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Molecular Neurobiology Jun 2024Arachidonic acid (AA), an important polyunsaturated fatty acid in the brain, is hydrolyzed by a direct action of phospholipase A(PLA) or through the combined action of... (Review)
Review
Arachidonic acid (AA), an important polyunsaturated fatty acid in the brain, is hydrolyzed by a direct action of phospholipase A(PLA) or through the combined action of phospholipase C and diacylglycerol lipase, and released into the cytoplasm. Various derivatives of AA can be synthesized mainly through the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (P450) enzyme pathways. AA and its metabolic enzymes and metabolites play important roles in a variety of neurophysiological activities. The abnormal metabolites and their catalytic enzymes in the AA cascade are related to the pathogenesis of various central nervous system (CNS) diseases, including epilepsy. Here, we systematically reviewed literatures in PubMed about the latest randomized controlled trials, animal studies and clinical studies concerning the known features of AA, its metabolic enzymes and metabolites, and their roles in epilepsy. The exclusion criteria include non-original studies and articles not in English.
PubMed: 38842673
DOI: 10.1007/s12035-024-04274-6 -
Biomedicine & Pharmacotherapy =... Jul 2023Thromboxane (TX) and prostaglandins are metabolites of arachidonic acid, a twenty-carbon unsaturated fatty acid, and have a variety of actions that are exerted via... (Review)
Review
Thromboxane (TX) and prostaglandins are metabolites of arachidonic acid, a twenty-carbon unsaturated fatty acid, and have a variety of actions that are exerted via specific receptors. Angiogenesis is defined as the formation of new blood vessels from pre-existing vascular beds and is a critical component of pathological conditions, including inflammation and cancer. Lymphatic vessels play crucial roles in the regulation of interstitial fluid, immune surveillance, and the absorption of dietary fat from the intestine; and they are also involved in the pathogenesis of various diseases. Similar to angiogenesis, lymphangiogenesis, the formation of new lymphatic vessels, is a critical component of pathological conditions. The TP-dependent accumulation of platelets in microvessels has been reported to enhance angiogenesis under pathological conditions. Although the roles of some growth factors and cytokines in angiogenesis and lymphangiogenesis have been well characterized, accumulating evidence suggests that TX induces the production of proangiogenic and prolymphangiogenic factors through the activation of adenylate cyclase, and upregulates angiogenesis and lymphangiogenesis under disease conditions. In this review, we discuss the role of TX as a regulator of angiogenesis and lymphangiogenesis, and its emerging importance as a therapeutic target.
Topics: Humans; Lymphangiogenesis; Thromboxanes; Lymphatic Vessels; Neoplasms; Inflammation
PubMed: 37150029
DOI: 10.1016/j.biopha.2023.114831 -
Wiley Interdisciplinary Reviews. RNA Nov 2023Long noncoding RNAs (lncRNAs) have emerged as critical regulators in numerous biological processes. The arachidonic acid (AA) metabolic pathway is a fundamental... (Review)
Review
Long noncoding RNAs (lncRNAs) have emerged as critical regulators in numerous biological processes. The arachidonic acid (AA) metabolic pathway is a fundamental biochemical pathway responsible for the enzymatic conversion of AA, a 20-carbon omega-six polyunsaturated fatty acid, into a variety of potent lipid signaling molecules known as eicosanoids. Eicosanoids are produced through the cyclooxygenase and lipoxygenase arms of the AA pathway and have diverse biological roles in both healthy and disease states, including cancer and inflammatory diseases. Cyclooxygenase 2 (COX-2), the inducible, rate-limiting enzyme of the cyclooxygenase arm, produces two main forms of eicosanoids: prostaglandins and thromboxanes. AA metabolized through the lipoxygenase arm by the action of 5-lipoxygenase (ALOX5) produces eicosanoids known as leukotrienes. COX-2 and ALOX5 gene expression are regulated through many different lncRNAs and microRNA (miRNA)-mediated mechanisms. As previously reviewed, noncoding RNAs affect transcription, splicing, alternative polyadenylation, messenger RNA stability, translation, and miRNA regulation of COX-2 and ALOX5 (Lutz and Cornett, 2013, Wiley Interdisciplinary Reviews. RNA, 4(5), 593-605). This current review discusses the intricate roles of lncRNAs, including MALAT1, NEAT1, HOTAIR, PACER, and others, in modulating the AA pathway. In this review update, we will delve into advancements in our understanding of AA gene expression regulation. We will explore the mechanisms of lncRNAs and their associated miRNAs and proteins known to regulate key components of the AA signaling pathway. We will also discuss the therapeutic potential of targeting lncRNA-mediated regulation, with a focus on modulating COX-2 and ALOX5 activity and downstream eicosanoid production for applications in inflammatory and oncological conditions. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA in Disease and Development > RNA in Disease.
