Microglial Cell Activation Increases Saturated and Decreases Monounsaturated Fatty Acid Content,but Both Lipid Species are Proinflammatory

Neuroinflammation is a component of age-related neurodegenerative diseases and cognitive decline. Saturated (SFA) and monounsaturated (MUFA) fatty acids are bioactive molecules that may play different extrinsic and intrinsic roles in neuroinflammation, serving as exogenous ligands for cellular receptors, or endogenous components of cell structural, energetic and signaling pathways. We determined the fatty acyl profile of BV2 microglial cells before and after acute activation with lipopolysaccharide (LPS). We also investigated the effect of SFA and MUFA pretreatment on the production of an invasive, neurotoxic phenotype in BV2 cells. Acute activation of BV2 microglia resulted in an increase in the relative content of SFA (12:0, 16:0, 18:0, 20:0, 22:0, and 24:0 increased significantly), and a relative decrease in the content of MUFA (16:1n7, 18:1n7, 18:1n9, 20:1n9, 24:1n9 decreased significantly). In agreement, the major stearoyl-CoA desaturase (SCD) isoform in BV2 cells, SCD2, was significantly down-regulated by LPS. We next treated cells with SFA (16:0 or 18:0) or MUFA (16:1n7 or 18:1n9), and found that levels of secreted IL6 were increased, as was secreted MMP9-mediated proteolytic activity. To test the functional significance, we treated SH-SY5Y neuronal cells with conditioned medium from BV2 cells pretreated with fatty acids, and found a small but significant induction of cell death. Our findings suggest differential intrinsic roles for SFA and MUFA in activated microglial cells, but similar extrinsic roles for these fatty acid species in inducing activation. Expansion of SFA is important during microglial cell activation, but either supplemental SFA or MUFA may contribute to chronic low-grade neuroinflammation.     

Eicosapentaenoic Acid,Arachidonic Acid and Eicosanoid Metabolism in Juvenile Barramundi Lates calcarifer

A two part experiment was conducted to assess the response of barramundi (Lates calcarifer; initial weight = 10.3 ± 0.03 g; mean ± S.D.) fed one of five diets with varying eicosapentaenoic acid (diets 1, 5, 10, 15 and 20 g/kg) or one of four diets with varying arachidonic acid (1, 6, 12, 18 g/kg) against a fish oil control diet. After 6 weeks of feeding, the addition of EPA or ARA did not impact on growth performance or feed utilisation. Analysis of the whole body fatty acids showed that these reflected those of the diets. The ARA retention demonstrated an inversely related curvilinear response to either EPA or ARA. The calculated marginal utilisation efficiencies of EPA and ARA were high (62.1 and 91.9 % respectively) and a dietary ARA requirement was defined (0.012 g/kg^0.796/day). The partial cDNA sequences of genes regulating eicosanoid biosynthesis were identified in barramundi tissues, namely cyclooxygenase 1 (Lc COX1a, Lc COX1b), cyclooxygenase 2 (Lc COX2) and lipoxygenase (Lc ALOX‐5). Both Lc COX2 and Lc ALOX‐5 expression in the liver tissue were elevated in response to increasing dietary ARA, meanwhile expression levels of Lc COX2 and the mitochondrial fatty acid oxidation gene carnitine palmitoyltransferase 1 (Lc CPT1a) were elevated in the kidney. A low level of EPA increased the expression of Lc COX1b in the liver. Consideration should be given to the EPA to ARA balance for juvenile barramundi in light of nutritionally inducible nature of the cyclooxygenase and lipoxygenase enzymes.     

