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Frontiers in Oncology 2024Arachidonic acid (AA) is a crucial polyunsaturated fatty acid in the human body, metabolized through the pathways of COX, LOX, and cytochrome P450 oxidase to generate... (Review)
Review
Arachidonic acid (AA) is a crucial polyunsaturated fatty acid in the human body, metabolized through the pathways of COX, LOX, and cytochrome P450 oxidase to generate various metabolites. Recent studies have indicated that AA and its metabolites play significant regulatory roles in the onset and progression of ovarian cancer. This article examines the recent research advancements on the correlation between AA metabolites and ovarian cancer, both domestically and internationally, suggesting their potential use as biological markers for early diagnosis, targeted therapy, and prognosis monitoring.
PubMed: 38764576
DOI: 10.3389/fonc.2024.1381894 -
MedRxiv : the Preprint Server For... Jun 2024We have shown that ω3 polyunsaturated fatty acids (PUFAs) reduce risk for heart failure, regardless of ejection fraction status. Ventricular remodeling and reduced...
BACKGROUND
We have shown that ω3 polyunsaturated fatty acids (PUFAs) reduce risk for heart failure, regardless of ejection fraction status. Ventricular remodeling and reduced ventricular performance precede overt hear failure, however there is little insight into how PUFAs contribute to maladaptive signaling over time. PUFAs are agonists for regulatory activity at g-protein coupled receptors such as Ffar4, and downstream as substrates for monooxygenases (e.g lipoxygenase, cytochrome p450, or cyclooxygenase (COX)) which mediate intracellular adaptive signaling.
METHODS
Plasma phospholipid PUFA abundance at Exam 1 as mass percent EPA, DHA, and arachidonic acid (AA) from the Multi-Ethnic Study of Atherosclerosis (MESA) were evaluated using pathway modeling to determine the association with time-dependent changes in left ventricular (LV) mass (LVM), end-diastolic LV volume (EDV), and end-systolic volume (ESV) measured by cardiac MRI at Exams 1 and 5. Ejection fraction (EF) and mass:volume (MV) were calculated posteriorly from the first three.
RESULTS
2,877 subjects had available MRI data. Participants with low AA and EPA had accelerated age-dependent declines in LVM. Males with low AA and EPA also had accelerated declines in EDV, but among females there was no PUFA association with EDV declines and exam 5 EDV status was positively associated with AA. Both sexes had nearly the same positive association of AA with changes in ESV.
CONCLUSION
Plasma phospholipid AA and EPA are prospectively associated with indices of heart remodeling, including ventricular remodeling and performance. Combined AA and EPA scarcity was associated with the most accelerated age-related changes and exam 5 status, while the greatest benefits were found among participants with both PUFAs. This suggests that both PUFAs are required for optimal slowing of age-related declines in ventricular function.
PubMed: 38883788
DOI: 10.1101/2024.06.05.24308494 -
Cell Reports Oct 2023As a prominent feature of gout, monosodium urate (MSU) crystal deposition induces gout flares, but its impact on immune inflammation in gout remission remains unclear....
As a prominent feature of gout, monosodium urate (MSU) crystal deposition induces gout flares, but its impact on immune inflammation in gout remission remains unclear. Using single-cell RNA sequencing (scRNA-seq), we characterize the transcription profiling of peripheral blood mononuclear cells (PBMCs) among intercritical remission gout, advanced remission gout, and normal controls. We find systemic inflammation in gout remission with MSU crystal deposition at the intercritical and advanced stages, evidenced by activated inflammatory pathways, strengthened inflammatory cell-cell interactions, and elevated arachidonic acid metabolic activity. We also find increased HLA-DQA1 classic monocytes and PTGS2 monocytes in advanced gout and overactivated CD8 T cell subtypes in intercritical and advanced gout. Additionally, the osteoclast differentiation pathway is significantly enriched in monocytes, T cells, and B cells from advanced gout. Overall, we demonstrate systemic inflammation and distinctive immune responses in gout remission with MSU crystal deposition, allowing further exploration of the underlying mechanism and clinical significance in conversion from intercritical to advanced stage.
Topics: Humans; Leukocytes, Mononuclear; Uric Acid; Gout; Inflammation; Monocytes; Chronic Disease
PubMed: 37756161
DOI: 10.1016/j.celrep.2023.113139 -
The Science of the Total Environment Dec 2023The plasticizer Diethylhexyl phthalate (DEHP), one of the most common contaminants, is widely detected in environmental and biological samples. However, the accumulation...
