Chiral polychlorinated biphenyls (PCBs) such as PCB 136 enantioselectively sensitize the ryanodine receptor (RyR). In light of recent evidence that PCBs cause developmental neurotoxicity via RyR-dependent mechanisms, this suggests that enantioselective PCB metabolism may influence the developmental neurotoxicity of chiral PCBs. However, enantioselective disposition of PCBs has not been fully characterized.The effect of sex and cytochrome P450 (P450) enzyme induction on the enantioselective metabolism of PCB 136 was studied using liver tissue slices prepared from naïve control (CTL), phenobarbital (PB; CYP2B inducer) or dexamethasone (DEX; CYP3A inducer) pretreated adult Sprague-Dawley rats. PCB 136 metabolism was also examined in hippocampal slices derived from untreated rat pups.In liver tissue slices, hydroxylated PCB (OH-PCB) profiles depended on sex and inducer pretreatment, and OH-PCB levels followed the rank orders male > female and PB > DEX > CTL. In contrast, the enantiomeric enrichment of PCB 136 and its metabolites was independent of sex and inducer pretreatment. Only small amounts of PCB 136 partitioned into hippocampal tissue slices and no OH-PCB metabolites were detected.Our results suggest that enantioselective metabolism, sex and induction status of P450 enzymes in the liver may modulate the neurotoxic outcomes of developmental exposure to chiral PCBs.
Several previous studies indicated that for optimal uptake by the brain, docosahexaenoic acid (DHA) should be present as phospholipid in the plasma. However most of dietary DHA is absorbed as triacylglycerol (TAG) because it is released as free fatty acid during digestion of either TAG-DHA (fish oil) or sn-2-DHA phospholipid (krill oil), and subsequently incorporated into TAG of chylomicrons. We tested the hypothesis that the absorption of DHA as phospholipid can be increased if it is present in the sn-1 position of dietary phospholipid or in lysophosphatidylcholine (LPC), because it would escape the hydrolysis by pancreatic phospholipase A2. We infused micelle containing the DHA either as LPC or as free acid, into the duodenum of lymph cannulated rats, and analyzed the chylomicrons and HDL of the lymph for the DHA-containing lipids. The results show that while the total amount of DHA absorbed was comparable from the two types of micelle, the percentage of DHA recovered in lymph phospholipids was 5 times greater with LPC-DHA, compared to free DHA. Furthermore, the amount of DHA recovered in lymph HDL was increased by 2-fold when LPC-DHA micelle was infused. These results could potentially lead to a novel strategy to increase brain DHA levels through the diet.
1. The endothelin (ET) system and NADPH oxidase play important roles in the regulation of cardiovascular function, as well as in the pathogenesis of hypertension and other cardiovascular diseases. 2. Endothelins activate NADPH oxidases and thereby increase superoxide production, resulting in oxidative stress and cardiovascular dysfunction. Thus, NADPH oxidases may mediate the role of endothelins in some cardiovascular diseases. However, the role of reactive oxygen species (ROS) in mediating ET-induced vasoconstriction and cardiovascular disease remains under debate, as evidenced by conflicting reports from different research teams. Conversely, activation of NADPH oxidase can stimulate ET secretion via ROS generation, which further enhances the cardiovascular effects of NADPH oxidase. However, little is known about how ROS activate the endothelin system. It seems that the relationship between ET-1 and ROS may vary with cardiovascular disorders. 3. Endothelins activate NADPH oxidase via the ET receptor-proline-rich tyrosine kinase-2 (Pyk2)-Rac1 pathway. Rac1 is an important regulator of NADPH oxidase. There is ample evidence supporting direct stimulation by Rac1 of NADPH oxidase activity. In addition, Rac1-induced cardiomyocyte hypertrophy is mediated by the generation of ROS.
