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Circulation Research Jun 2024Cardiometabolic disease has become a major health burden worldwide, with sharply increasing prevalence but highly limited therapeutic interventions. Emerging evidence... (Review)
Review
Cardiometabolic disease has become a major health burden worldwide, with sharply increasing prevalence but highly limited therapeutic interventions. Emerging evidence has revealed that arachidonic acid derivatives and pathway factors link metabolic disorders to cardiovascular risks and intimately participate in the progression and severity of cardiometabolic diseases. In this review, we systemically summarized and updated the biological functions of arachidonic acid pathways in cardiometabolic diseases, mainly focusing on heart failure, hypertension, atherosclerosis, nonalcoholic fatty liver disease, obesity, and diabetes. We further discussed the cellular and molecular mechanisms of arachidonic acid pathway-mediated regulation of cardiometabolic diseases and highlighted the emerging clinical advances to improve these pathological conditions by targeting arachidonic acid metabolites and pathway factors.
Topics: Humans; Arachidonic Acid; Animals; Cardiovascular Diseases; Signal Transduction; Metabolic Diseases; Cardiometabolic Risk Factors; Obesity
PubMed: 38900855
DOI: 10.1161/CIRCRESAHA.124.324383 -
Clinical Nutrition (Edinburgh, Scotland) Jan 2024Arachidonic acid (ARA) and docosahexaenoic acid (DHA) are important structural components of neural cellular membranes and possess anti-inflammatory properties. Very... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Arachidonic acid (ARA) and docosahexaenoic acid (DHA) are important structural components of neural cellular membranes and possess anti-inflammatory properties. Very preterm infants are deprived of the enhanced placental supply of these fatty acids, but the benefit of postnatal supplementation on brain development is uncertain. The aim of this study was to test the hypothesis that early enteral supplementation with ARA and DHA in preterm infants improves white matter (WM) microstructure assessed by diffusion-weighted MRI at term equivalent age.
METHODS
In this double-blind, randomized controlled trial, infants born before 29 weeks gestational age were allocated to either 100 mg/kg ARA and 50 mg/kg DHA (ARA:DHA group) or medium chain triglycerides (control). Supplements were started on the second day of life and provided until 36 weeks postmenstrual age. The primary outcome was brain maturation assessed by diffusion tensor imaging (DTI) using Tract-Based Spatial Statistics (TBSS) analysis.
RESULTS
We included 120 infants (60 per group) in the trial; mean (range) gestational age was 26 (22 - 28) weeks and postmenstrual age at scan was 41 (39 - 47+) weeks. Ninety-two infants underwent MRI imaging, and of these, 90 had successful T1/T2 weighted MR images and 74 had DTI data of acceptable quality. TBSS did not show significant differences in mean or axial diffusivity between the groups, but demonstrated significantly higher fractional anisotropy in several large WM tracts in the ARA:DHA group, including corpus callosum, the anterior and posterior limb of the internal capsula, inferior occipitofrontal fasciculus, uncinate fasciculus, and the inferior longitudinal fasciculus. Radial diffusivity was also significantly lower in several of the same WM tracts in the ARA:DHA group.
CONCLUSION
This study suggests that supplementation with ARA and DHA at doses matching estimated fetal accretion rates improves WM maturation compared to control treatment, but further studies are needed to ascertain any functional benefit.
CLINICAL TRIAL REGISTRATION
www.
CLINICALTRIALS
gov; ID:NCT03555019.