The Effects of Omega‐3 Polyunsaturated Fatty Acid Consumption on Mammary Carcinogenesis

The consumption of omega‐3 polyunsaturated fatty acids (n‐3 PUFA) is associated with a reduced risk of breast cancer. Studies in animals and in vitro have demonstrated mechanisms that could explain this apparent effect, but clinical and epidemiological studies have returned conflicting results on the practical benefits of dietary n‐3 PUFA for prevention of breast cancer. Effects are often only significant within a population when comparing the highest n‐3 PUFA consumption group to the lowest n‐3 group or highest n‐6 group. The beneficial effects of n‐3 PUFA eicosapentaenoic and docosahexaenoic on the risk of breast cancer are dose dependent and are negatively affected by total n‐6 consumption. The majority of the world population, including the most highly developed regions, consumes insufficient n‐3 PUFA to significantly reduce breast cancer risk. This review discusses the physiological and dietary context in which reduction of breast cancer risk may occur, some proposed mechanisms of action and meaningful recommendations for consumption of n‐3 PUFA in the diet of developed regions.     

Terpenoids from Stinking toe (Hymneae courbaril) fruits with cyclooxygenase and lipid peroxidation inhibitory activities

Stinking toe (Hymenaea courbaril), also called Jatoba and Kerosene tree, is a medicinal plant commonly found in the central and South American countries. In the Caribbean, Mexico and Brazil, the powdery sweet dust of its fruit is consumed for energy. The chemical examination of the yellowish sweet powder of the fruit yielded sucrose and linolenic acid as major compounds. The pods yielded the labdane diterpenoids crotomachlin (1), labd-13E-en-8-ol-15-oic acid (2), labdanolic acid (4), (13E)-labda 7, 13 dien-15-oic acid (5) and labd-8 (17), 13E- dien-15-oic acid (6), along with the sesquiterpene, spathulenol (7), as confirmed by ¹H and ¹³C NMR spectral studies. The methyl ester of labd-13E-en-8-ol-15-oic acid (3) was also characterized during the purification of compound 5. The total amount of these terpenoids in the fruit was about 0.1% (w/w) of the dried fruit. Compounds 1–5 and 7 were assayed for anti-inflammatory activity using cyclooxygenase-1 (COX-1) and -2 (COX-2) enzymes. At 100 ppm, compounds 3 and 4 showed selective COX-2 enzyme inhibition. Also, compounds 1, 2 and 5 inhibited lipid peroxidation by 46%, 48% and 75%, respectively, at 100 ppm. These compounds were isolated from this fruit and their COX and lipid peroxidation inhibitory activities are reported for the first time in this paper.     

Antidiabetic and anti-inflammatory potential of sulphated polygalactans from red seaweeds Kappaphycus alvarezii and Gracilaria opuntia

Antidiabetic and anti-inflammatory potential of sulphated polygalactans isolated from the red seaweeds Kappaphycus alvarezii and Gracilaria opuntia were acquired by employing different in vitro systems. The sulphated galactopyran motif derived from G. opuntia possessed significant antidiabetic properties as identified by α-amylase (IC₅₀ 0.04 mg/mL), α-glucosidase (IC₅₀ 0.09 mg/mL) and dipeptidyl peptidase-4 (DPP-4, IC₅₀ 0.09 mg/mL) inhibitory activities. Based on the detailed nuclear magnetic resonance spectroscopy experiments the sulphated galactopyran motif of G. opuntia was designated as →3)-4-O-sulfonato-(6-O-acetyl)-β-D-galactopyranosyl-(1→4)-3,6-anhydro-(2-O-sulfonato)-α-D-galactopyranosyl-(1→3)-4-O-sulfonato-(6-O-acetyl)-β-D-xylosyl-(1→3)-4-O-sulfonato-(6-O-acetyl)-β-D-galactopyranosyl-(1→4)-3,6-anhydro-(2-O-sulfonato)-α-D-galactopyranan, while the one from K. alvarezii was demonstrated to be →4)-4-O-sulfonato-(2-O-methyl)-β-D-galactopyranosyl-(1→4)-3,6-anhydro-(2-O-methyl)-α-D-galactopyranan. The sulphated galactans from G. opuntia showed greater anti-inflammatory inhibitory activities as determined by cyclooxygenase-1 (COX-1, IC₅₀ 0.01 mg/mL), cyclooxygenase-2 (COX-2, IC₅₀ 0.03 mg/mL), and 5-lipoxygenase inhibitory activities (5-LOX, IC₅₀ 0.24 mg/mL). This study revealed that the sulfated polygalactan enriched concentrate from G. opuntia can be used as potential therapeutic candidate to suppress the hyperglycemic response in diabetic conditions and inflammatory activity. They can be used to develop functional food ingredient in nutraceutical products.     

