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1.  Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism 
Biochimica et biophysica acta  2014;1851(4):356-365.
Polyunsaturated fatty acids (PUFA) are oxidized by cytochrome P450 epoxygenases to PUFA epoxides which function as potent lipid mediators. The major metabolic pathways of PUFA epoxides are incorporation into phospholipids and hydrolysis to the corresponding PUFA diols by soluble epoxide hydrolase. Inhibitors of soluble epoxide hydrolase stabilize PUFA epoxides and potentiate their functional effects. The epoxyeicosatrienoic acids (EETs) synthesized from arachidonic acid produce vasodilation, stimulate angiogenesis, have anti-inflammatory actions, and protect the heart against ischemia-reperfusion injury. EETs produce these functional effects by activating receptor-mediated signaling pathways and ion channels. The epoxyeicosatetraenoic acids synthesized from eicosapentaenoic acid and epoxydocosapentaenoic acids synthesized from docosahexaenoic acid are potent inhibitors of cardiac arrhythmias. Epoxydocosapentaenoic acids also inhibit angiogenesis, decrease inflammatory and neuropathic pain, and reduce tumor metastasis. These findings indicate that a number of the beneficial functions of PUFA may be due to their conversion to PUFA epoxides.
PMCID: PMC4314516  PMID: 25093613
arachidonic acid (AA); epoxyeicosatrienoic acid (EET); eicosapentaenoic acid (EPA); docosahexaenoic acid (DHA); epoxyeicosatetraenoic acid (EpETE); epoxydocosapentaenoic acid (EpDPE)
2.  Phosphatidylserine in the Brain: Metabolism and Function 
Phosphatidylserine (PS) is the major anionic phospholipid class particularly enriched in the inner leaflet of the plasma membrane in neural tissues. PS is synthesized from phosphatidylcholine or phosphatidylethanolamine by exchanging the base head group with serine in reactions are catalyzed by phosphatidylserine synthase 1 and phosphatidylserine synthase 2 located in the endoplasmic reticulum. Activation of Akt, Raf-1 and protein kinase C signaling, which supports neuronal survival and differentiation, requires interaction of these proteins with PS localized in the cytoplasmic leaflet of the plasma membrane. Furthermore, neurotransmitter release by exocytosis and a number of synaptic receptors and proteins are modulated by PS present in the neuronal membranes. Brain is highly enriched with docosahexaenoic acid (DHA), and brain PS has a high DHA content. By promoting PS synthesis, DHA can uniquely expand the PS pool in neuronal membranes and thereby influence PS-dependent signaling and protein function. Ethanol decreases DHA-promoted PS synthesis and accumulation in neurons, which may contribute to the deleterious effects of ethanol intake. Improvement of some memory functions has been observed in cognitively impaired subjects as a result of PS supplementation, but the mechanism is unclear.
PMCID: PMC4258547  PMID: 24992464
Docosahexaenoic acid; serine; signal transduction; membranes; neuron; cognition
3.  Overexpression of Human Catalase Inhibits Proliferation and Promotes Apoptosis in Vascular Smooth Muscle Cells 
Circulation research  1999;85(6):524-533.
