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Geometrical isomerization of arachidonic acid during lipid peroxidation interferes with ferroptosis.Free Radical Biology & Medicine Aug 2023Geometrical mono-trans isomers of arachidonic acid (mtAA) are endogenous products of free radical-induced cis-trans double bond isomerization occurring to natural fatty...
Geometrical mono-trans isomers of arachidonic acid (mtAA) are endogenous products of free radical-induced cis-trans double bond isomerization occurring to natural fatty acids during cell metabolism, including lipid peroxidation (LPO). Very little is known about the functional roles of mtAA and in general on the effects of mono-trans isomers of polyunsaturated fatty acids (mtPUFA) in various types of programmed cell death, including ferroptosis. Using HT1080 and MEF cell cultures, supplemented with 20 μM PUFA (i.e., AA, EPA or DHA) and their mtPUFA congeners, ferroptosis occurred in the presence of RSL3 (a direct inhibitor of glutathione peroxidase 4) only with the PUFA in their natural cis configuration, whereas mtPUFA showed an anti-ferroptotic effect. By performing the fatty acid-based membrane lipidome analyses, substantial differences emerged in the membrane fatty acid remodeling of the two different cell fates. In particular, during ferroptosis mtPUFA formation and their incorporation, together with the enrichment of SFA, occurred. This opens new perspectives in the role of the membrane composition for a ferroptotic outcome. While pre-treatment with AA promoted cell death for treatment with HO and RSL3, mtAA did not. Cell death by AA supplementation was suppressed also in the presence of either ferroptosis inhibitors, such as the lipophilic antioxidant ferrostatin-1, or NADPH oxidase (NOX) inhibitors, including diphenyleneiodonium chloride and apocynin. Our results confirm a more complex scenario for ferroptosis than actually believed. While LPO processes are active, the importance of environmental lipid levels, balance among SFA, MUFA and PUFA in lipid pools and formation of mtPUFA influence the membrane phospholipid turnover, with crucial effects in the occurrence of cell death by ferroptosis.
Topics: Lipid Peroxidation; Isomerism; Arachidonic Acid; Ferroptosis; Hydrogen Peroxide; Fatty Acids; Fatty Acids, Unsaturated
PubMed: 37257700
DOI: 10.1016/j.freeradbiomed.2023.05.026 -
BMC Women's Health Oct 2023This study aimed to explore metabolic abnormalities in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) for metabolism-related genes.
OBJECTIVE
This study aimed to explore metabolic abnormalities in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) for metabolism-related genes.
METHODS
We downloaded expression data for metabolism-related genes, performed differential expression analysis, and applied weighted gene co-expression network analysis (WGCNA) to identify metabolism-related functional modules. We obtained normalised miRNA expression data and identified master methylation regulators for metabolism-related genes. Cox regression of data on metabolism-related genes was performed to screen for genes that affect the prognosis of patients with CESC. Furthermore, we selected key genes for validation.
RESULTS
Our results identified 3620 metabolism-related genes in CESC, 2493 of which contained related mutations. The co-occurrence of CUBN, KALRN, and HERC1 was related to the prognosis of CESC. The fraction of genome altered (FGA) closely correlated with overall survival. In expression analysis, 374 genes were related to the occurrence and prognosis of CESC. We then identified four metabolic pathway modules in WGCNA. Further analysis revealed that glycolysis/gluconeogenesis was related to endothelial cells and that arachidonic acid metabolism was related to cell proliferation. These four modules were also related to the prognosis of CESC. Among CESC-related metabolic genes, two genes were found to be regulated by microRNAs (miRNAs) and methylation, whereas another two genes were coregulated by miRNAs and mutations.
CONCLUSIONS
Among metabolism-related genes, 15 genes were related to the prognosis of CESC. The co-occurrence of CUBN/KALRN/HERC1 was associated with CESC prognosis. Glycolysis/gluconeogenesis was related to endothelial cells, and arachidonic acid metabolism was related to cell proliferation.
Topics: Female; Humans; Uterine Cervical Neoplasms; Carcinoma, Squamous Cell; Arachidonic Acid; Endothelial Cells; MicroRNAs; Prognosis
PubMed: 37884919
DOI: 10.1186/s12905-023-02712-6 -
Cell Death Discovery Sep 2023Allicin exhibits various pharmacological activities and has been suggested to be beneficial in the treatment of stroke. However, the underlying mechanisms are largely...