PubMed: 37994271
DOI: 10.1002/wrna.1828 -
Prostaglandins & Other Lipid Mediators Aug 2024Menopause is a normal stage in the human female aging process characterized by the cessation of menstruation and the ovarian production of estrogen and progesterone... (Review)
Review
Menopause is a normal stage in the human female aging process characterized by the cessation of menstruation and the ovarian production of estrogen and progesterone hormones. Menopause is associated with an increased risk of several different diseases. Cardiovascular diseases are generally less common in females than in age-matched males. However, this female advantage is lost after menopause. Cardiac hypertrophy is a disease characterized by increased cardiac size that develops as a response to chronic overload or stress. Similar to other cardiovascular diseases, the risk of cardiac hypertrophy significantly increases after menopause. However, the exact underlying mechanisms are not yet fully elucidated. Several studies have shown that surgical or chemical induction of menopause in experimental animals is associated with cardiac hypertrophy, or aggravates cardiac hypertrophy induced by other stressors. Arachidonic acid (AA) released from the myocardial phospholipids is metabolized by cardiac cytochrome P450 (CYP), cyclooxygenase (COX), and lipoxygenase (LOX) enzymes to produce several eicosanoids. AA-metabolizing enzymes and their respective metabolites play an important role in the pathogenesis of cardiac hypertrophy. Menopause is associated with changes in the cardiovascular levels of CYP, COX, and LOX enzymes and the levels of their metabolites. It is possible that these changes might play a role in the increased risk of cardiac hypertrophy after menopause.
Topics: Cardiomegaly; Arachidonic Acid; Humans; Animals; Female; Menopause; Postmenopause; Cytochrome P-450 Enzyme System; Prostaglandin-Endoperoxide Synthases; Lipoxygenase; Disease Models, Animal
PubMed: 38740361
DOI: 10.1016/j.prostaglandins.2024.106851 -
Clinical Nutrition (Edinburgh, Scotland) Nov 2023To investigate the relationships among docosahexaenoic acid (DHA) intake, nutrient intake, and maternal characteristics on pregnancy outcomes in a phase III randomised... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To investigate the relationships among docosahexaenoic acid (DHA) intake, nutrient intake, and maternal characteristics on pregnancy outcomes in a phase III randomised clinical trial designed to determine the effect of a DHA dose of 1000 mg/day compared to 200 mg/day on early preterm birth (<34 weeks gestation).
METHODS
A secondary aim of the phase III randomised trial was to explore the relationships among pregnancy outcomes (maternal red blood cell phospholipid (RBC-PL) DHA at delivery, preterm birth, gestational age at delivery, labor type, birth anthropometric measures, low birth weight, gestational diabetes, pre-eclampsia, and admission to a neonatal intensive care unit) in participants (n = 1100). We used Bayesian multiple imputation and linear and logistic regression models to conduct an analysis of five general classes of predictor variables collected during the trial: a) DHA intake, b) nutrient intake from food and supplements, c) environmental exposure to tobacco and alcohol, d) maternal demographics, and e) maternal medical history.
RESULTS
DHA supplementation lowered the risk of preterm birth and NICU admission, and increased gestation and birth weight as observed in the primary analysis. Higher maternal RBC-PL-DHA at delivery was associated with DHA supplementation and formal education of a bachelor's degree or higher. DHA supplementation and maternal age were associated with a higher risk of gestational diabetes. Total vitamin A intake was associated with longer gestation, while fructose and intake of the long chain omega-6 fatty acid, arachidonic acid, were associated with shorter gestation. Risk of preterm birth was associated with a history of low birth weight, preterm birth, pre-eclampsia, and NICU admission.
CONCLUSION
Bayesian models provide a comprehensive approach to relationships among DHA intake, nutrient intake, maternal characteristics, and pregnancy outcomes. We observed previously unreported relationships between gestation duration and fructose, vitamin A, and arachidonic acid that could be the basis for future research.
TRIAL REGISTRATION NUMBER AND DATE
ClinicalTrials.gov (NCT02626299); December 10, 2015.
