenteral nutrition initially and studies of enhanced parenteral provision of lipids and amino acids have suggested a beneficial effect on ROP. Higher amino acid intake was associated with lower incidence of hyperglycemia, a risk factor for ROP. For very preterm infants, providing unpasteurized fortified raw maternal breast milk appears to have a dose-dependent preventive effect on ROP. These infants become deficient in arachidonic acid (ArA) and docosahexaenoic acid (DHA) after birth when the maternal supply is lost. Earlier studies have investigated the impact of omega-3 fatty acids on ROP with mixed results. In a recent study, early enteral supplementation of ArA 100 mg/kg/d and DHA 50 mg/kg/d until term equivalent age reduced the incidence of severe ROP by 50%. IMPACT: Previous reviews of nutritional interventions to prevent morbidities in preterm infants have mainly addressed bronchopulmonary dysplasia, brain lesions and neurodevelopmental outcome. This review focusses on ROP. Neonatal enteral supplementation with arachidonic acid and docosahexaenoic acid, at levels similar to the fetal accretion rate, has been found to reduce severe ROP by 50% in randomized controlled trials.
PubMed: 38684884
DOI: 10.1038/s41390-024-03208-1 -
Heliyon Apr 2024Endocannabinoids (eCBs) exert considerable influence over energy metabolism, lipid metabolism, and glucose metabolism within the human body. Among the most biologically...
Endocannabinoids (eCBs) exert considerable influence over energy metabolism, lipid metabolism, and glucose metabolism within the human body. Among the most biologically active cannabinoids identified thus far are 2-arachidonoylglycerol (2-AG), arachidonoyl ethanolamide (AEA), 1-stearoylglycerol (1-SRG), and stearoyl ethanolamide (SEA), which are derived from arachidonic acid (AA) and stearic acid (SA). However, despite the unique in bioactivities exhibited by eCBs, their determination in plasma has been hindered by the lack of sensitive analytical methods. The aim of this study was to develop and validate a highly sensitive and rapid method using ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for accurate measurement of AEA, SEA, 2-AG, 1-SRG, AA, and SA levels in human plasma samples. Sample preparation involved a protein precipitation method and a methyl -butyl ether liquid-liquid extraction method. Chromatographic separation was accomplished by utilizing an ACQUITY UPLC BEH C column with a mobile phase of acetonitrile containing 0.1% formic acid and water containing 0.1% formic acid, flowing at a rate of 0.35 mL/min. AA-d, 2-AG-d, and AEA-d were selected as deuterated internal standards. The analytes were determined with MRM in both positive and negative ion mode. The lower limit of quantification ranged from 0.1 to 400 ng/mL, and the correlation coefficient (R) was >0.99. Inter-day and intra-day precision exhibited values of 0.55-13.29% and 0.62%-13.90%, respectively. Recovery and matrix effect were within the range of 77.7%-109.7%, and 90.0%-113.5%, respectively. Stability tests confirmed the acceptability of all analytes. To demonstrate the effectiveness of the approach, it was implemented to assess and compare plasma samples from healthy volunteers (n = 49) and individuals with non-alcoholic fatty liver disease (NAFLD) (n = 62). The study revealed significant differences in AEA, SEA, AA, and SA levels between the two groups.
PubMed: 38560270
DOI: 10.1016/j.heliyon.2024.e28467 -
Frontiers in Pharmacology 2024Arachidonic acid (AA) is a main component of cell membrane lipids. AA is mainly metabolized by three enzymes: cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome... (Review)
Review
Arachidonic acid (AA) is a main component of cell membrane lipids. AA is mainly metabolized by three enzymes: cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP450). Esterified AA is hydrolysed by phospholipase A into a free form that is further metabolized by COX, LOX and CYP450 to a wide range of bioactive mediators, including prostaglandins, lipoxins, thromboxanes, leukotrienes, hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids. Increased mitochondrial oxidative stress is considered to be a central mechanism in the pathophysiology of the kidney. Along with increased oxidative stress, apoptosis, inflammation and tissue fibrosis drive the progressive loss of kidney function, affecting the glomerular filtration barrier and the tubulointerstitium. Recent studies have shown that AA and its active derivative eicosanoids play important roles in the regulation of physiological kidney function and the pathogenesis of kidney disease. These factors are potentially novel biomarkers, especially in the context of their involvement in inflammatory processes and oxidative stress. In this review, we introduce the three main metabolic pathways of AA and discuss the molecular mechanisms by which these pathways affect the progression of acute kidney injury (AKI), diabetic nephropathy (DN) and renal cell carcinoma (RCC). This review may provide new therapeutic targets for the identification of AKI to CKD continuum.