Topics: Pregnancy; Infant; Infant, Newborn; Humans; Female; Infant, Premature; Docosahexaenoic Acids; Diffusion Tensor Imaging; Placenta; White Matter; Dietary Supplements; Arachidonic Acid; Brain
PubMed: 38061271
DOI: 10.1016/j.clnu.2023.11.037 -
Biomolecules Aug 2023Sepsis is triggered by microbial infection, injury, or even major surgery. Both innate and adaptive immune systems are involved in its pathogenesis. Cytoplasmic presence... (Review)
Review
Sepsis is triggered by microbial infection, injury, or even major surgery. Both innate and adaptive immune systems are involved in its pathogenesis. Cytoplasmic presence of DNA or RNA of the invading organisms or damaged nuclear material (in the form of micronucleus in the cytoplasm) in the host cell need to be eliminated by various nucleases; failure to do so leads to the triggering of inflammation by the cellular cGAS-STING system, which induces the release of IL-6, TNF-α, and IFNs. These cytokines activate phospholipase A2 (PLA2), leading to the release of polyunsaturated fatty acids (PUFAs), gamma-linolenic acid (GLA), arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), which form precursors to various pro- and anti-inflammatory eicosanoids. On the other hand, corticosteroids inhibit PLA2 activity and, thus, suppress the release of GLA, AA, EPA, and DHA. PUFAs and their metabolites have a negative regulatory action on the cGAS-STING pathway and, thus, suppress the inflammatory process and initiate inflammation resolution. Pro-inflammatory cytokines and corticosteroids (corticosteroids > IL-6, TNF-α) suppress desaturases, which results in decreased formation of GLA, AA, and other PUFAs from the dietary essential fatty acids (EFAs). A deficiency of GLA, AA, EPA, and DHA results in decreased production of anti-inflammatory eicosanoids and failure to suppress the cGAS-STING system. This results in the continuation of the inflammatory process. Thus, altered concentrations of PUFAs and their metabolites, and failure to suppress the cGAS-STING system at an appropriate time, leads to the onset of sepsis. Similar abnormalities are also seen in radiation-induced inflammation. These results imply that timely administration of GLA, AA, EPA, and DHA, in combination with corticosteroids and anti-IL-6 and anti-TNF-α antibodies, may be of benefit in mitigating radiation-induced damage and sepsis.
Topics: Humans; Tumor Necrosis Factor-alpha; Interleukin-6; Tumor Necrosis Factor Inhibitors; Inflammation; Fatty Acids, Unsaturated; Eicosanoids; Eicosapentaenoic Acid; Arachidonic Acid; Cytokines; Docosahexaenoic Acids; Anti-Inflammatory Agents; Sepsis
PubMed: 37759732
DOI: 10.3390/biom13091332 -
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 -
ELife Jul 2023Decidualization is a process in which endometrial stromal fibroblasts differentiate into specialized secretory decidual cells and essential for the successful...
Decidualization is a process in which endometrial stromal fibroblasts differentiate into specialized secretory decidual cells and essential for the successful establishment of pregnancy. The underlying mechanism during decidualization still remains poorly defined. Because decidualization and fibroblast activation share similar characteristics, this study was to examine whether fibroblast activation is involved in decidualization. In our study, fibroblast activation-related markers are obviously detected in pregnant decidua and under in vitro decidualization. ACTIVIN A secreted under fibroblast activation promotes in vitro decidualization. We showed that arachidonic acid released from uterine luminal epithelium can induce fibroblast activation and decidualization through PGI and its nuclear receptor PPARδ. Based on the significant difference of fibroblast activation-related markers between pregnant and pseudopregnant mice, we found that embryo-derived TNF promotes CPLA phosphorylation and arachidonic acid release from luminal epithelium. Fibroblast activation is also detected under human in vitro decidualization. Similar arachidonic acid-PGI-PPARδ-ACTIVIN A pathway is conserved in human endometrium. Collectively, our data indicate that embryo-derived TNF promotes CPLA phosphorylation and arachidonic acid release from luminal epithelium to induce fibroblast activation and decidualization.
Topics: Pregnancy; Female; Humans; Animals; Mice; Decidua; PPAR delta; Arachidonic Acid; Endometrium; Fibroblasts; Stromal Cells
PubMed: 37458359
DOI: 10.7554/eLife.82970 -
Prostaglandins, Leukotrienes, and... Aug 2023This study investigated whether non-esterified erythrocyte omega-6 PUFAs were associated with subjective assessment of sleep quality and duration, and risk for...