Topics: Pregnancy; Female; Infant, Newborn; Humans; Pregnancy Outcome; Premature Birth; Pre-Eclampsia; Diabetes, Gestational; Vitamin A; Arachidonic Acid; Bayes Theorem; Dietary Supplements; Eating; Fructose; Docosahexaenoic Acids
PubMed: 37806075
DOI: 10.1016/j.clnu.2023.09.005 -
The Journal of Maternal-fetal &... Dec 2023: Macrosomia is a common disorder that occurs during pregnancy. We investigated the comprehensive metabolite profiles of pregnant maternal and fetal sera in...
: Macrosomia is a common disorder that occurs during pregnancy. We investigated the comprehensive metabolite profiles of pregnant maternal and fetal sera in normoglycemic macrosomia in a Chinese population. Forty pregnant women and their fetuses were included in the study (twenty macrosomia patients and twenty normal-weight controls). Maternal and umbilical cord serum metabolites were identified using ultra-performance liquid chromatography coupled with tandem mass spectrometry. In total, 203 metabolites were identified. Lipids and lipid-like molecules were the predominant metabolites. Fifty-three metabolites with significant differences were obtained in the maternal samples. In the macrosomia group, the levels of docosahexaenoic acid, eicosapentaenoic acid, and arachidonic acid were significantly higher than those in the control group. Umbilical cord serum samples were obtained for 24 different metabolites. The maternal-fetal gradient of polyunsaturated fatty acids was decreased in the macrosomia group. Aconitic acid, citric acid, isocitric acid, 2-methylhexanoic acid, and 12-hydroxystearic acid were the common differential metabolites in the maternal and umbilical cord serum samples. There were obvious metabolic abnormalities in the sera of pregnant women and fetuses with macrosomia. Lipids and lipid-like molecules were the predominant differential metabolites but had different classifications in the maternal and umbilical cord serum. These results may provide new insights into the long-term metabolic disorders associated with macrosomia.
Topics: Humans; Pregnancy; Female; Fetal Macrosomia; Fetal Blood; Metabolomics; Docosahexaenoic Acids; Chromatography, Liquid
PubMed: 37848386
DOI: 10.1080/14767058.2023.2270761 -
BMC Microbiology Nov 2023Infantile cholestasis (IC) is the most common hepatobiliary disease in infants, resulting in elevated direct bilirubin levels. Indeed, hepatointestinal circulation...
BACKGROUND
Infantile cholestasis (IC) is the most common hepatobiliary disease in infants, resulting in elevated direct bilirubin levels. Indeed, hepatointestinal circulation impacts bile acid and bilirubin metabolism. This study evaluates changes in the gut microbiota composition in children with IC and identifies abnormal metabolite profiles associated with microbial alterations.
RESULTS
The gut microbiota in the IC group exhibits the higher abundance of Veillonella, Streptococcus and Clostridium spp. (P < 0.05), compared to healthy infants (CON) group. Moreover, the abundance of Ruminococcus, Vibrio butyricum, Eubacterium coprostanogenes group, Intestinibacter, and Faecalibacterium were lower (P < 0.05). In terms of microbiota-derived metabolites, the levels of fatty acids (palmitoleic, α-linolenic, arachidonic, and linoleic) (P < 0.05) increased and the levels of amino acids decreased in IC group. Furthermore, the abundances of Ruminococcus, Eubacterium coprostanoligenes group, Intestinibacter and Butyrivibrio are positively correlated with proline, asparagine and aspartic acid, but negatively correlated with the α-linolenic acid, linoleic acid, palmitoleic acid and arachidonic acid. For analysis of the relationship between the microbiota and clinical index, it was found that the abundance of Veillonella and Streptococcus was positively correlated with serum bile acid content (P < 0.05), while APTT, PT and INR were negatively correlated with Faecalibalum and Ruminococcus (P < 0.05).
CONCLUSION
Microbiota dysbiosis happened in IC children, which also can lead to the abnormal metabolism, thus obstructing the absorption of enteral nutrition and aggravating liver cell damage. Veillonella, Ruminococcus and Butyrivibrio may be important microbiome related with IC and need further research.
Topics: Infant; Child; Humans; Gastrointestinal Microbiome; Cholestasis; Liver; Streptococcus; Bilirubin; Bile Acids and Salts
PubMed: 37980506
DOI: 10.1186/s12866-023-03115-1 -
Cellular Signalling Aug 2023Macrophages in hypoxic regions of advanced colorectal tumors often exhibit M2-type features, but prefer oxygen-consuming lipid catabolism, which is contradictory in...
