Interaction between GPR110 (ADGRF1) and tight junction protein occludin implicated in blood-brain barrier permeability.

Activation of adhesion receptor GPR110 by the endogenous ligand synaptamide promotes neurogenesis, neurite growth, and synaptogenesis in developing brains through cAMP signal transduction. However, interacting partners of GPR110 and their involvement in cellular function remain unclear. Here, we demonstrate using chemical crosslinking, affinity purification, and quantitative mass spectrometry that GPR110 interacts with the tight junction adhesion protein occludin.

Molecular and Signaling Mechanisms for Docosahexaenoic Acid-Derived Neurodevelopment and Neuroprotection.

The neurodevelopmental and neuroprotective actions of docosahexaenoic acid (DHA) are mediated by mechanisms involving membrane- and metabolite-related signal transduction. A key characteristic in the membrane-mediated action of DHA results from the stimulated synthesis of neuronal phosphatidylserine (PS). The resulting DHA-PS-rich membrane domains facilitate the translocation and activation of kinases such as Raf-1, protein kinase C (PKC), and Akt.

Biosynthesis of Docosahexanoylethanolamine from Unesterified Docosahexaenoic Acid and Docosahexaenoyl-Lysophosphatidylcholine in Neuronal Cells.

We investigated the synthesis of docosahexaenoylethanolamine (synaptamide) in neuronal cells from unesterified docosahexaenoic acid (DHA) or DHA-lysophosphatidylcholine (DHA-lysoPC), the two major lipid forms that deliver DHA to the brain, in order to understand the formation of this neurotrophic and neuroprotective metabolite of DHA in the brain. Both substrates were taken up in Neuro2A cells and metabolized to docosahexaenoylphosphatidylethanolamine (NDoPE) and synaptamide in a time- and concentration-dependent manner, but unesterified DHA was 1.5 to 2.

Emergence of omega-3 fatty acids in biomedical research.

Shortly after the discovery that linoleic acid was an essential fatty acid in 1930, α-linolenic acid also was reported to prevent the fatty acid deficiency syndrome in animals. However, several prominent laboratories could not confirm the findings with α-linolenic acid, and as a result there was a loss of interest in omega-3 fatty acids in lipid research. Even the findings that a prostaglandin can be synthesized from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is necessary for optimum retinal function generated only limited interest in omega-3 fatty acids.

N-Docosahexaenoylethanolamine: A neurotrophic and neuroprotective metabolite of docosahexaenoic acid.

N-Docosahexaenoylethanolamine (synaptamide) is an endocannabinoid-like metabolite endogenously synthesized from docosahexaenoic acid (DHA, 22:6n-3), the major omega-3 polyunsaturated fatty acid present in the brain. Although its biosynthetic mechanism has yet to be established, there is a closely linked relationship between the levels of synaptamide and its precursor DHA in the brain. Synaptamide at nanomolar concentrations promotes neurogenesis, neurite outgrowth and synaptogenesis in developing neurons.

Discovery of essential fatty acids.

Dietary fat was recognized as a good source of energy and fat-soluble vitamins by the first part of the 20th century, but fatty acids were not considered to be essential nutrients because they could be synthesized from dietary carbohydrate. This well-established view was challenged in 1929 by George and Mildred Burr who reported that dietary fatty acid was required to prevent a deficiency disease that occurred in rats fed a fat-free diet. They concluded that fatty acids were essential nutrients and showed that linoleic acid prevented the disease and is an essential fatty acid.

Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism.

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.

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, and this reaction is 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.

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.

Peroxisome proliferator-activated receptor γ decouples fatty acid uptake from lipid inhibition of insulin signaling in skeletal muscle.

Peroxisome proliferator-activated receptor γ (PPARγ) is expressed at low levels in skeletal muscle, where it protects against adiposity and insulin resistance via unclear mechanisms. To test the hypothesis that PPARγ directly modulates skeletal muscle metabolism, we created two models that isolate direct PPARγ actions on skeletal myocytes. PPARγ was overexpressed in murine myotubes by adenotransfection and in mouse skeletal muscle by plasmid electroporation.

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.

Neuroticism but not omega-3 fatty acid levels correlate with early responsiveness to escitalopram.

Background: 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.

Methods: Twenty-four participants were enrolled in an open-label trial of escitalopram 10 mg/d for 4 weeks.

Characterization of transgenic mice with neuron-specific expression of soluble epoxide hydrolase.

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.

Size-dependent waveguide dispersion in nanowire optical cavities: slowed light and dispersionless guiding.

Fundamental understanding of the size dependence of nanoscale optical confinement in semiconductor nanowire waveguides, as expressed by changes in the dispersion of light, is crucial for the optimal design of nanophotonic devices. Measurements of the dispersion are particularly challenging for nanoscale cavities due to difficulties associated with the in- and out-coupling of light resulting from diffraction effects. We report the strong size dependence of optical dispersion and associated group velocities in subwavelength width ZnSe nanowire waveguide cavities, using a technique based on Fabry-Perot resonator modes as probes over a wide energy range.

Arachidonic acid cytochrome P450 epoxygenase pathway.