The role of reactive oxygen species, such as superoxide anions (O2·−) and hydrogen peroxide (H2O2), in modulating vascular smooth muscle cell proliferation and viability is controversial. To investigate the role of endogenously produced H2O2, rat aortic smooth muscle cells were infected with adenoviral vectors containing cDNA for human catalase (AdCat) or a control gene, β-galactosidase (AdLacZ). Infection with AdCat resulted in dose-dependent increases in intracellular catalase protein, which was predominantly localized to peroxisomes. After infection with 100 multiplicity of infection (MOI) of AdCat, cellular catalase activity was increased by 50- to 100-fold, and intracellular H2O2 concentration was reduced, as compared with control. Infection with AdCat reduced [3H]thymidine uptake, an index of DNA synthesis, in cells maintained in medium supplemented with 2% serum (0.37±0.09 disintegrations per minute per cell [AdLacZ] versus 0.22±0.08 disintegrations per minute per cell [AdCat], P<0.05). Five days after infection with 100 MOI of AdCat, cell numbers were reduced as compared with noninfected or AdLacZ-infected cells (157 780±8413 [AdCat], P<0.05 versus 233 700±3032 [noninfected] or 222 410±5332 [AdLacZ]). Furthermore, the number of apoptotic cells was increased 5-fold after infection with 100 MOI of AdCat as compared with control. Infection with AdCat resulted in induction of cyclooxygenase (COX)–2, and treatment with a COX-2 inhibitor overcame the AdCat-induced reduction in cell numbers. These findings indicate that overexpression of catalase inhibited smooth muscle proliferation while increasing the rate of apoptosis, possibly through a COX-2–dependent mechanism. Our results suggest that endogenously produced H2O2 importantly modulates survival and proliferation of vascular smooth muscle cells.
PMCID: PMC3972612  PMID: 10488055
catalase; apoptosis; vascular smooth muscle cell; cell proliferation; hydrogen peroxide
4.  Enhanced H2O2-Induced Cytotoxicity in “Epithelioid” Smooth Muscle Cells 
Vascular smooth muscle cells (SMCs) are phenotypically diverse. Although most medial SMCs can be classified as “fusiform,” others are of the “epithelioid” phenotype. Proliferation and apoptosis of epithelioid SMCs may contribute importantly to neointimal formation and regression, respectively. Because reactive oxygen species (ROS) are increased in vascular injury and can induce apoptosis of SMCs, we compared the effects of ROS on epithelioid and fusiform SMCs. Epithelioid and fusiform SMC lines were clonally isolated from rat aortic media and studied under similar conditions and passage numbers. H2O2 produced dose- and time-dependent cytotoxicity that was enhanced in epithelioid compared with fusiform cells. After 24-hour exposure to 50 μmol/L H2O2, epithelioid cell numbers were reduced by 34±5% versus a 3±5% (P<0.05) reduction in fusiform cell numbers. Similar results were obtained whether H2O2 was administered to growth-arrested or growing cells or when epithelioid and fusiform cells were exposed to extracellular O2·−. To investigate whether apoptosis contributed to enhanced ROS-induced cytotoxicity in epithelioid SMCs, terminal deoxyribonucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick-end labeling (TUNEL) staining was performed. The incidence of TUNEL positivity was 5-fold increased in epithelioid versus fusiform SMCs after treatment with 50 μmol/L H2O2 (19±1% epithelioid versus 5±1% fusiform, P<0.05). Enhanced H2O2-induced apoptosis in epithelioid SMCs was confirmed by DNA laddering. Furthermore, when balloon-injured aortas were exposed to H2O2 ex vivo, enhanced apoptosis was observed in neointimal compared with medial SMCs. These results suggest that epithelioid SMCs exhibit enhanced sensitivity to ROS-induced apoptosis, which may play an important role in neointimal regression.
PMCID: PMC3972812  PMID: 10845860
smooth muscle cells; apoptosis; reactive oxygen species; hydrogen peroxide; neointima
5.  Synaptamide, endocannabinoid-like derivative of docosahexaenoic acid with cannabinoid-independent function 
Docosahexaenoylethanolamide, the structural analog of the endogenous cannabinoid receptor ligand anandamide, is synthesized from docosahexaenoic acid (DHA) in the brain. Although docosahexaenoylethanolamide binds weakly to cannabinoid receptors, it stimulates neurite growth, synaptogenesis and glutamatergic synaptic activity in developing hippocampal neurons at concentrations of 10–100 nM. We have previously proposed the term synaptamide for docosahexaenoylethanolamide to emphasize its potent synaptogenic activity and structural similarity to anandamide. Synaptamide is subjected to hydrolysis by fatty acid amide hydrolase, and can be oxygenated to bioactive metabolites. The brain synaptamide content is dependent on the dietary DHA intake, suggesting an endogenous mechanism whereby diets containing adequate amounts of omega-3 fatty acids improve synaptogenesis in addition to well-recognized anti-inflammatory effects.