The plasticizer Diethylhexyl phthalate (DEHP), one of the most common contaminants, is widely detected in environmental and biological samples. However, the accumulation of DEHP in tissue and the molecular mechanisms underlying its physiological damage in the spleen of aquatic organisms have not yet been reported. In this study, gas chromatography-mass spectrometry (GC-MS), histology and multi-omics analysis were used to investigate DEHP exposure-induced alterations in transcriptomic profiles and metabolic network of zebrafish model. After exposure to DEHP, higher concentrations of DEHP were found in the intestine, liver and spleen. Anatomical and histological analyses showed that the zebrafish spleen index was significantly increased and inflammatory damage was observed. Increased splenic neutrophil counts indicate inflammation and tissue damage. Transcriptomic filtering showed that 3579 genes were significantly altered. Metabolomic analysis detected 543 differential metabolites. Multi-omics annotation results indicated that arachidonic acid and 12-Hydroperoxyicosatetraenoic acid (HPETE) are involved in the key inflammatory pathway "Inflammatory mediator regulation of TRP channels". This study demonstrated the accumulation characteristics of DEHP in aquatic zebrafish and the mechanisms of inflammation and tissue damage in the spleen which involve endogenous arachidonic acid. This will provide theoretical basis and data support for health risk assessments and tissue damage of DEHP.
Topics: Animals; Diethylhexyl Phthalate; Zebrafish; Arachidonic Acid; Spleen; Inflammation
PubMed: 37690753
DOI: 10.1016/j.scitotenv.2023.166841 -
Journal of Atherosclerosis and... Nov 2023Eicosapentaenoic acid (EPA) has shown beneficial effects on coronary plaque stabilization. Based on our previous study, we speculated that EPA might be associated with...
AIMS
Eicosapentaenoic acid (EPA) has shown beneficial effects on coronary plaque stabilization. Based on our previous study, we speculated that EPA might be associated with the development of healed plaques and might limit thrombus size. This study aimed to elucidate the association between EPA and arachidonic acid (AA) ratios and various plaque characteristics in patients with plaque rupture.
METHODS
A total of 95 patients with acute coronary syndrome (ACS) caused by plaque rupture who did not take lipid-lowering drugs and underwent percutaneous coronary intervention using optical coherence tomography (OCT) were included. Clinical characteristics, lipid profiles, and OCT findings were compared between patients with lower and higher EPA/AA ratios (0.41) according to the levels in the Japanese general population.
RESULTS
In the high EPA/AA (n=29, 30.5%) and low EPA/AA (n=66, 69.5 %) groups, the high EPA/AA group was significantly older (76.1 vs. 66.1 years, P<0.01) and had lower peak creatine kinase (556 vs. 1651 U/L, P=0.03) than those with low EPA/AA. Similarly, patients with high EPA/AA had higher prevalence of layered and calcified plaque (75.9 vs. 39.4 %, P<0.01; 79.3 vs. 50.0 %, P<0.01, respectively) than low EPA/AA group. Multivariate logistic regression analysis demonstrated that a high EPA/AA ratio was an independent factor in determining the development of layered and calcified plaques.
CONCLUSION
A high EPA/AA ratio may be associated with the development of layered and calcified plaques in patients with plaque rupture.
Topics: Humans; Eicosapentaenoic Acid; Arachidonic Acid; Risk Factors; Plaque, Atherosclerotic; Acute Coronary Syndrome
PubMed: 36967129
DOI: 10.5551/jat.63806 -
Cell Biology International Jan 2024Arachidonic acid metabolism plays a crucial role in the development and progression of inflammatory and metabolic liver diseases. However, its role in hepatocellular...