Allicin exhibits various pharmacological activities and has been suggested to be beneficial in the treatment of stroke. However, the underlying mechanisms are largely unknown. Here, we confirmed that allicin protected the brain from cerebral injury, which could be ascribed to its anti‑apoptotic and anti‑inflammatory effects, as well as the regulation of lipid metabolism, using proteomics and metabolomics analysis. Our results suggested that allicin could significantly ameliorate behavioral characteristics, cerebral infarct area, cell apoptosis, inflammatory factors, and lipid metabolic-related factors (arachidonic acid, 15-hydroperoxy-eicosatetraenoic acid (15S-HPETE), palmitoylcarnitine, and acylcarnitine) by recalibrating astrocyte homeostasis in mice with photothrombotic stroke (PT). In astrocytes, allicin significantly increased glutathione peroxidase 1 (GPX1) levels and inhibited the arachidonic acid-related pathway, which was also observed in the brains of mice with PT. Allicin was proven to inhibit hypoxia-induced astrocyte apoptosis by increasing GPX1 expression, activating proto-oncogene tyrosine-protein kinase Src (Src)- protein kinase B (AKT)-extracellular signal-regulated kinase (ERK) phosphorylation, and decreasing lipid peroxidation. Thus, we concluded that allicin significantly prevented and ameliorated ischemic stroke by increasing GPX1 levels to complete the complex physiological process.
PubMed: 37673878
DOI: 10.1038/s41420-023-01633-5 -
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 -
Marine Drugs May 2024A predigested product from arachidonic acid oil (ARA) and docosahexaenoic acid (DHA) oil in a 2:1 (/) ratio has been developed and evaluated in an in vitro digestion...
A predigested product from arachidonic acid oil (ARA) and docosahexaenoic acid (DHA) oil in a 2:1 (/) ratio has been developed and evaluated in an in vitro digestion model. To produce this predigested lipid mixture, first, the two oils were enzymatically hydrolyzed up to 90% of free fatty acids (FFAs) were achieved. Then, these two fatty acid (FA) mixtures were mixed in a 2:1 ARA-to-DHA ratio (/) and enzymatically esterified with glycerol to produce a mixture of FFAs, mono-, di-, and triacylglycerides. Different glycerol ratios and temperatures were evaluated. The best results were attained at 10 °C and a glycerol-to-FA molar ratio of 3:1. The bio-accessibility of this predigested mixture was studied in an in vitro digestion model. A total of 90% of the digestion product was found in the micellar phase, which contained 30% monoacylglycerides, more than 50% FFAs, and a very small amount of triacylglycerols (3% /). All these data indicate an excellent bio-accessibility of this predigested mixture.
Topics: Docosahexaenoic Acids; Digestion; Arachidonic Acid; Glycerol; Temperature; Hydrolysis; Triglycerides; Animals; Fatty Acids, Nonesterified; Humans
PubMed: 38786615
DOI: 10.3390/md22050224 -
ACS Omega Jun 2024Arachidonic acid (ARA) was shown to possess safe and effective schistosomicidal impact on larval and adult and in vitro and in vivo in laboratory rodents and in...
Arachidonic acid (ARA) was shown to possess safe and effective schistosomicidal impact on larval and adult and in vitro and in vivo in laboratory rodents and in children residing in low and high endemicity regions. We herein examine mechanisms underlying ARA schistosomicidal potential over two experiments, using in each pool a minimum of 50 adult male, female, or mixed-sex freshly recovered, ex vivo . Worms incubated in fetal calf serum-free medium were exposed to 0 or 10 mM ARA for 1 h at 37 °C and immediately processed for preparation of surface membrane and whole worm body homogenate extracts. Mixed-sex worms were additionally used for evaluating the impact of ARA exposure on the visualization of outer membrane cholesterol, sphingomyelin (SM), and ceramide in immunofluorescence assays. Following assessment of protein content, extracts of intact and ARA-treated worms were examined and compared for SM content, neutral sphingomyelinase activity, reactive oxygen species levels, and caspase 3/7 activity. Arachidonic acid principally led to perturbation of the organization, integrity, and SM content of the outer membrane of male and female worms and additionally impacted female parasites via stimulating neutral sphingomyelinase activity and oxidative stress. Arachidonic powerful action on female worms combined with its previously documented ovocidal activities supports its use as safe and effective therapy against schistosomiasis, provided implementation of the sorely needed and long waited-for chemical synthesis.
PubMed: 38854551
DOI: 10.1021/acsomega.3c09906 -
Frontiers in Microbiology 2023Mammalian gut microbiota plays an important role in the host's nutrient metabolism, growth, and immune regulation. Hybridization can enable a progeny to acquire superior...
