The Effect of Omega-3 and Omega-6 Polyunsaturated Fatty Acids on the Production of Cyclooxygenase and Lipoxygenase Metabolites by Human Umbilical Vein Endothelial Cells.
Ontology highlight
ABSTRACT:
SUBMITTER: Araujo P
PROVIDER: S-EPMC6567278 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Hepatocellular carcinoma (HCC) is a common human cancer with high mortality, and currently, there is no effective chemoprevention or systematic treatment. Recent evidence suggests that cyclooxygenase-2 (COX-2)-derived PGE(2) and Wnt/beta-catenin signaling pathways are implicated in hepatocarcinogenesis. Here, we report that omega-3 polyunsaturated fatty acids (PUFA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) inhibit HCC growth through simultaneously inhibition of COX-2 and beta-catenin. DHA and EPA treatment resulted in a dose-dependent reduction of cell viability with cleavage of poly ADP ribose polymerase, caspase-3, and caspase-9 in three human HCC cell lines (Hep3B, Huh-7, HepG2). In contrast, AA, a omega-6 PUFA, exhibited no significant effect. DHA and EPA treatment caused dephosphorylation and thus activation of GSK-3beta, leading to beta-catenin degradation in Hep3B cells. The GSK-3beta inhibitor, LiCl, partially prevented DHA-induced beta-catenin protein degradation and apoptosis. Additionally, DHA induced the formation of beta-catenin/Axin/GSK-3beta binding complex, which serves as a parallel mechanism for beta-catenin degradation. Furthermore, DHA inhibited PGE(2) signaling through downregulation of COX-2 and upregulation of the COX-2 antagonist, 15-hydroxyprostaglandin dehydrogenase. Finally, the growth of HCC in vivo was significantly reduced when mouse HCCs (Hepa1-6) were inoculated into the Fat-1 transgenic mice, which express a Caenorhabditis elegans desaturase converting omega-6 to omega-3 PUFAs endogenously. These findings provide important preclinical evidence and molecular insight for utilization of omega-3 PUFAs for the chemoprevention and treatment of human HCC.
| S-EPMC2783299 | biostudies-literature
Project description:Diets high in saturated fatty acids are linked to increased cardiovascular disease risk, whereas monounsaturated fatty acids have been associated with improved cardiovascular outcomes. Accordingly, cell culture studies have demonstrated that saturated fatty acids, particularly long chain saturated fatty acids such as palmitate, induce dysfunction and cell death in a variety of cell types, and monounsaturated fatty acids may confer protection against palmitate-mediated damage. The aim of the present study was to examine whether monounsaturated fatty acids could protect against palmitate-mediated cell death in endothelial cells, to determine if AMPK inactivation and activation (via compound C and AICAR, respectively) underlies both palmitate-induced damage and monounsaturated fatty acid-mediated protection, and to explore the role of ER stress in this context. Human umbilical vein endothelial cells were examined for cell viability and apoptosis following treatment for 24 hours with palmitate (0.25 and 0.5mM) alone or in combination with the monounsaturated fatty acids oleate or palmitoleate (0.25 and 0.5mM), AICAR, compound C, 4?8C, or TUDCA. Compared to control cells, palmitate significantly decreased cell viability and increased apoptosis in a dose-dependent manner. The monounsaturated fatty acids oleate and palmitoleate completely prevented the cytotoxic effects of palmitate. Although palmitate induced markers of ER stress, chemical inhibition of ER stress did not prevent palmitate-induced lipoapoptosis. Conversely, the AMPK activator AICAR (0.1 and 0.5mM) conferred protection from palmitate mediated-alterations in viability, apoptosis and ER stress, whereas the AMPK inhibitor compound C (20 and 40?M) significantly exacerbated palmitate-mediated damage. Lastly, co-incubation with palmitate, monounsaturated fatty acids, and compound C significantly mitigated the protective effects of both oleate and palmitoleate. In conclusion, monounsaturated fatty acids confer protection against the cytotoxic effects of palmitate in vascular endothelial cells; and palmitate-mediated damage, as well as monounsaturated-mediated protection, are due in part to inactivation and activation, respectively, of the metabolic regulator AMPK. These results may have implications for understanding the deleterious effects of high saturated fat diets on cardiovascular dysfunction and disease risk.