Arachidonic acid metabolism plays a crucial role in the development and progression of inflammatory and metabolic liver diseases. However, its role in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigated the expression of key genes involved in the arachidonic acid metabolism pathway in HCC using a combination of bioinformatics, proteomics and immunohistochemistry analyses. Through a comprehensive analysis of publicly available datasets, clinical HCC tissues, and tissue microarrays, we compared the expression of hepatic arachidonic acid metabolic genes. We observed significant downregulation of cytochrome P450 (CYP450) pathway genes at both the messenger RNA and protein levels in HCC tissues compared to normal liver tissues. Furthermore, we observed a strong correlation between the deregulation of the arachidonic acid metabolism CYP450 pathway and the pathological features and prognosis of HCC. Specifically, the expression of CYP2C8/9/18/19 was significantly correlated with pathological grade (r = -.484, p < .0001), vascular invasion (r = -.402, p < .0001), aspartate transaminase (r = -.246, p = .025), gamma-glutamyl transpeptidase (r = -.252, p = .022), alkaline phosphatase (r = -.342, p = .002), alpha-fetoprotein (r = -.311, p = .004) and carbohydrate antigen 19-9 (r = -.227, p = .047). Moreover, we discovered a significant association between CYP450 pathway activity and vascular invasion in HCC. Collectively, these data indicate that arachidonic acid CYP450 metabolic pathway deregulation is implicated in HCC progression and may be a potential predictive factor for early recurrence in patients with HCC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Arachidonic Acid; Cytochrome P-450 Enzyme System
PubMed: 37655528
DOI: 10.1002/cbin.12086 -
European Journal of Pharmacology Jan 2024We identified circNFIB (hsa_circ_0086376) as a down-regulated circRNA in breast cancer but its effect is unclear. We aimed to explore the roles of circNFIB in breast...
We identified circNFIB (hsa_circ_0086376) as a down-regulated circRNA in breast cancer but its effect is unclear. We aimed to explore the roles of circNFIB in breast cancer. The expression levels of circNFIB in breast cancer tissues and cells were detected. Both in vitro and in vivo experiments were used to assess the effects and mechanisms of circNFIB. circNFIB was down-regulated in 29 breast cancer tissues compared to adjacent normal tissues. circNFIB is a highly conserved circRNA and mainly located in cytoplasm of breast cancer cells. In vitro experiments showed that overexpression of circNFIB inhibited proliferation and invasion of breast cancer cells, whereas knockdown of circNFIB induced proliferation and invasion. Animal experiments indicated that circNFIB inhibited tumor growth and metastasis in vivo. Bioinformatics analysis showed that circNFIB contained an open reading frame (ORF) spanning its spliced junction, an internal ribosome entry site (IRES) and a N-methyladenosine (mA) site, suggesting circNFIB had the potential to encode a 56 amino acid (aa) protein, which was then confirmed by experiments. Metabonomics analysis results indicated that circNFIB may inhibit synthesis of arachidonic acid (AA) by regulating phospholipase. EIF4A3 and U2AF65 may regulate circNFIB expression by binding to the flanking sequence of circNFIB. In conclusion, circNFIB is a down-regulated circRNA in breast cancer tissues and encodes a 56 aa protein. circNFIB down-regulates AA in breast cancer cells, thus decreasing AA metabolites. Based on reported evidences of AA metabolites on cancer, we speculated that circNFIB may inhibit breast tumor growth and metastasis partly by inhibiting AA.
Topics: Animals; MicroRNAs; RNA, Circular; Arachidonic Acid; Cell Line, Tumor; Cell Proliferation; Cell Movement; Gene Expression Regulation, Neoplastic
PubMed: 38128869
DOI: 10.1016/j.ejphar.2023.176221 -
Journal of Lipid Research Sep 2023Natural variations in the C:C ratio (carbon-13 isotopic abundance [δC]) of the food supply have been used to determine the dietary origin and metabolism of fatty acids,... (Randomized Controlled Trial)
Randomized Controlled Trial
Natural variations in the C:C ratio (carbon-13 isotopic abundance [δC]) of the food supply have been used to determine the dietary origin and metabolism of fatty acids, especially in the n-3 PUFA biosynthesis pathway. However, n-6 PUFA metabolism following linoleic acid (LNA) intake remains under investigation. Here, we sought to use natural variations in the δC signature of dietary oils and fatty fish to analyze n-3 and n-6 PUFA metabolism following dietary changes in LNA and eicosapentaenoic acid (EPA) + DHA in adult humans. Participants with migraine (aged 38.6 ± 2.3 years, 93% female, body mass index of 27.0 ± 1.1 kg/m) were randomly assigned to one of three dietary groups for 16 weeks: 1) low omega-3, high omega-6 (H6), 2) high omega-3, high omega-6 (H3H6), or 3) high omega-3, low omega-6 (H3). Blood was collected at baseline, 4, 10, and 16 weeks. Plasma PUFA concentrations and δC were determined. The H6 intervention exhibited increases in plasma LNA δC signature over time; meanwhile, plasma LNA concentrations were unchanged. No changes in plasma arachidonic acid δC or concentration were observed. Participants on the H3H6 and H3 interventions demonstrated increases in plasma EPA and DHA concentration over time. Plasma δC-EPA increased in total lipids of the H3 group and phospholipids of the H3H6 group compared with baseline. Compound-specific isotope analysis supports a tracer-free technique that can track metabolism of dietary fatty acids in humans, provided that the isotopic signature of the dietary source is sufficiently different from plasma δC.