OBJECTIVE
This study investigated whether non-esterified erythrocyte omega-6 PUFAs were associated with subjective assessment of sleep quality and duration, and risk for obstructive sleep apnea.
METHODS
In this secondary analysis of the cross-sectional OPPERA-II study, 538 adults completed the Pittsburgh Sleep Quality Index (PSQI), reported their usual hours of sleep, and answered STOP screening questions for obstructive sleep apnea. Circulating non-esterified erythrocyte concentrations of omega-6 PUFA linoleic acid and arachidonic acid were quantified by liquid chromatography tandem mass spectroscopy. Sleep outcomes were dichotomized as poor (PSQI ≤5) vs good (PSQI ≥6) sleep quality, insufficient or excessive (≤6 or >9 h) vs good (7-9 h) sleep duration, and high (≥2 affirmative responses) vs low (<2 affirmative responses) risk for obstructive sleep apnea. Non-esterified omega-6 PUFAs and the continuous covariates of body mass index, Short Form (SF) 12 Health Survey Physical and Mental Component scores and resting measures of systolic and diastolic blood pressure were standardized for multivariable analysis. Categorical covariates were study site, age, sex, and race/ethnicity. Multivariable-adjusted logistic regression first estimated odds ratios (OR) and 95% confidence limits (CL) for sleep outcomes using linoleic acid as the main exposure. Analysis was then repeated using arachidonic acid as the main exposure.
RESULTS
In the multivariable-adjusted model, each standard deviation increase in non-esterified erythrocyte linoleic acid was associated with higher odds of poor sleep quality (OR=1.2, 95% CL: 1.1, 1.5), insufficient or excessive sleep (OR= 1.3, 95% CL: 1.1, 1.6) and high-risk for obstructive sleep apnea (OR=1.3, 95% CL: 1.1, 1.6). Likewise, for each standard deviation increase in non-esterified erythrocyte arachidonic acid, odds increased of poor sleep quality (OR=1.2, 95% CL: 1.1, 1.5), and insufficient or excessive sleep (OR=1.2, 95% CL: 1.1, 1.5). Odds of being high risk for obstructive sleep apnea increased with greater circulating arachidonic acid, but the association did not reach statistical significance (OR=1.1, 95% CL: 0.9, 1.4).
CONCLUSION
Non-esterified erythrocyte linoleic acid and arachidonic acid were associated with poor sleep quality and insufficient or excessive sleep duration. Linoleic acid, but not arachidonic acid, was also associated with high risk for obstructive sleep apnea.
Topics: Adult; Humans; Linoleic Acid; Arachidonic Acid; Cross-Sectional Studies; Sleep; Fatty Acids, Omega-6; Sleep Apnea, Obstructive; Erythrocytes
PubMed: 37451068
DOI: 10.1016/j.plefa.2023.102580 -
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 -
Pharmacology & Therapeutics Aug 2023Cancer is a major burden of disease worldwide and increasing evidence shows that inflammation contributes to cancer development and progression. Eicosanoids are derived... (Review)
Review
BACKGROUND
Cancer is a major burden of disease worldwide and increasing evidence shows that inflammation contributes to cancer development and progression. Eicosanoids are derived from dietary polyunsaturated fatty acids, such as arachidonic acid (AA), and are mainly produced by a series of enzymatic pathways that include cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P-450 epoxygenase (CYP). Eicosanoids consist of at least several hundred individual molecules and play important roles in the inflammatory response and inflammation-related cancers.
SCOPE AND APPROACH
Dietary sources of AA and biosynthesis of eicosanoids from AA through different metabolic pathways are summarized. The bioactivities of eicosanoids and their potential molecular mechanisms on inflammation and cancer are revealed. Additionally, current challenges and limitations in eicosanoid research on inflammation-related cancer are discussed.