PMCID: PMC3541447  PMID: 22959887
Synaptamide; Synaptogenesis; Neuritogenesis; N-docosahexaenoylethanolamine; Docosahexaenoic acid; Omega-3 fatty acid; Fatty acid amide hydrolase; Endocannabinoids; Anandamide
6.  A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development 
Docosahexaenoic acid (DHA), the n-3 essential fatty acid that is highly enriched in the brain, increases neurite growth and synaptogenesis in cultured mouse fetal hippocampal neurons. These cellular effects may underlie the DHA-induced enhancement of hippocampus-dependent learning and memory functions. We found that N-docsahexaenoylethanolamide (DEA), an ethanolamide derivative of DHA, is a potent mediator for these actions. This is supported by the observation that DHA is converted to DEA by fetal mouse hippocampal neuron cultures and a hippocampal homogenate, and DEA is present endogenously in the mouse hippocampus. Furthermore, DEA stimulates neurite growth and synaptogenesis at substantially lower concentrations than DHA, and it enhances glutamatergic synaptic activities with concomitant increases in synapsin and glutamate receptor subunit expression in the hippocampal neurons. These findings suggest that DEA, an ethanolamide derivative of DHA, is a synaptogenic factor, and therefore we suggest utilizing the term ‘synaptamide’. This brief review summarizes the neuronal production and actions of synaptamide and describes other N-docosahexaenoyl amides that are present in the brain.
PMCID: PMC3215906  PMID: 21810478
N-Docosahexaenoylethanolamide; Synaptamide; DHA; Hippocampus; Neuron; Anandamide; N-Docosahexaenoyl-amino acylamide
7.  Neuroticism but not omega-3 fatty acid levels correlate with early responsiveness to escitalopram 
Omega-3 fatty acid (O3FA) levels and dimensional personality measures have been associated with major depression and the course of depressive illness. We sought to study the utility of O3FA levels and dimensional personality measures as predictors of early improvement with escitalopram.
Twenty-four participants were enrolled in an open-label trial of escitalopram 10 mg/d for 4 weeks. Baseline erythrocyte O3 levels and dimensional personal assessments were obtained.
Using a conservative, intention-to-treat analysis, baseline neuroticism (r = −0.57; P = .007), as measured by the Revised NEO Personality Inventory (NEO-PI-R) but not erythrocyte O3 levels, was correlated with improvements on escitalopram. A facet analysis of the neuroticism domain showed the relationship with antidepressant response to be focused on trait anxiety (r = −0.65; P = .002).
Anxiety may have important prognostic implications on subsequent response to selective serotonin reuptake inhibitors, such as escitalopram.
PMCID: PMC3035677  PMID: 20680188
omega-3 fatty acids; anxiety; major depression; neuroticism; antidepressant
8.  Characterization of Transgenic Mice with Neuron-Specific Expression of Soluble Epoxide Hydrolase 
Brain research  2009;1291:60-72.
Soluble epoxide hydrolase (sEH) is the major enzyme responsible for the metabolism and inactivation of epoxyeicosatrienoic acids (EETs). EETs are produced by the cytochrome P450 (CYP) epoxygenase pathway of arachidonic acid (AA) metabolism and tend to be anti-hypertensive, anti-inflammatory and protective against ischemic injury. Since the metabolism of EETs by sEH reduces or eliminates their bioactivity, inhibition of sEH has become a therapeutic strategy for hypertension and inflammation. sEH is found in nearly all tissues so the systemic application of inhibitors is likely to affect more than blood pressure and inflammation. In the central nervous system, EETs are thought to play a role in the regulation of local blood flow, protection from ischemic injury, inhibition of inflammation, the release of peptide hormones and modulation of fever. However, little is known about region- and cell-specific expression of sEH in the brain. In the mouse brain, expression of sEH was found widely in cortical and hippocampal astrocytes and also in a few specific neuron-types in the cortex, cerebellum, and medulla. To assess the functional significance of neuronal sEH, we generated a transgenic mouse model, which over-expresses sEH specifically in neurons. Transgenic mice showed increased neuron labeling in cortex and hippocampus with little change in labeling of other brain regions. Despite a 3-fold increase in sEH activity in the brain, there was no change in arterial pressure. This data provides new information required for studying the central roles of the cytochrome P450 epoxygenase pathway.