Topics: Adult; Animals; Humans; Female; Male; Fatty Acids, Omega-6; Fatty Acids, Omega-3; Eicosapentaenoic Acid; Fatty Acids; Phospholipids; Docosahexaenoic Acids
PubMed: 37572791
DOI: 10.1016/j.jlr.2023.100424 -
Lipids in Health and Disease Nov 2023Intervertebral disc degeneration (IVDD) is widely recognized as the primary etiological factor underlying low back pain, often necessitating surgical intervention as the...
Role of arachidonic acid metabolism in intervertebral disc degeneration: identification of potential biomarkers and therapeutic targets via multi-omics analysis and artificial intelligence strategies.
BACKGROUND
Intervertebral disc degeneration (IVDD) is widely recognized as the primary etiological factor underlying low back pain, often necessitating surgical intervention as the sole recourse in severe cases. The metabolic pathway of arachidonic acid (AA), a pivotal regulator of inflammatory responses, influences the development and progression of IVDD.
METHODS
Initially, a comparative analysis was conducted to investigate the relationship between AA expression patterns and different stages of IVDD using single-cell sequencing (scRNA-seq) data. Additionally, three machine learning methods (LASSO, random forest, and support vector machine recursive feature elimination) were employed to identify hub genes associated with IVDD. Subsequently, a novel artificial intelligence prediction model was developed for IVDD based on an artificial neural network algorithm and validated using an independent dataset. The identified hub genes were further subjected to functional enrichment, immune infiltration, and Connectivity Map analysis. Moreover, external validation was performed using flow cytometry and real-time reverse transcription polymerase chain reaction analysis.
RESULTS
Both scRNA-seq and bulk RNA-seq data revealed a positive correlation between the severity of IVDD and the AA metabolic pathway. They also revealed increased AA metabolic activity in macrophages and neutrophils, as well as enhanced intercellular communication with nucleus pulposus cells. Utilizing advanced machine learning algorithms, five hub genes (AKR1C3, ALOX5, CYP2B6, EPHX2, and PLB1) were identified, and an incipient diagnostic model was developed with an AUC of 0.961 in the training cohort and 0.72 in the validation cohort. An in-depth exploration of the functionality of these hub genes revealed their notable association with inflammatory responses and immune cell infiltration. Lastly, AH6809 was found to delay IVDD by inhibiting AKR1C3.
CONCLUSIONS
This study offers comprehensive insights into potential biomarkers and small molecules associated with the early pathogenesis of IVDD. The identified biomarkers and the developed integrated diagnostic model hold great promise in predicting the onset of early IVDD. AH6809 was established as a therapeutic target for AKR1C3 in the treatment of IVDD, as evidenced by computer simulations and biological experiments.
Topics: Humans; Artificial Intelligence; Arachidonic Acid; Intervertebral Disc Degeneration; Multiomics; Biomarkers
PubMed: 38007425
DOI: 10.1186/s12944-023-01962-5 -
Cell Reports Sep 2023Ferroptosis is a form of regulated cell death with roles in degenerative diseases and cancer. Excessive iron-catalyzed peroxidation of membrane phospholipids, especially...
Ferroptosis is a form of regulated cell death with roles in degenerative diseases and cancer. Excessive iron-catalyzed peroxidation of membrane phospholipids, especially those containing the polyunsaturated fatty acid arachidonic acid (AA), is central in driving ferroptosis. Here, we reveal that an understudied Golgi-resident scaffold protein, MMD, promotes susceptibility to ferroptosis in ovarian and renal carcinoma cells in an ACSL4- and MBOAT7-dependent manner. Mechanistically, MMD physically interacts with both ACSL4 and MBOAT7, two enzymes that catalyze sequential steps to incorporate AA in phosphatidylinositol (PI) lipids. Thus, MMD increases the flux of AA into PI, resulting in heightened cellular levels of AA-PI and other AA-containing phospholipid species. This molecular mechanism points to a pro-ferroptotic role for MBOAT7 and AA-PI, with potential therapeutic implications, and reveals that MMD is an important regulator of cellular lipid metabolism.
Topics: Cell Line; Fatty Acids, Unsaturated; Ferroptosis; Phosphatidylinositols; Phospholipids; Humans
PubMed: 37691145
DOI: 10.1016/j.celrep.2023.113023