Macrophages in hypoxic regions of advanced colorectal tumors often exhibit M2-type features, but prefer oxygen-consuming lipid catabolism, which is contradictory in oxygen demand and supply. In this study, the results from bioinformatics analysis and intestinal lesions immunohistochemistry of 40 colorectal cancer patients illustrated that glucose-regulatory protein 78 (GRP78) was positively correlated with M2 macrophages. Furthermore, tumor-secreted GRP78 could enter macrophages and polarize them to M2-type. Mechanistically, entered GRP78 located in lipid droplets of macrophages, and elevated protein stabilization of adipose triglyceride lipase ATGL by interacting with it to inhibit its ubiquitination. Increased ATGL promoted the hydrolysis of triglycerides and the production of arachidonic acid (ARA) and docosahexaenoic acid (DHA). Excessive ARA and DHA interacted with PPARγ to encourage its activation, which mediated the M2 polarization of macrophages. In summary, our study showed that secreted GRP78 in the tumor hypoxic microenvironment mediated the domestication of tumor cells to macrophages and maintained tumor immunosuppressive microenvironment by promoting lipolysis, and the lipid catabolism not only provides energy for macrophages but also plays an important role in maintenance of immunosuppressive properties.
Topics: Humans; Colorectal Neoplasms; Endoplasmic Reticulum Chaperone BiP; Glucose; Lipids; Lipolysis; Macrophages; Neoplasm Proteins; Tumor Microenvironment
PubMed: 37207940
DOI: 10.1016/j.cellsig.2023.110719 -
Phytomedicine : International Journal... Dec 2023The combination of Astragalus membranaceus and Salvia miltiorrhiza (AS) is an effective prescription for treating diabetic kidney disease (DKD) in traditional Chinese...
BACKGROUND
The combination of Astragalus membranaceus and Salvia miltiorrhiza (AS) is an effective prescription for treating diabetic kidney disease (DKD) in traditional Chinese medicine. Its efficacy in treating DKD has been confirmed, but the potential regulatory mechanism has not yet been fully clarified.
PURPOSE
To explore the mechanism by which AS regulates the "gut-metabolism-transcription" coexpression network under the action of the "gut-kidney axis" to ameliorate DKD.
METHODS
SD rats were used to establish the DKD model by injecting STZ. After AS intervention, the structure and function of the kidney and colon were observed. We sequenced the gut microbiota utilizing 16S rDNA, identified serum differential metabolites using LC‒MS/MS, and observed renal mRNA expression by RNA seq. The "gut-metabolism-transcription" coexpression network was further constructed, and the target bacteria, target metabolites, and target genes of AS were ultimately screened and validated.
RESULTS
AS improved renal pathology and functional damage and increased the abundance of Akkermansia, Akkermansia_muciniphila, Lactobacillus and Lactobacillus_murinus. Fourteen target metabolites of AS were identified, which were mainly concentrated in 19 KEGG pathways, including sphingolipid metabolism and glycerophospholipid metabolism. Sixty-three target mRNAs of AS were identified. The top 20 pathways were closely related to glycolipid metabolism, and 14 differential mRNAs were expressed in these pathways. Correlation analysis showed that Akkermansia, Akkermansia muciniphila, Lactobacillus and Lactobacillus murinus were closely associated with sphingolipid metabolism, glycerophospholipid metabolism, arachidonic acid metabolism, ascorbate and aldarate metabolism and galactose metabolism. Moreover, the target metabolites and target mRNAs of AS were also enriched in five identical pathways of sphingolipid metabolism, glycerophospholipid metabolism, arachidonic acid metabolism, ascorbate and aldarate metabolism and galactose metabolism, including 8 different metabolites, such as sphingosine, and 5 different genes, such as Kng1. The 8 metabolites had high AUC prediction values, and the validation of the 5 genes was consistent with the sequencing results.
CONCLUSION
Our research showed that AS can improve DKD via the "gut-kidney axis". Akkermansia muciniphila and Lactobacillus murinus were the main driving bacteria, and five pathways related to glycolipid metabolism, especially sphingolipid metabolism and glycerophospholipid metabolism, may be important follow-up reactions and regulatory mechanisms.
Topics: Rats; Animals; Diabetic Nephropathies; Astragalus propinquus; Salvia miltiorrhiza; Arachidonic Acid; Chromatography, Liquid; Galactose; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Kidney; Bacteria; Glycolipids; Glycerophospholipids; Sphingolipids
PubMed: 37804821
DOI: 10.1016/j.phymed.2023.155129 -
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