Cytochrome P450 (CYP) epoxygenases convert arachidonic acid to four epoxyeicosatrienoic acid (EET) regioisomers, 5,6-, 8,9-, 11,12-, and 14,15-EET, that function as autacrine and paracrine mediators. EETs produce vascular relaxation by activating smooth muscle large-conductance Ca2+-activated K+ channels (BKCa). In addition, they have anti-inflammatory effects on blood vessels and in the kidney, promote angiogenesis, and protect ischemic myocardium and brain.

Docosahexaenoic acid synthesis from n-3 fatty acid precursors in rat hippocampal neurons.

Docosahexaenoic acid (DHA), the most abundant n-3 polyunsaturated fatty acid in the brain, has important functions in the hippocampus. To better understand essential fatty acid homeostasis in this region of the brain, we investigated the contributions of n-3 fatty acid precursors in supplying hippocampal neurons with DHA. Primary cultures of rat hippocampal neurons incorporated radiolabeled 18-, 20-, 22-, and 24-carbon n-3 fatty acid and converted some of the uptake to DHA, but the amounts produced from either [1-14C]alpha-linolenic or [1-14C]eicosapentaenoic acid were considerably less than the amounts incorporated when the cultures were incubated with [1-14C]22:6n-3.

Brain uptake and utilization of fatty acids, lipids and lipoproteins: application to neurological disorders.

Transport, synthesis, and utilization of brain fatty acids and other lipids have been topics of investigation for more than a century, yet many fundamental aspects are unresolved and, indeed, subject to controversy. Understanding the mechanisms by which lipids cross the blood brain barrier and how they are utilized by neurons and glia is critical to understanding normal brain development and function, for the diagnosis and therapy of human diseases, and for the planning and delivery of optimal human nutrition throughout the world. Two particularly important fatty acids, both of which are abundant in neuronal membranes are: (a) the omega3 polyunsaturated fatty acid docosahexaenoic acid, deficiencies of which can impede brain development and compromise optimal brain function, and (b) the omega6 polyunsaturated fatty acid arachidonic acid, which yields essential, but potentially toxic, metabolic products.

20-carboxy-arachidonic acid is a dual activator of peroxisome proliferator-activated receptors alpha and gamma.

20-carboxy-arachidonic acid (20-COOH-AA) is a metabolite of 20-hydroxyeicosatetraenoic acid (20-HETE), an eicosanoid produced from arachidonic acid by cytochrome P450 (CYP) omega-oxidases. Alcohol dehydrogenases convert 20-HETE to 20-COOH-AA, and we now find that a microsomal preparation containing recombinant human CYP4F3B converts arachidonic acid to 20-HETE and 20-COOH-AA. Studies with transfected COS-7 cell expression systems indicate that 20-COOH-AA activates peroxisome proliferators-activated receptor (PPAR) alpha and PPARgamma.

Action of epoxyeicosatrienoic acids on cellular function.

Epoxyeicosatrienoic acids (EETs), which function primarily as autocrine and paracrine mediators in the cardiovascular and renal systems, are synthesized from arachidonic acid by cytochrome P-450 epoxygenases. They activate smooth muscle large-conductance Ca(2+)-activated K(+) channels, producing hyperpolarization and vasorelaxation. EETs also have anti-inflammatory effects in the vasculature and kidney, stimulate angiogenesis, and have mitogenic effects in the kidney.

Inhibition of PGI2 signaling by miconazole in vascular smooth muscle cells.

Miconazole is widely used clinically as an anti-fungal agent and experimentally as a cytochrome P450 (CYP) inhibitor. In rat coronary arteries that produce PGI(2) as the major arachidonic acid (AA) metabolite, activation of the large-conductance K(+) (BK) channels in coronary arterial smooth muscle cells by AA was inhibited by miconazole but not by the CYP inhibitor SKF525A. Activation of BK currents in coronary smooth muscle cells by carbacyclin or iloprost also was inhibited by miconazole but not by SKF525A, suggesting that miconazole might have properties other than those of CYP inhibition.

Oxygenation of omega-3 fatty acids by human cytochrome P450 4F3B: effect on 20-hydroxyeicosatetraenoic acid production.

Cytochrome P450 (CYP) omega-oxidases convert arachidonic acid (AA) to 20-hydroxyeicosatetraenoic acid (20-HETE), a lipid mediator that modulates vascular tone. We observed that a microsomal preparation containing recombinant human CYP4F3B, which converts AA to 20-HETE, converted eicosapentaenoic acid (EPA) to 20-OH-EPA. Likewise, docosahexaenoic acid (DHA) was converted to 22-OH-DHA, indicating that human CYP4F3B also can oxidize 22-carbon omega-3 fatty acids.

20-Hydroxyeicosatetraenoic acid is a potent dilator of mouse basilar artery: role of cyclooxygenase.

20-Hydroxyeicosatetraenoic acid (20-HETE), an arachidonic acid (AA) metabolite synthesized by cytochrome P-450 omega-oxidases, is reported to produce vasoconstriction in the cerebral circulation. However, we find that like 14,15-epoxyeicosatrienoic acid (14,15-EET), 20-HETE produces dilation of mouse basilar artery preconstricted with U-46619 in vitro. Indomethacin inhibited the vasodilation produced by 20-HETE but not by 14,15-EET, suggesting a cyclooxygenase (COX)-dependent mechanism.