| S-EPMC6938355 | biostudies-literature
Project description:Recent evidence has suggested that dietary polyunsaturated fatty acids (PUFAs) modulate inflammation; however, few studies have focused on the pathobiology of PUFA using isocaloric and isolipidic diets and it is unclear if the associated pathologies are due to dietary PUFA composition, lipid metabolism or obesity, as most studies compare diets fed ad libitum. Our studies used isocaloric and isolipidic liquid diets (35% of calories from fat), with differing compositions of omega (?)-6 or long chain (Lc) ?-3 PUFA that were pair-fed and assessed hepatic pathology, inflammation and lipid metabolism. Consistent with an isocaloric, pair-fed model we observed no significant difference in diet consumption between the groups. In contrast, the body and liver weight, total lipid level and abdominal fat deposits were significantly higher in mice fed an ?-6 diet. An analysis of the fatty acid profile in plasma and liver showed that mice on the ?-6 diet had significantly more arachidonic acid (AA) in the plasma and liver, whereas, in these mice ?-3 fatty acids such as eicosapentaenoic acid (EPA) were not detected and docosahexaenoic acid (DHA) was significantly lower. Histopathologic analyses documented that mice on the ?-6 diet had a significant increase in macrovesicular steatosis, extramedullary myelopoiesis (EMM), apoptotic hepatocytes and decreased glycogen storage in lobular hepatocytes, and hepatocyte proliferation relative to mice fed the Lc ?-3 diet. Together, these results support PUFA dietary regulation of hepatic pathology and inflammation with implications for enteral feeding regulation of steatosis and other hepatic lesions.
| S-EPMC5996979 | biostudies-literature
Project description: Not available
| S-EPMC6917524 | biostudies-literature
Project description:The beneficial effects of long-chain polyunsaturated omega-3 fatty acids (omega-3 PUFAs) in cardioprotection are widely known and generally accepted. In this literature review, we have focused on the known and postulated mechanisms of action of omega-3 PUFAs and their metabolites on various components of the haemostatic system, in particular on blood platelets and endothelium. We have also made an attempt to provide a comprehensive review of epidemiological studies with particular regard to clinical trials. Notably, the results of these studies are contradictory, and some of them failed to report the beneficial effects of taking or supplementing omega-3 PUFAs in the diet. A potential explanation, in our opinion, could be the need to use higher doses of omega-3 PUFAs and a proper ratio of omega-3 and omega-6 PUFAs. An additional problem which is difficult to solve is the use of a proper neutral placebo for interventional studies. Despite some controversies regarding the beneficial effects of supplementation of omega-3 PUFAs in cardiovascular disease, our review suggests that a promising aspect of future studies and applications is to focus on the anti-thrombotic properties of these compounds. An argument supporting this assumption is the recent use of omega-3 PUFAs as a supporting tool for the treatment of COVID-19 complications.
| S-EPMC7957531 | biostudies-literature
Project description:Twenty percent of deaths in the United States are secondary to cardiovascular diseases (CVD). In patients with hyperlipidemia and hypertriglyceridemia, studies have shown high atherosclerotic CVD (ASCVD) event rates despite the use of statins. Given the association of high triglyceride (TG) levels with elevated cholesterol and low levels of high-density lipoprotein cholesterol, the American Heart Association (AHA)/American College of Cardiology (ACC) cholesterol guidelines recommend using elevated TGs as a “risk-enhancing factor” for ASCVD and using omega 3 fatty acids (Ω3FAs) for patients with persistently elevated severe hypertriglyceridemia. Ω3FA, or fish oils (FOs), have been shown to reduce very high TG levels, hospitalizations, and CVD mortality in randomized controlled trials (RCTs). We have published the largest meta-analysis to date demonstrating significant effects on several CVD outcomes, especially fatal myocardial infarctions (MIs) and total MIs. Despite the most intensive research on Ω3FAs on CVD, their benefits have been demonstrated to cluster across multiple systems and pathologies, including autoimmune diseases, infectious diseases, chronic kidney disease, central nervous system diseases, and, most recently, the COVID-19 pandemic. A review and summary of the controversies surrounding Ω3FAs, some of the latest evidence-based findings, and the current and most updated recommendations on Ω3FAs are presented in this paper.
| S-EPMC9739673 | biostudies-literature
Project description:Reconstitution of nonnative, very-long-chain polyunsaturated fatty acid (VLC-PUFA) biosynthetic pathways in Arabidopsis thaliana was undertaken. The introduction of three primary biosynthetic activities to cells requires the stable coexpression of multiple proteins within the same cell. Herein, we report that C22 VLC-PUFAs were synthesized from C18 precursors by reactions catalyzed by Δ(6)-desaturase, an ELOVL5-like enzyme involved in VLC-PUFA elongation, and Δ(5)-desaturase. Coexpression of the corresponding genes (McD6DES, AsELOVL5, and PtD5DES) under the control of the seed-specific vicilin promoter resulted in production of docosapentaenoic acid (22:5 n-3) and docosatetraenoic acid (22:4 n-6) as well as eicosapentaenoic acid (20:5 n-3) and arachidonic acid (20:4 n-6) in Arabidopsis seeds. The contributions of the transgenic enzymes and endogenous fatty acid metabolism were determined. Specifically, the reasonable synthesis of omega-3 stearidonic acid (18:4 n-3) could be a useful tool to obtain a sustainable system for the production of omega-3 fatty acids in seeds of a transgenic T3 line 63-1. The results indicated that coexpression of the three proteins was stable. Therefore, this study suggests that metabolic engineering of oilseed crops to produce VLC-PUFAs is feasible.
