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Drug Metabolism Reviews Aug 2023The metabolism of arachidonic acid (AA) occurs different pathways leading to the production of a great number of metabolites with a wide range of biological effects.... (Review)
Review
The metabolism of arachidonic acid (AA) occurs different pathways leading to the production of a great number of metabolites with a wide range of biological effects. Hepoxilins (HXs) are physiologically active AA metabolites produced through the lipoxygenase pathway. Since their discovery, several researchers have investigated their biological effects. They were proven to have pro-inflammatory, anti-apoptotic, and skin-protective effects. HXs also contribute to the processes of neutrophil activation and migration and inflammatory hyperalgesia. The major limitation to their effects is that they are highly labile and are metabolized into less active compounds which led to the synthesis of stable HXs analogs called proprietary bioactive therapeutics (PBTs). Although PBTs were synthesized to further study the effect of HXs, they showed different effects than natural HXs under some conditions. PBTs were proven to have anti-inflammatory and anti-cancer effects and were found to be potent antagonists of the thromboxane receptor. In this review article, we aimed to provide an overview of some physiological and pathophysiological effects of hepoxilins and their analogs on the skin, platelet, blood vessel, neutrophil, and cell survival.
Topics: Humans; Arachidonic Acids
PubMed: 37264550
DOI: 10.1080/03602532.2023.2219035 -
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 -
Birth Defects Research Jun 2024To determine the effect of maternal status in (plasma and red blood cell) folate, vitamin B12, homocysteine, and vitamin D, as well as their interaction with MTHFR...
OBJECTIVE
To determine the effect of maternal status in (plasma and red blood cell) folate, vitamin B12, homocysteine, and vitamin D, as well as their interaction with MTHFR (C677T and A1298C) and MTRR A66G polymorphisms, on maternal plasma docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (ARA) levels and the risk of neural tube defects (NTDs).
METHODS
ARA, EPA, and DHA composition was assessed using capillary gas chromatography.
RESULTS
ARA and DHA levels were higher in controls than in case mothers for low plasma folate status. For low red blood cell folate status, DHA levels were higher in controls than in case mothers. For high homocysteine levels, ARA and DHA levels were higher in controls than in case mothers. NTD mothers had lower EPA and DHA levels for low vitamin B12 levels. NTD mothers had lower DHA levels for low vitamin D levels. For low plasma folate status, DHA levels in the MTHFR C677T gene and ARA and EPA levels in MTHFR A1298C gene were different among the three genotypes in case mothers. DHA levels in the MTHFR C677T gene were different among the three genotypes in case mothers for both low and high homocysteine levels. For low vitamin B12 levels, ARA and DHA levels were different among the three genotypes of the MTHFR C677T gene in case mothers. In the MTHFR C677T gene, ARA and DHA levels were different among the three genotypes in case mothers for low vitamin D levels.
CONCLUSIONS
More advanced research is required to verify a suitable biochemical parameter status in relation to the genotypes in pregnant women.
Topics: Humans; Eicosapentaenoic Acid; Docosahexaenoic Acids; Female; Neural Tube Defects; Arachidonic Acid; Folic Acid; Adult; Tunisia; Methylenetetrahydrofolate Reductase (NADPH2); Homocysteine; Pregnancy; Vitamin B 12; Case-Control Studies; Genotype; Vitamin D
PubMed: 38877667
DOI: 10.1002/bdr2.2372 -
The Journal of Neuroscience : the... Jun 2024Aberrant increase of arachidonic acid (ARA) has long been implicated in the pathology of Alzheimer's disease (AD), while the underlying causal mechanism remains unclear....