PMCID: PMC2745107  PMID: 19643090
9.  Excretion of sterols from the skin of normal and hypercholesterolemic humans 
Journal of Clinical Investigation  1972;51(8):2060-2070.
The 24 hr sterol excretion from the entire skin surface was determined in six normal and five hypercholesterolemic (Type II) patients fed a controlled, eucaloric diet containing 400 mg of plant sterols. All subjects received radiolabeled cholesterol intravenously in order to measure cholesterol turnover and exchange. The 24 hr skin surface lipids were collected subsequently at intervals of 7-10 days. Sterols were quantified and identified by a combination of thin-layer and gas-liquid chromatographic methods. The mean 24 hr excretion of cholesterol in milligrams was 82.6 in the normal subjects and 82.7 in the hypercholesterolemic patients. Cholesterol constituted 89% of the total sterol excretion through the skin surface in both groups.
The specific radioactivity of cholesterol in the skin surface lipids increased gradually after the intravenous administration of the isotope. Within 4-5 wk the specific activity equaled and then remained higher than that of the plasma up to 10 wk. These specific activity curves suggested that, for at least some of skin surface cholesterol, there was a precursor-product relationship between the plasma cholesterol and the skin cholesterol.
The presence of plant sterols, β-sitosterol, campesterol, and stigmasterol in the skin surface lipids of man has not been reported previously. We identified these sterols in the skin surface lipids of all of our subjects. They constituted about 7% of the total skin surface sterols. The occurrence of plant sterols in the skin surface lipids suggested that plasma sterols were transferred from the plasma into the skin. 1-2% of the skin surface sterols were tentatively identified as lathosterol and lanosterol.
The present study documented that a significant amount of cholesterol was excreted from the skin surface and that probably there was a net transfer of plasma cholesterol into the skin surface lipids. Both normal subjects and hypercholesterolemic patients excreted similar amounts of cholesterol per day into the skin surface lipids. We suggest that this daily loss of cholesterol from the skin surface may need to be considered in sterol balance studies.
PMCID: PMC292362  PMID: 5054464
10.  Utilization of long-chain free fatty acids by human platelets 
Journal of Clinical Investigation  1970;49(8):1489-1496.
There was a rapid net uptake of free fatty acid (FFA) by human platelets when long-chain FFA, bound to human serum albumin, were incubated with platelet suspensions. Results from experiments in which both palmitate and albumin were labeled indicated that the fatty acid dissociated from the protein during uptake. Much of the FFA taken up by the platelet in short-term incubations remained in unesterified form, i.e., it was recovered as platelet FFA. As the incubation continued, increasing amounts of FFA were oxidized to CO2 and incorporated into platelet lipid esters, particularly lecithin. Essentially all of the fatty acid that was incorporated into the platelet FFA fraction was released rapidly from the cells when they were exposed to a medium containing FFA-free albumin. The magnitude of uptake into the platelet FFA fraction was similiar at 0° and 37°C. Likewise, the rate and magnitude of FFA release from the platelet were similar at 0° and 37°C. Therefore, it is likely that both FFA uptake and FFA release occur by energy-independent mechanisms. The major effect of increasing the FFA concentration of the incubation medium was increased fatty acid uptake into the platelet FFA fraction. Similar results occurred when platelets were incubated in human plasma containing increasing amounts of added palmitate. At a given extracellular FFA concentration, considerably more of the saturated fatty acids, palmitate and stearate, were taken up as platelet FFA than either oleate or linoleate.
PMCID: PMC322628  PMID: 5431660

Results 1-10 (10)