PubMed: 38523633
DOI: 10.3389/fphar.2024.1365802 -
Nutrients Jul 2023Polyunsaturated fatty acids (PUFAs) are vital for brain development, yet limited knowledge exists regarding PUFA intake during complementary feeding (CF) and its impact... (Randomized Controlled Trial)
Randomized Controlled Trial
Polyunsaturated fatty acids (PUFAs) are vital for brain development, yet limited knowledge exists regarding PUFA intake during complementary feeding (CF) and its impact on neurodevelopmental outcomes in very low birth weight (VLBW) infants. This secondary analysis of a randomized intervention trial, aimed to investigate the association between dietary intake of total PUFAs, arachidonic acid (AA), and docosahexaenoic acid (DHA) during CF and neurodevelopmental outcomes at 12 and 24 months of corrected age (CA). Dietary intakes were assessed using monthly 3 day dietary protocols from 3 to 12 months CA. Neurodevelopmental outcome was evaluated using the Bayley Scales of Infant Development-III. Among the 177 randomized patients, PUFA intake and neurodevelopmental outcomes were evaluated in 140 (79%) infants. Higher total PUFA and DHA intakes significantly correlated with improved cognitive and motor function at 12 months CA, while increased AA intake notably enhanced motor scores at 12 months CA. However, median dietary intakes of AA and DHA (AA: 53.50-84.25 mg/d; DHA: 51.47-76.23 mg/d) fell short of recommended levels (AA: 140 mg/d; DHA: 100 mg/d) at any of the investigated timepoints. These findings emphasize the need to enhance total PUFA, DHA and AA intakes during CF, ensuring adherence to guidelines and unlocking the potential to improve neurodevelopmental outcomes in VLBW infants.
Topics: Humans; Infant; Infant, Newborn; Arachidonic Acid; Docosahexaenoic Acids; Fatty Acids, Unsaturated; Infant Nutritional Physiological Phenomena; Infant, Very Low Birth Weight
PubMed: 37513559
DOI: 10.3390/nu15143141 -
Clinical Nutrition (Edinburgh, Scotland) Jul 2024Aging-related type 2 diabetes (T2DM) is characterized by hyperinsulinemia, insulin resistance, and β-cell dysfunction. However, the underlying molecular mechanisms...
BACKGROUND
Aging-related type 2 diabetes (T2DM) is characterized by hyperinsulinemia, insulin resistance, and β-cell dysfunction. However, the underlying molecular mechanisms remain to be unclear.
METHODS
We conducted non-targeted metabolomics to compare human serum samples from young adults (YA), elderly adults (EA), and elderly adults with diabetes (EA + DM) of Chinese population. Adult mice and aged mice were intragastrically administered with varespladib every day for two weeks and metabolic characteristics were monitored. Serum levels of arachidonic acid, insulin, and C-peptide, as well as serum activity of secretory phospholipase A2 (sPLA2) were detected in mice. Mouse islet perfusion assays were used to assess insulin secretion ability. Phosphorylated AKT levels were measured to evaluate insulin sensitivities of peripheral tissues in mice.
RESULTS
Non-targeted metabolomics analysis of human serum samples revealed differential metabolic signatures among the YA, EA, and EA + DM groups. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed significant enhancement of arachidonic acid metabolism and glycerophospholipid metabolism in the EA group compared with the YA group. Further analysis identified two metabolic fluxes that favored the accumulation of arachidonic acid in the elderly. Increased levels of arachidonic acid were also confirmed in aged mice with hyperinsulinemia and insulin resistance, together with subsequent glucose intolerance. Conversely, inhibiting the generation of arachidonic acid with varespladib, an inhibitor of sPLA2, reduced aging-associated diabetes by improving hyperinsulinemia and hepatic insulin resistance in aged mice but not in adult mice. Islet perfusion assays also showed that varespladib treatment suppressed the enhanced insulin secretion observed in aged islets.
CONCLUSIONS
Collectively, our findings uncover that arachidonic acid serves as a metabolic hub in Chinese elderly population. Our results also suggest that arachidonic acid plays a fundamental role in regulating β-cell function during aging and point to a novel therapy for aging-associated diabetes.
Topics: Animals; Insulin Resistance; Arachidonic Acid; Humans; Mice; Aging; Hyperinsulinism; Male; Aged; Diabetes Mellitus, Type 2; Adult; Mice, Inbred C57BL; Female; Young Adult; Metabolomics; Insulin; Middle Aged
PubMed: 38843581
DOI: 10.1016/j.clnu.2024.05.043 -
Biomolecules Sep 2023Psoriasis is a skin disease characterized by epidermal hyperplasia and an inappropriate activation of the adaptive immunity. A dysregulation of the skin's lipid...
