Differential effects of eicosapentaenoic and docosahexaenoic acids upon oxidant-stimulated release and uptake of arachidonic acid in human lymphoma U937 cells

Obajimi, Oluwakemi; Black, Kenneth D.; MacDonald, Donald J.; Boyle, Rose M.; Glen, Iain; Ross, Brian M.

doi:10.1016/j.phrs.2005.02.024

Cited by 19 publications

(10 citation statements)

References 44 publications

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“…The biological mechanisms underlying differential effects of EPA with regard to depression are unknown; however, one possible explanation arises from certain anti-inflammatory effects specific to EPA. For example, EPA, to a much higher degree than DHA, competes with the omega-6 PUFA AA, its 20-carbon congener, for uptake into phospholipids in human lymphoma U937 cells (Obajimi et al, 2005) and for enzymatic metabolism via cyclooxygenase-2 in T-helper cells and monocytes (Jaudszus et al, 2013). Additionally, dietary studies in autoimmune-prone mice found that higher proportions of EPA to DHA in the diet results in a reduction of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukins (IL) IL-6 and IL-1β (Bhattacharya, Sun, Rahman, & Fernandes, 2007).…”

Section: Discussionmentioning

confidence: 99%

Low plasma eicosapentaenoic acid levels are associated with elevated trait aggression and impulsivity in major depressive disorder with a history of comorbid substance use disorder

Beier¹,

Lauritzen²,

Galfalvy³

et al. 2014

Journal of Psychiatric Research

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Major depressive disorder (MDD) is associated with low levels of omega-3 polyunsaturated fatty acids (PUFAs), holding promise for new perspectives on disease etiology and treatment targets. As aggressive and impulsive behaviors are associated with low omega-3 PUFA levels in some clinical contexts, we investigated plasma PUFA relationships with trait aggression and impulsivity in patients with MDD. Medication-free MDD patients (n=48) and healthy volunteers (HV, n=35) were assessed with the Brown-Goodwin Aggression Inventory. A subset (MDD, n=39; HV, n=33) completed the Barratt Impulsiveness Scale. Plasma PUFAs eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), and arachidonic acid (AA, 20:4n-6) were quantified and ln-transformed to mitigate distributional skew. Ln-transformed PUFA (lnPUFA) levels were predictors in regression models, with aggression or impulsivity scores as outcomes, and cofactors of sex and diagnostic status (MDD with or without a history of substance use disorder [SUD], or HV). Interactions were tested between relevant PUFAs and diagnostic status. Additional analyses explored possible confounds of depression severity, self-reported childhood abuse history, and, in MDD patients, suicide attempt history. Among PUFA, lnEPA but not lnDHA predicted aggression (F1,76=12.493, p=0.001), and impulsivity (F1,65=5.598, p=0.021), with interactions between lnEPA and history of SUD for both aggression (F1,76=7.941, p=0.001) and impulsivity (F1,65=3.485, p=0.037). Results remained significant when adjusted for childhood abuse, depression severity, or history of suicide attempt. In conclusion, low EPA levels were associated with aggression and impulsivity only in patients with MDD and comorbid SUD, even though in most cases SUD was in full sustained remission.

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Section: Discussionmentioning

confidence: 99%

Low plasma eicosapentaenoic acid levels are associated with elevated trait aggression and impulsivity in major depressive disorder with a history of comorbid substance use disorder

Beier¹,

Lauritzen²,

Galfalvy³

et al. 2014

Journal of Psychiatric Research

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“…Exclusive EPA supplementation, however, increased only EPA and even decreased DHA concentration in serum phospholipids after 7 weeks of supplementation, both in serum and in RBC membrane phospholipids, similar to the results in this study (42,43). Experimental in vitro studies have shown that supplementation with EPA influences cellular metabolism of AA while supplementation with DHA influences both AA metabolism and membrane fluidity (43–45). Thus, although EPA supplementation decreased the DHA concentrations in RBC phospholipids in this study, it was compensated by decreasing AA concentrations in the same compartment, thereby maintaining an unchanged AA/DHA ratio.…”