Aberrant increase of arachidonic acid (ARA) has long been implicated in the pathology of Alzheimer's disease (AD), while the underlying causal mechanism remains unclear. In this study, we revealed a link between ARA mobilization and microglial dysfunction in Aβ pathology. Lipidomic analysis of primary microglia from App mice showed a marked increase in free ARA and lysophospholipids (LPLs) along with a decrease in ARA-containing phospholipids, suggesting increased ARA release from phospholipids (PLs). To manipulate ARA-containing PLs in microglia, we genetically deleted Lysophosphatidylcholine Acyltransferase 3 (), the main enzyme catalyzing the incorporation of ARA into PLs. Loss of microglial reduced the levels of ARA-containing phospholipids, free ARA and LPLs, leading to a compensatory increase in monounsaturated fatty acid (MUFA)-containing PLs in both male and female mice. Notably, the reduction of ARA in microglia significantly ameliorated oxidative stress and inflammatory responses while enhancing the phagocytosis of Aβ plaques and promoting the compaction of Aβ deposits. Mechanistically, sc-RNA seq suggested that LPCAT3 deficiency facilitates phagocytosis by facilitating de novo lipid synthesis while protecting microglia from oxidative damage. Collectively, our study reveals a novel mechanistic link between ARA mobilization and microglial dysfunction in AD. Lowering brain ARA levels through pharmacological or dietary interventions may be a potential therapeutic strategy to slow down AD progression. This study revealed a novel mechanistic link between the increase of arachidonic acid and microglial dysfunction in Alzheimer's disease. We discovered that microglia in an AD mouse model show heightened free ARA, pointing to increased ARA release from phospholipids. By targeting Lysophosphatidylcholine Acyltransferase in microglia, we effectively reduced ARA levels, leading to decreased oxidative stress and inflammation, and enhanced clearance of Aβ plaques. This study suggests that lowering brain ARA levels could be a viable approach to slow AD progression.
PubMed: 38866484
DOI: 10.1523/JNEUROSCI.0202-24.2024 -
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 -
Molecular Neurobiology Aug 2023Hair is a noninvasive valuable biospecimen for the long-term assessment of endogenous metabolic disturbance. Whether the hair is suitable for identifying biomarkers of...
Rat Hair Metabolomics Analysis Reveals Perturbations of Unsaturated Fatty Acid Biosynthesis, Phenylalanine, and Arachidonic Acid Metabolism Pathways Are Associated with Amyloid-β-Induced Cognitive Deficits.
Hair is a noninvasive valuable biospecimen for the long-term assessment of endogenous metabolic disturbance. Whether the hair is suitable for identifying biomarkers of the Alzheimer's disease (AD) process remains unknown. We aim to investigate the metabolism changes in hair after β-amyloid (Aβ) exposure in rats using ultra-high-performance liquid chromatography-high-resolution mass spectrometry-based untargeted and targeted methods. Thirty-five days after Aβ induction, rats displayed significant cognitive deficits, and forty metabolites were changed, of which twenty belonged to three perturbed pathways: (1) phenylalanine metabolism and phenylalanine, tyrosine, and tryptophan biosynthesis-L-phenylalanine, phenylpyruvate, ortho-hydroxyphenylacetic acid, and phenyllactic acid are up-regulated; (2) arachidonic acid (ARA) metabolism-leukotriene B4 (LTB4), arachidonyl carnitine, and 5(S)-HPETE are upregulation, but ARA, 14,15-DiHETrE, 5(S)-HETE, and PGB2 are opposite; and (3) unsaturated fatty acid biosynthesis- eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), FA 18:3 + 1O, and FA 18:3 + 2O are downregulated. Linoleic acid metabolism belonging to the biosynthesis of unsaturated fatty acid includes the upregulation of 8-hydroxy-9,10-epoxystearic acid, 13-oxoODE, and FA 18:2 + 4O, and downregulation of 9(S)-HPODE and dihomo-γ-linolenic acid. In addition, cortisone and dehydroepiandrosterone belonging to steroid hormone biosynthesis are upregulated. These three perturbed metabolic pathways also correlate with cognitive impairment after Aβ stimulation. Furthermore, ARA, DHA, EPA, L-phenylalanine, and cortisone have been previously implicated in the cerebrospinal fluid of AD patients and show a similar changing trend in Aβ rats' hair. These data suggest hair can be a useful biospecimen that well reflects the expression of non-polar molecules under Aβ stimulation, and the five metabolites have the potential to serve as novel AD biomarkers.
Topics: Animals; Rats; Arachidonic Acid; Phenylalanine; Cortisone; Fatty Acids, Unsaturated; Amyloid beta-Peptides; Metabolomics; Cognitive Dysfunction; Alzheimer Disease; Cognition; Hair; Biomarkers
PubMed: 37095368
DOI: 10.1007/s12035-023-03343-6 -
American Journal of Physiology. Lung... Aug 2023Asthma is one of the most common noncommunicable diseases in the world. Approximately 30% of severe cases are associated with fungal sensitization, often associated with...