| S-EPMC4538586 | biostudies-literature
Project description:ObjectiveOmega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), likely prevent cardiovascular disease, however their mechanisms remain unclear. Recently, the role of DNA damage in atherogenesis has been receiving considerable attention. Here, we investigated the effects of EPA and DHA on DNA damage in vascular endothelial cells to clarify their antiatherogenic mechanisms.Methods and resultsWe determined the effect of EPA and DHA on H2O2-induced DNA damage response in human aortic endothelial cells. Immunofluorescence staining showed that γ-H2AX foci formation, a prominent marker of DNA damage, was significantly reduced in the cells treated with EPA and DHA (by 47% and 48%, respectively). H2O2-induced activation of ATM, a major kinase orchestrating DNA damage response, was significantly reduced with EPA and DHA treatment (by 31% and 33%, respectively). These results indicated EPA and DHA attenuated DNA damage independently of the DNA damage response. Thus the effects of EPA and DHA on a source of DNA damage were examined. EPA and DHA significantly reduced intracellular reactive oxygen species under both basal condition and H2O2 stimulation. In addition, the mRNA levels of antioxidant molecules, such as heme oxygenase-1, thioredoxin reductase 1, ferritin light chain, ferritin heavy chain and manganese superoxide dismutase, were significantly increased with EPA and DHA. Silencing nuclear factor erythroid 2-related factor 2 (NRF2) remarkably abrogated the increases in mRNA levels of antioxidant molecules and the decrease in intracellular reactive oxygen species. Furthermore, EPA and DHA significantly reduced H2O2-induced senescence-associated β-galactosidase activity in the cells (by 31% and 22%, respectively), which was revoked by NRF2 silencing.ConclusionsOur results suggested that EPA and DHA attenuate oxidative stress-induced DNA damage in vascular endothelial cells through upregulation of NRF2-mediated antioxidant response. Therefore omega-3 fatty acids likely help prevent cardiovascular disease, at least in part, by their genome protective properties.
| S-EPMC5679535 | biostudies-literature
Project description:Electrophilic fatty acids are generated during inflammation by non-enzymatic reactions and can modulate inflammatory responses. We used a new mass spectrometry-based electrophile capture strategy to reveal the formation of electrophilic oxo-derivatives (EFOX) from the omega-3 fatty acids docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). These EFOX were generated by a cyclooxygenase-2 (COX-2)-catalyzed mechanism in activated macrophages. Modulation of COX-2 activity by aspirin increased the rate of EFOX production and their intracellular levels. Owing to their electrophilic nature, EFOX adducted to cysteine and histidine residues of proteins and activated Nrf2-dependent anti-oxidant gene expression. We confirmed the anti-inflammatory nature of DHA- and DPA-derived EFOX by showing that they can act as peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists and inhibit pro-inflammatory cytokine and nitric oxide production, all within biological concentration ranges. These data support the idea that EFOX are signaling mediators that transduce the beneficial clinical effects of omega-3 fatty acids, COX-2 and aspirin.
| S-EPMC3077712 | biostudies-literature
Project description:5-hydroxyeicosatetraenoic acid (5-HETE) and 5-hydroxyeicosapentaenoic acid (5-HEPE) are major metabolites produced by 5-lipoxygenase (5-LOX) from arachidonic acid (AA) and eicosapentaenoic acid (EPA). Effects of hydroxides on endothelial cells are unclear, although 5-LOX is known to increase at arteriosclerotic lesions. To investigate the effects of hydroxides on human umbilical vein endothelial cells (HUVECs), the cells were treated with 50 ?M each of AA, EPA, 5-HETE, and 5-HEPE. Treatment of HUVECs with 5-HETE and 5-HEPE, rather than with AA and EPA, increased the nuclear translocation of NF-E2 related factor 2 (Nrf2) and upregulated the expression of heme oxygenase-1 and cystine/glutamate transporter regulated by Nrf2. Reactive oxygen species (ROS) generation was markedly elevated in HUVECs after treatment with 5-HETE and 5-HEPE, and the pretreatment with ?-tocopherol abrogated ROS levels similar to those in the vehicle control. However, ROS generation was independent of Nrf2 activation induced by 5-HETE and 5-HEPE. 5-HETE was converted to 5-oxo-eicosatetraenoic acid (5-oxo-ETE) in HUVECs, and 5-oxo-ETE increased Nrf2 activation. These results suggest that 5-HETE works as an Nrf2 activator through the metabolite 5-oxo-ETE in HUVECs. Similarly, 5-HEPE works in the same way, because 5-HEPE is metabolized to 5-oxo-eicosapentaenoic acid through the same pathway as that for 5-HETE.
| S-EPMC5622761 | biostudies-literature