Section: Discussionmentioning

confidence: 99%

EPA supplementation improves teacher‐rated behaviour and oppositional symptoms in children with ADHD

et al. 2010

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“…DHA has previously been shown to lead to an increase in reactive oxygen species (ROS) levels leading to oxidative damage of membranes and lipids (Al-Gubory, 2012; Kang et al, 2010). Considering PUFAs are susceptible to oxidation, this can trigger significant lipid peroxidation cascades leading to cell death (Al-Gubory, 2012; Obajimi et al, 2005; Premanathan et al, 2011; Xiong et al, 2012). While evidence suggests that DHA-induced cytotoxicity can involve initiation of oxidative stress, our results demonstrated that neither ROS production nor lipid peroxidation were markedly increased in our experimental model.…”

Section: Discussionmentioning

confidence: 99%

PPARδ signaling mediates the cytotoxicity of DHA in H9c2 cells

et al. 2015

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Docosahexaenoic acid (22:6n3, DHA) is an n-3 polyunsaturated fatty acid (PUFA) known to affect numerous biological functions. While DHA possesses many properties that impact cell survival such as suppressing cell growth and inducing apoptosis, the exact molecular and cellular mechanism(s) remain unknown. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate many cell pathways including cell death. As DHA acts as a ligand to PPARs the aim of this study was to examine the involvement of PPARδ in DHA-mediated cytotoxicity toward H9c2 cells. Treatment with DHA (100 µM) resulted in a significant decline in cell viability, cellular metabolic activity and total antioxidant capacity coinciding with increased total proteasome activities and activity of released lactate dehydrogenase (LDH). No changes in reactive oxygen species (ROS) production or accumulation of lipid peroxidation products were observed but DHA promoted apoptotic cell death as detected by flow cytometry, increased caspase-3 activity and decreased phosphorylation of Akt. Importantly, DHA enhanced PPARδ DNA binding activity in H9c2 cells strongly signifying that the cytotoxic effect of DHA might be mediated via PPARδ signaling. Co-treatment with the selective PPARδ antagonist GSK 3787 (1 µM) abolished the cytotoxic effects of DHA in H9c2 cells. Cytotoxic effects of DHA were attenuated by co-treatment with myriocin, a selective inhibitor of serine palmitoyl transferase (SPT), preventing de novo ceramide biosynthesis. LC/MS analysis revealed that treatment with DHA resulted in the accumulation of ceramide, which was blocked by GSK 3787. Interestingly, inhibition of cytochrome P450 (CYP) oxidase with MS-PPOH (50 µM) abolished DHA-mediated cytotoxicity suggesting downstream metabolites as the active mediators. We further demonstrate that CYP oxidase metabolites of DHA, methyl epoxy docosapentaenoate (EDP methyl esters,1 µM) (mix 1:1:1:1:1:1; 4,5-, 7,8-, 10,11-, 13,14-,16,17- and 19,20-EDP methyl esters) and 19,20-EDP cause cytotoxicity via activation of PPARδ signaling leading to increased levels of intracellular ceramide. These results illustrate novel pathways for DHA-induced cytotoxicity that suggest an important role for CYP-derived metabolites, EDPs.

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Differential effects of eicosapentaenoic and docosahexaenoic acids upon oxidant-stimulated release and uptake of arachidonic acid in human lymphoma U937 cells

Cited by 19 publications

References 44 publications

Low plasma eicosapentaenoic acid levels are associated with elevated trait aggression and impulsivity in major depressive disorder with a history of comorbid substance use disorder

Low plasma eicosapentaenoic acid levels are associated with elevated trait aggression and impulsivity in major depressive disorder with a history of comorbid substance use disorder

EPA supplementation improves teacher‐rated behaviour and oppositional symptoms in children with ADHD

PPARδ signaling mediates the cytotoxicity of DHA in H9c2 cells

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