Asthma is one of the most common noncommunicable diseases in the world. Approximately 30% of severe cases are associated with fungal sensitization, often associated with allergy to the opportunistic mold . Leukotrienes, immunopathogenic mediators derived from the metabolism of arachidonic acid (AA) by 5-lipoxygenase (5-LOX), are often elevated in severe asthma. As such, these mediators are Food and Drug Administration-approved therapeutic targets of the antiasthmatic drugs Zileuton/Zyflo and Singulair/Montelukast. A second enzyme involved in AA metabolism is 12/15-lipoxygenase (12/15-LOX; ). Here, C57BL/6 wild-type (WT) mice subjected to experimental fungal asthma had increased expression of mRNA and increased levels of 12-HETE, a product of 12/15-LOX activity, in the lung when compared with naïve and vehicle-treated mice. Mice deficient in 12/15-LOX () demonstrated better lung function, as measured by airway hyperresponsiveness (AHR), during fungal asthma. Histological assessment revealed reduced inflammation in the lungs of mice compared with WT mice, which was corroborated by flow cytometric analysis of multiple myeloid (eosinophils and neutrophils) and lymphoid (CD4+ T and γδ T) cell populations. This was further supported by decreased levels of specific chemokines that promote the recruitment of these cells. Likewise, type 1 and 2, but not type 17 cytokines, were significantly lower in the lungs of mice. Bone marrow chimera studies revealed that the presence of 12/15-LOX in hematopoietic cells contributed to AHR during fungal asthma. Taken together, our data support the hypothesis that hematopoietic-associated 12/15-LOX contributes to type 1 and 2 responses and exacerbation of allergic fungal asthma. Humans with asthma sensitized to fungi often have more severe asthma than those who are not sensitized to fungi. Products of arachidonic acid generated via 5-lipoxygenase are often elevated in severe asthma and are successful FDA-approved drug targets. Less understood is the role of products generated via 12/15-lipoxygenase. We demonstrate that 12/15-lipoxygenase expression in hematopoietic cells contributes to type 1 and 2 responses and impaired lung function during allergic fungal asthma.
Topics: Animals; Humans; Mice; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Arachidonic Acid; Asthma; Disease Models, Animal; Mice, Inbred C57BL; Mice, Knockout
PubMed: 37253655
DOI: 10.1152/ajplung.00090.2023 -
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 -
Chemosphere Oct 2023In industrialized societies, the prevalence of metabolic diseases has substantially increased over the past few decades, yet the underlying causes remain unclear....
In industrialized societies, the prevalence of metabolic diseases has substantially increased over the past few decades, yet the underlying causes remain unclear. Cadmium (Cd) is a hazardous heavy metal and pervasive environmental endocrine disruptor. Here, we investigate the effects of paternal Cd exposure on offspring glucolipid metabolism. Paternal Cd exposure (1 mg kg body weight) impaired glucose tolerance, increased random serum glucose and fasting serum insulin, elevated serum total cholesterol, and low-density lipoprotein in offspring mice. Untargeted metabolomics analysis of male offspring liver tissue revealed that paternal Cd exposure can affect offspring glucolipid metabolic reprogramming, which involved biosynthesis of phenylalanine, tyrosine and tryptophan, biosynthesis of unsaturated fatty acids, metabolism of linoleic acid, arachidonic acid and α-linolenic acid. Transcriptome sequencing of male offspring liver tissue showed that arachidonic acid metabolism, AMPK signaling pathway, PPAR signaling pathway and adipocytokine signaling pathway were significantly inhibited in the Cd-exposed group. The mRNA expression levels of PPAR signaling pathway related genes (Acsl1, Cyp4a14, Cyp4a10, Cd36, Ppard and Pck1) were significantly decreased. The protein expression levels of ACSL1, CD36, PPARD and PCK1 were also significantly reduced. Collectively, our findings suggest that paternal Cd exposure affect offspring glucolipid metabolic reprogramming via PPAR signaling pathway.
Topics: Humans; Mice; Animals; Male; Cadmium; Peroxisome Proliferator-Activated Receptors; Fathers; Signal Transduction; Arachidonic Acids
PubMed: 37482320
DOI: 10.1016/j.chemosphere.2023.139592