Transformation of Prostaglandin D2 to 11-Dehydro Thromboxane B2 by Baeyer-Villiger Oxidation

Prostaglandin D₂ is one of five chief prostanoids formed in the cyclooxygenase pathway of arachidonic acid oxidation. Except for a single oxygen atom, PGD₂ is structurally identical to 11-dehydro thromboxane B₂ (11d-TxB₂), a urinary metabolite of the pro-aggregatory platelet activator, thromboxane A₂. The close structural relationship suggested that one might be transformed to the other. Accordingly, we tested whether the cyclopentanone of PGD₂ can be expanded to the δ-lactone of 11d-TxB₂ in a Baeyer-Villiger oxidation. Oxidation of PGD₂ with two standard oxidants showed that 11d-TxB₂ was formed only with H₂O₂ but not with peracetic acid. Byproducts of the H₂O₂-mediated oxidation were hydroperoxide derivatives and isomers of PGD₂. Chemical oxidation of PGD₂ to 11d-TxB₂ may be a model for an equivalent enzymatic transformation, suggesting a possible link in the metabolism of PGD₂ and thromboxane A₂.     

A Comparison of the Anti-Inflammatory Effects of <Emphasis Type="Italic">Cis</Emphasis>-9, <Emphasis Type="Italic">Trans</Emphasis>-11 Conjugated Linoleic Acid to Celecoxib in the Collagen-Induced Arthritis Model

Cyclooxygenase (COX)‐2 inhibitors, such as celecoxib, for chronic inflammatory disease are associated with adverse health events, while cis‐9, trans‐11 (c9t11) conjugated linoleic acid (CLA) is anti‐inflammatory without adverse events attributed to pure intake. Mechanistically, celecoxib and c9t11 disrupt the arachidonic acid cascade; however, the equivalency of anti‐inflammatory effects between these compounds is unknown. Therefore, to test the hypothesis that 0.5% dietary c9t11 reduces inflammation equivalently to a celecoxib dose intended to treat rheumatoid arthritis (RA; 5 mg/kg bw), arthritic mice received diets containing one of the following supplements: 1% corn oil (CO, w/w), 0.5% c9t11 (>91% purity) +0.5% CO, or 1% CO + 0.5, 5, or 50 mg/kg bw celecoxib, and were assessed for changes in arthritic severity over 6 weeks. Overall, arthritic severity in mice fed c9t11 was reduced (34%, P < 0.01) while celecoxib doses (0.5, 5, 50 mg/kg) reduced arthritic severity (16, 56, 48%, respectively) compared to CO‐fed arthritic mice. Linear regression of the celecoxib dose‐response showed 0.5% c9t11 (570 mg/kg bw) reduced arthritic severity equivalently to 1.5 mg/kg celecoxib. Interleukin‐6 (IL‐6) was increased in paws of arthritic mice fed CO compared to shams, but was decreased in arthritic groups fed 0.5% c9t11 and 5 mg/kg celecoxib, compared to arthritic mice fed CO (Ps ≤ 0.05). Additionally, paw and plasma IL‐10 levels in arthritic mice were decreased by 5 mg/kg celecoxib, but were unaffected by c9t11 compared to CO. Results suggest dietary c9t11 may be an effective adjunct to COX‐2 inhibition for treating chronic inflammation.     