Psoriasis is a skin disease characterized by epidermal hyperplasia and an inappropriate activation of the adaptive immunity. A dysregulation of the skin's lipid mediators is reported in the disease with a predominance of the inflammatory cascade derived from n-6 polyunsaturated fatty acids (n-6 PUFAs). Bioactive lipid mediators derived from arachidonic acid (AA) are involved in the inflammatory functions of T cells in psoriasis, whereas n-3 PUFAs' derivatives are anti-inflammatory metabolites. Here, we sought to evaluate the influence of a supplementation of the culture media with eicosapentaenoic acid (EPA) on the lipid profile of a psoriatic skin model produced with polarized T cells. Healthy and psoriatic skin substitutes were produced following the auto-assembly technique. Psoriatic skin substitutes produced with or without T cells presented increased epidermal and dermal linolenic acid (LA) and AA levels. N-6 PUFA lipid mediators were strongly measured in psoriatic substitutes, namely, 13-hydroxyoctadecadienoic acid (13-HODE), prostaglandin E (PGE) and 12-hydroxyeicosatetraenoic acid (12-HETE). The added EPA elevated the amounts of EPA, n-3 docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) in the epidermal and dermal phospholipids. The EPA supplementation balanced the production of epidermal lipid mediators, with an increase in prostaglandin E (PGE), 12-hydroxyeicosapentaenoic acid (12-HEPE) and -eicosapentaenoyl-ethanolamine (EPEA) levels. These findings show that EPA modulates the lipid composition of psoriatic skin substitutes by encouraging the return to a cutaneous homeostatic state.
Topics: Humans; Eicosapentaenoic Acid; T-Lymphocytes; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Eicosanoids; Arachidonic Acid; Skin Diseases; Psoriasis; Dinoprostone
PubMed: 37759812
DOI: 10.3390/biom13091413 -
Liver International : Official Journal... Sep 2023PIEZO1 and TRPV4 are mechanically and osmotically regulated calcium-permeable channels. The aim of this study was to determine the relevance and relationship of these...
BACKGROUND & AIMS
PIEZO1 and TRPV4 are mechanically and osmotically regulated calcium-permeable channels. The aim of this study was to determine the relevance and relationship of these channels in the contractile tone of the hepatic portal vein, which experiences mechanical and osmotic variations as it delivers blood to the liver from the intestines, gallbladder, pancreas and spleen.
METHODS
Wall tension was measured in freshly dissected portal veins from adult male mice, which were genetically unmodified or modified for either a non-disruptive tag in native PIEZO1 or endothelial-specific PIEZO1 deletion. Pharmacological agents were used to activate or inhibit PIEZO1, TRPV4 and associated pathways, including Yoda1 and Yoda2 for PIEZO1 and GSK1016790A for TRPV4 agonism, respectively.
RESULTS
PIEZO1 activation leads to nitric oxide synthase- and endothelium-dependent relaxation of the portal vein. TRPV4 activation causes contraction, which is also endothelium-dependent but independent of nitric oxide synthase. The TRPV4-mediated contraction is suppressed by inhibitors of phospholipase A and cyclooxygenases and mimicked by prostaglandin E , suggesting mediation by arachidonic acid metabolism. TRPV4 antagonism inhibits the effect of agonising TRPV4 but not PIEZO1. Increased wall stretch and hypo-osmolality inhibit TRPV4 responses while lacking effects on or amplifying PIEZO1 responses.
CONCLUSIONS
The portal vein contains independently functioning PIEZO1 channels and TRPV4 channels in the endothelium, the pharmacological activation of which leads to opposing effects of vessel relaxation (PIEZO1) and contraction (TRPV4). In mechanical and osmotic strain, the PIEZO1 mechanism dominates. Modulators of these channels could present important new opportunities for manipulating liver perfusion and regeneration in disease and surgical procedures.
Topics: Animals; Male; Mice; Endothelium; Nitric Oxide; Nitric Oxide Synthase; Osmotic Pressure; Portal Vein; TRPV Cation Channels; Vasodilation; Ion Channels
PubMed: 37349903
DOI: 10.1111/liv.15646 -
Life Sciences Nov 2023Toxicity caused by chronic hyperglycemia is a significant factor affecting skeletal muscle myogenesis, resulting in diabetic myopathy. Chronic and persistent...
Toxicity caused by chronic hyperglycemia is a significant factor affecting skeletal muscle myogenesis, resulting in diabetic myopathy. Chronic and persistent hyperglycemia causes activation of the atrophy-related pathways in the skeletal muscles, which eventually results in inflammation and muscle degeneration. To counteract this process, various bioactive compound has been studied for their reversal or hypertrophic effect. In this study, we explored the molecular mechanisms associated with reversing glucotoxicity's effect in C2C12 cells by arachidonic acid (AA). We found a substantial increase in the pro-inflammatory cytokines and ROS production in hyperglycemic conditions, mitigated by AA supplementation. We found that AA supplementation restored protein synthesis that was downregulated under glucotoxicity conditions. AA enhanced myogenesis by suppressing high glucose induced inflammation and ROS production and enhancing protein synthesis. These results imply that AA has cytoprotective actions against hyperglycemia-induced cytotoxicity.
Topics: Humans; Arachidonic Acid; Reactive Oxygen Species; Muscular Atrophy; Muscle, Skeletal; Hyperglycemia; Inflammation
PubMed: 37797688
DOI: 10.1016/j.lfs.2023.122141