The pantetheinase vanin-1 generates cysteamine, which inhibits reduced glutathione (GSH) synthesis. Vanin-1 promotes inflammation and tissue injury partly by inducing oxidative stress, and partly by peroxisome proliferator-activated receptor gamma (PPARγ) expression. Vascular smooth muscle cells (SMCs) contribute to neointimal hyperplasia in response to injury, by multiple mechanisms including modulation of oxidative stress and PPARγ. Therefore, we tested the hypothesis that vanin-1 drives SMC activation and neointimal hyperplasia. We studied reactive oxygen species (ROS) generation and functional responses to platelet-derived growth factor (PDGF) and the pro-oxidant diamide in cultured mouse aortic SMCs, and also assessed neointima formation after carotid artery ligation in vanin-1 deficiency. Vnn1 −/− SMCs demonstrated decreased oxidative stress, proliferation, migration, and matrix metalloproteinase 9 (MMP-9) activity in response to PDGF and/or diamide, with the effects on proliferation linked, in these studies, to both increased GSH levels and PPARγ expression. Vnn1−/− mice displayed markedly decreased neointima formation in response to carotid artery ligation, including decreased intima:media ratio and cross-sectional area of the neointima. We conclude that vanin-1, via dual modulation of GSH and PPARγ, critically regulates the activation of cultured SMCs and development of neointimal hyperplasia in response to carotid artery ligation. Vanin-1 is a novel potential therapeutic target for neointimal hyperplasia following revascularization.
In this study, we tested the hypothesis that the presence of dietary DHA in the sn‐1 position of phosphatidylcholine (PC) results in greater incorporation of absorbed DHA into the phospholipids of plasma lipoproteins, compared to its presence in triacylglycerol (TG) or in the sn‐2 position of PC, because of the positional specificities of the pancreatic enzymes. Micelle containing the DHA either in lyso PC (LPC) form (surrogate for the dietary sn‐1 DHA PC) or as free fatty acid (surrogate for dietary DHA TG and sn‐2 DHA PC) were infused intraduodenally into lymph fistula rats, and the concentration of DHA in PC and TG of lymph chylomicrons and HDL was determined by GC and LC/MS. The total amount of DHA absorbed was comparable with the two preparations. However the ratio of DHA in PC/TG in lymph was much higher (0.4) after LPC‐DHA infusion, compared to free DHA infusion (0.1). Also, more DHA appeared in HDL fraction of lymph after LPC‐DHA infusion, and more of the HDL DHA was in PC than in TG. Similar results were obtained with CACO‐2 cells grown on micropore membranes in transwell plates. The two types of DHA micelle were added to the apical medium and the lipoproteins in the basolateral medium were analyzed after 24 h. The results showed a 4‐fold higher incorporation of DHA into PC in presence of LPC DHA compared to free DHA. These data indicate that the dietary DHA in the sn‐1 position of PC is potentially more available than the DHA in sn‐2 position of PC (krill oil) or in TG (fish oil) for uptake by the brain since the phospholipid form of DHA, especially from HDL, is transported more efficiently into the brain. Supported by NIH R21 AT008457.
Hypothesis.Endothelin‐1 (ET‐1) inhibits Nox1 activity and decreases superoxide production and cell proliferation in human abdominal aortic endothelial cells (HAAECs).Methods and Results.HAAECs were exposed ET‐1 (10–30 nM) at different time intervals and superoxide production was measured by flow cytometry. Intracellular reactive oxygen species (ROS) was examined by confocal microscopy using 2′,7′‐dichlorodihydrofluorescein diacetate. NADPH oxidase activity was determined using lucigenin enhanced chemiluminescence in the presence and absence of siRNA for ETB1 receptors or Nox1. ET1 significantly attenuated Nox1 activity, ROS generation, and cell proliferation which could be abolished by silence of Nox1 gene. Furthermore, RNAi silence of ETB1 receptors significantly increased Nox1 activity and blocked the inhibitory effect of ET1 on Nox1 activity. ET1 enhanced bioavailability of intracellular NO measured using DAF‐2. ET1 did not affect Nox1 protein expression. Nox2 was not dectable in HAAECs. Activation of ETB1 receptors by ET1 suppressed protein phosphorylation of pyk2 (Y402) and Rac1, suggesting that ET1 inhibits Nox1 activity via ETB1‐Pyk2‐Rac1 pathway.Conclusions.This study demonstrated, for the first time, that that ET1 inhibited Nox1 activity, ROS production, and ell proliferation in HAAECs via ETB1‐Pyk2‐Rac1 pathway.
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