Mammalian gut microbiota plays an important role in the host's nutrient metabolism, growth, and immune regulation. Hybridization can enable a progeny to acquire superior traits of the parents, resulting in the hybridization advantage. However, studies on the effects of hybridization on the pigs' gut microbiota are lacking. Therefore, this study used multi-omics technologies to compare and analyze the gut microbiota of the primary wild boar and its offspring. The gene sequencing results revealed that the gut microbiota of F4 exhibited a host-like dominance phenomenon with a significant increase in the abundance of and . The beta diversity of Duroc was significantly different from those of F0, F2, and F4; after the host hybridization, the similarity of the beta diversity in the progeny decreased with the decrease in the similarity of the F0 lineage. The metagenomic sequencing results showed that the significantly enriched metabolic pathways in F4, such as environmental, circulatory system, fatty acid degradation adaptation, and fatty acid biosynthesis, were similar to those in F0. Moreover, it also exhibited similar significantly enriched metabolic pathways as those in Duroc, such as carbohydrate metabolism, starch and sucrose metabolism, starch-degrading CAZymes, lactose-degrading CAZymes, and various amino acid metabolism pathways. However, the alpha-amylase-related KOs, lipid metabolism, and galactose metabolism in F4 were significantly higher than those in Duroc and F0. Non-targeted metabolome technology analysis found that several metabolites, such as docosahexaenoic acid, arachidonic acid, and citric acid were significantly enriched in the F4 pigs as compared to those in F0. Based on Spearman correlation analysis, and were significantly positively correlated with these metabolites. Finally, the combined metagenomic and metabolomic analysis suggested that the metabolic pathways, such as valine, leucine, and isoleucine biosynthesis and alanine aspartate and glutamate metabolism were significantly enriched in F4 pigs. In conclusion, the gut microbiota of F4 showed a similar host "dominance" phenomenon, which provided reference data for the genetics and evolution of microbiota and the theory of microbial-assisted breeding.
PubMed: 37465027
DOI: 10.3389/fmicb.2023.1177947 -
Neurology Aug 2023Excessive activation of certain lipid mediator (LM) pathways plays a role in the complex pathogenesis of multiple sclerosis (MS). However, the relationship between...
BACKGROUND AND OBJECTIVES
Excessive activation of certain lipid mediator (LM) pathways plays a role in the complex pathogenesis of multiple sclerosis (MS). However, the relationship between bioactive LMs and different aspects of CNS-related pathophysiologic processes remains largely unknown. Therefore, in this study, we assessed the association of bioactive LMs belonging to the ω-3/ω-6 lipid classes with clinical and biochemical (serum neurofilament light [sNfL] and serum glial fibrillary acidic protein [sGFAP]) parameters and MRI-based brain volumes in patients with MS (PwMS) and healthy controls (HCs).
METHODS
A targeted high-performance liquid chromatography-tandem mass spectrometry approach was used on plasma samples of PwMS and HCs of the Project Y cohort, a cross-sectional population-based cohort that contains PwMS all born in 1966 in the Netherlands and age-matched HCs. LMs were compared between PwMS and HCs and were correlated with levels of sNfL, sGFAP, disability (Expanded Disability Status Scale [EDSS]), and brain volumes. Finally, significant correlates were included in a backward multivariate regression model to identify which LMs best related to disability.
RESULTS
The study sample consisted of 170 patients with relapsing remitting MS (RRMS), 115 patients with progressive MS (PMS), and 125 HCs. LM profiles of patients with PMS significantly differed from those of patients with RRMS and HCs, particularly patients with PMS showed elevated levels of several arachidonic acid (AA) derivatives. In particular, 15-hydroxyeicosatetraenoic acid (HETE) ( = 0.24, < 0.001) correlated (average = 0.2, < 0.05) with clinical and biochemical parameters such as EDSS and sNfL. In addition, higher 15-HETE levels were related to lower total brain ( = -0.24, = 0.04) and deep gray matter volumes ( = -0.27, = 0.02) in patients with PMS and higher lesion volume ( = 0.15, = 0.03) in all PwMS.
DISCUSSION
In PwMS of the same birth year, we show that ω-3 and ω-6 LMs are associated with disability, biochemical parameters (sNfL, GFAP), and MRI measures. Furthermore, our findings indicate that, particularly, in patients with PMS, elevated levels of specific products of the AA pathway, such as 15-HETE, associate with neurodegenerative processes. Our findings highlight the potential relevance of ω-6 LMs in the pathogenesis of MS.
Topics: Humans; Middle Aged; Multiple Sclerosis; Arachidonic Acid; Cross-Sectional Studies; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Patient Acuity
PubMed: 37290971
DOI: 10.1212/WNL.0000000000207459 -
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 -
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