Lipid Emulsions Containing Medium Chain Triacylglycerols Blunt Bradykinin-Induced Endothelium-Dependent Relaxation in Porcine Coronary Artery Rings

Lipid emulsions for parenteral nutrition are used to provide calories and essential fatty acids for patients. They have been associated with hypertriglyceridemia, hypercholesterolemia, and metabolic stress, which may promote the development of endothelial dysfunction in patients. The aim of the present study was to determine whether five different industrial lipid emulsions may affect the endothelial function of coronary arteries. Porcine coronary artery rings were incubated with lipid emulsions 0.5, 1, or 2% (v/v) for 30 min before the determination of vascular reactivity in organ chambers and the level of oxidative stress using electron paramagnetic resonance. Incubation of coronary artery rings with either Lipidem^®, Medialipid^® containing long- and medium-chain triacylglycerols (LCT/MCT), or SMOFlipid^® containing LCT, MCT, omega-9, and -3, significantly reduced the bradykinin-induced endothelium-dependent relaxation, affecting both the nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) components, whereas, Intralipid^® containing LCT (soybean oil) and ClinOleic^® containing LCT (soybean and olive oil) did not have such an effect. The endothelial dysfunction induced by Lipidem^® was significantly improved by indomethacin, a cyclooxygenase (COX) inhibitor, inhibitors of oxidative stress (N-acetylcysteine, superoxide dismutase, catalase) and transition metal chelating agents (neocuproine, tetrathiomolybdate, deferoxamine and l-histidine). Lipidem^® significantly increased the arterial level of oxidative stress. The present findings indicate that lipid emulsions containing LCT/MCT induce endothelial dysfunction in coronary artery rings by blunting both NO- and EDH-mediated relaxations. The Lipidem^®-induced endothelial dysfunction is associated with increased vascular oxidative stress and the formation of COX-derived vasoconstrictor prostanoids.     

昔布类药物的心血管副作用研究综述

昔布类药物(COX-2抑制剂)在治疗炎症、疼痛时,可以明显降低溃疡的发生,但临床应用发现这些药物都存在一定程度的心血管副作用,大量临床研究表明并不是昔布类药物的"类效应",欧洲药品监管机构和美国FDA有关表决也认为昔布类药物的益处大于危险.     

Uptake and Incorporation of Pinolenic Acid Reduces n-6 Polyunsaturated Fatty Acid and Downstream Prostaglandin Formation in Murine Macrophage

Many reports have shown the beneficial effects of consumption of pine seeds and pine seed oil. However, few studies have examined the biological effect of pinolenic acid (PNA; ∆5,9,12–18:3), the main fatty acid in pine seed oil. In this study, using murine macrophage RAW264.7 cells as a model, we examined the effect of PNA on polyunsaturated fatty acid (PUFA) metabolism, prostaglandin (PG) biosynthesis and cyclooxygenase-2 (COX-2) expression. Results showed that PNA was readily taken up, incorporated and elongated to form eicosatrienoic acid (ETrA, ∆7,11,14–20:3) in macrophage cells. A small portion of this elongated metabolite was further elongated to form ∆9,13,16–22:3. The degree of incorporation of PNA and its metabolites into cellular phospholipids varied with the length of incubation time and the concentration of PNA in the medium. Incubation of PNA also modified the fatty acid profile of phospholipids: the levels of 18- and 20-carbon PUFA were significantly decreased, whereas those of 22-carbon fatty acids increased. This finding suggests that PNA enhances the elongation of 20-carbon fatty acids to 22-carbon fatty acids. The syntheses of PGE₁ from dihomo-γ-linolenic acid (DGLA, ∆8,11,14–20:4) and PGE₂ from arachidonic acid (ARA, ∆5,8,11,14–20:4) were also suppressed by the presence of PNA and its metabolite. As the expression of COX-2 was not suppressed, the inhibitory effect of PNA on PG activity was attributed in part to substrate competition between the PNA metabolite (i.e., ∆7,11,14–20:3) and DGLA (or ARA).