KEY FINDINGS AND CONCLUSIONS
Dietary AA generates a large variety of eicosanoids, including prostaglandins, thromboxane A2, leukotrienes, cysteinyl leukotrienes, lipoxins, hydroxyeicosatetraenoic acids (HETEs), and epoxyeicosatrienoic acids (EETs). Eicosanoids exert different bioactivities and mechanisms involved in the inflammation and related cancer developments. A deeper understanding of eicosanoid biology may be advantageous in cancer treatment and help to define cellular targets for further therapeutic development.
Topics: Humans; Eicosanoids; Arachidonic Acid; Neoplasms; Leukotrienes; Inflammation; Cyclooxygenase 2
PubMed: 37257760
DOI: 10.1016/j.pharmthera.2023.108455 -
PeerJ 2023Arachidonic acid 15-lipoxygenase (ALOX15), as one of the lipoxygenase family, is mainly responsible for catalyzing the oxidation of various fatty acids to produce a... (Review)
Review
Arachidonic acid 15-lipoxygenase (ALOX15), as one of the lipoxygenase family, is mainly responsible for catalyzing the oxidation of various fatty acids to produce a variety of lipid components, contributing to the pathophysiological processes of various immune and inflammatory diseases. Studies have shown that ALOX15 and its related products are widely distributed in human tissues and related to multiple diseases such as liver, cardiovascular, cerebrovascular diseases, diabetes mellitus and other diseases. Diabetes mellitus (DM), the disease studied in this article, is a metabolic disease characterized by a chronic increase in blood glucose levels, which is significantly related to inflammation, oxidative stress, ferroptosis and other mechanisms, and it has a high incidence in the population, accompanied by a variety of complications. Figuring out how ALOX15 is involved in DM is critical to understanding its role in diseases. Therefore, ALOX15 inhibitors or combination therapy containing inhibitors may deliver a novel research direction for the treatment of DM and its complications. This article aims to review the biological effect and the possible function of ALOX15 in the pathogenesis of DM.
Topics: Humans; Arachidonate 15-Lipoxygenase; Diabetes Mellitus; Fatty Acids; Oxidative Stress; Inflammation
PubMed: 37849828
DOI: 10.7717/peerj.16239 -
Liver International : Official Journal... Nov 2023MBOAT7 is a protein anchored to endomembranes by several transmembrane domains. It has a catalytic dyad involved in remodelling of phosphatidylinositol with... (Review)
Review
MBOAT7 is a protein anchored to endomembranes by several transmembrane domains. It has a catalytic dyad involved in remodelling of phosphatidylinositol with polyunsaturated fatty acids. Genetic variants in the MBOAT7 gene have been associated with the entire spectrum of non-alcoholic fatty liver (NAFLD), recently redefined as metabolic dysfunction-associated fatty liver disease (MAFLD) and, lately, steatotic liver disease (SLD), and to an increasing number of extrahepatic conditions. In this review, we will (a) elucidate the molecular mechanisms by which MBOAT7 loss-of-function predisposes to MAFLD and neurodevelopmental disorders and (b) discuss the growing number of genetic studies linking MBOAT7 to hepatic and extrahepatic diseases. MBOAT7 complete loss of function causes severe changes in brain development resulting in several neurological manifestations. Lower MBOAT7 hepatic expression at both the mRNA and protein levels, due to missense nucleotide polymorphisms (SNPs) in the locus containing the MBOAT7 gene, affects specifically metabolic and viral diseases in the liver from simple steatosis to hepatocellular carcinoma, and potentially COVID-19 disease. This body of evidence shows that phosphatidylinositol remodelling is a key factor for human health.
Topics: Humans; Acyltransferases; COVID-19; Liver Neoplasms; Membrane Proteins; Non-alcoholic Fatty Liver Disease; Phosphatidylinositols; Polymorphism, Single Nucleotide
PubMed: 37605540
DOI: 10.1111/liv.15706