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PUFAs and nitric oxide (NO)
(36 References)
Dixon, G., J. Nolan, et al. (2004). "Arachidonic acid, palmitic acid and glucose are important for the modulation of clonal pancreatic beta-cell insulin secretion, growth and functional integrity." Clin Sci (Lond) 106(2): 191-9.
Insulin-resistant states such as obesity can result in an increase in the function and mass of pancreatic beta-cells, so that insulin secretion is up-regulated and Type II diabetes does not develop. However, expansion of beta-cell mass is not indefinite and may well decrease with time. Changes in circulating concentrations of nutritional factors, such as fatty acids and/or glucose, may lead to a reduction in beta-cell mass in vivo. Few previous studies have attempted to explore the interplay between glucose, amino acids and fatty acids with respect to beta-cell mass and functional integrity. In the present study, we demonstrate that culture of clonal BRIN-BD11 cells for 24 h with the polyunsaturated fatty acid arachidonic acid (AA) increased beta-cell proliferation and enhanced alanine-stimulated insulin secretion. These effects of AA were associated with significant decreases in the cellular consumption of D-glucose and L-alanine as well as decreased rates of production of nitric oxide and ammonia. Conversely 24 h exposure to the saturated fatty acid palmitic acid (PA) was found to decrease beta-cell viability (by increasing apoptosis), increase the intracellular concentration of triacylglycerol (triglyceride), while inhibiting alanine-stimulated insulin secretion. These effects of PA were associated with significant increases in D-glucose and L-glutamine consumption as well as nitric oxide and ammonia production. However, L-alanine consumption was decreased in the presence of PA. The effects of AA, but not PA, were additionally dependent on glucose concentration. These studies indicate that AA may have a critical role in maintaining the appropriate mass and function of islet beta-cells by influencing rates of cell proliferation and insulin secretion. This regulatory effect may be compromised by high circulating levels of glucose and/or PA, both of which are elevated in Type II diabetes and may impact upon dysfunctional and apoptotic intracellular events in the beta-cell.
Das, U. N. (2004). "Long-chain polyunsaturated fatty acids interact with nitric oxide, superoxide anion, and transforming growth factor-beta to prevent human essential hypertension." Eur J Clin Nutr 58(2): 195-203.
Patients with uncontrolled essential hypertension have elevated concentrations of superoxide anion (O(2)(-*)), hydrogen peroxide (H(2)O(2)), lipid peroxides, endothelin, and transforming growth factor-beta (TGF-beta) with a simultaneous decrease in endothelial nitric oxide (eNO), superoxide dismutase (SOD), vitamin E, and long-chain polyunsaturated fatty acids (LCPUFAs). Physiological concentrations of angiotensin II activate NAD(P)H oxidase and trigger free radical generation (especially that of O(2)(-*)). Normally, angiotensin II-induced oxidative stress is abrogated by adequate production and release of eNO, which quenches O(2)(-*) to restore normotension. Angiotensin II also stimulates the production of endothelin and TGF-beta. TGF-beta enhances NO generation, which in turn suppresses TGF-beta production. Thus, NO has a regulatory role on TGF-beta production and is also a physiological antagonist of endothelin. Antihypertensive drugs suppress the production of O(2)(-*) and TGF-beta and enhance eNO synthesis to bring about their beneficial actions. LCPUFAs suppress angiotensin-converting enzyme (ACE) activity, reduce angiotensin II formation, enhance eNO generation, and suppress TGF-beta expression. Perinatal supplementation of LCPUFAs decreases insulin resistance and prevents the development of hypertension in adult life, whereas deficiency of LCPUFAs in the perinatal period results in raised blood pressure later in life. Patients with essential hypertension have low concentrations of various LCPUFAs in their plasma phospholipid fraction. Based on this, it is proposed that LCPUFAs serve as endogenous regulators of ACE activity, O(2)(-*), eNO generation, and TGF-beta expression. Further, LCPUFAs have actions similar to statins, inhibit (especially omega-3 fatty acids) cyclooxygenase activity and suppress the synthesis of proinflammatory cytokines, and activate the parasympathetic nervous system, all actions that reduce the risk of major vascular events. Hence, it is proposed that availability of adequate amounts of LCPUFAs during the critical periods of growth prevents the development of hypertension in adulthood.European Journal of Clinical Nutrition (2004) 58, 195-203. doi:10.1038/sj.ejcn.1601766
Weber, L. W., M. Boll, et al. (2003). "Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model." Crit Rev Toxicol 33(2): 105-36.
The use of many halogenated alkanes such as carbon tetrachloride (CCl4), chloroform (CHCl3) or iodoform (CHI3), has been banned or severely restricted because of their distinct toxicity. Yet CCl4 continues to provide an important service today as a model substance to elucidate the mechanisms of action of hepatotoxic effects such as fatty degeneration, fibrosis, hepatocellular death, and carcinogenicity. In a matter of dose,exposure time, presence of potentiating agents, or age of the affected organism, regeneration can take place and lead to full recovery from liver damage. CCl4 is activated by cytochrome (CYP)2E1, CYP2B1 or CYP2B2, and possibly CYP3A, to form the trichloromethyl radical, CCl3*. This radical can bind to cellular molecules (nucleic acid, protein, lipid), impairing crucial cellular processes such as lipid metabolism, with the potential outcome of fatty degeneration (steatosis). Adduct formation between CCl3* and DNA is thought to function as initiator of hepatic cancer. This radical can also react with oxygen to form the trichloromethylperoxy radical CCl3OO*, a highly reactive species. CCl3OO* initiates the chain reaction of lipid peroxidation, which attacks and destroys polyunsaturated fatty acids, in particular those associated with phospholipids. This affects the permeabilities of mitochondrial, endoplasmic reticulum, and plasma membranes, resulting in the loss of cellular calcium sequestration and homeostasis, which can contribute heavily to subsequent cell damage. Among the degradation products of fatty acids are reactive aldehydes, especially 4-hydroxynonenal, which bind easily to functional groups of proteins and inhibit important enzyme activities. CCl4 intoxication also leads to hypomethylation of cellular components; in the case of RNA the outcome is thought to be inhibition of protein synthesis, in the case of phospholipids it plays a role in the inhibition of lipoprotein secretion. None of these processes per se is considered the ultimate cause of CCl4-induced cell death; it is by cooperation that they achieve a fatal outcome, provided the toxicant acts in a high single dose, or over longer periods of time at low doses. At the molecular level CCl4 activates tumor necrosis factor (TNF)alpha, nitric oxide (NO), and transforming growth factors (TGF)-alpha and -beta in the cell, processes that appear to direct the cell primarily toward (self-)destruction or fibrosis. TNFalpha pushes toward apoptosis, whereas the TGFs appear to direct toward fibrosis. Interleukin (IL)-6, although induced by TNFalpha, has a clearly antiapoptotic effect, and IL-10 also counteracts TNFalpha action. Thus, both interleukins have the potential to initiate recovery of the CCl4-damaged hepatocyte. Several of the above-mentioned toxication processes can be specifically interrupted with the use of antioxidants and mitogens, respectively, by restoring cellular methylation, or by preserving calcium sequestration. Chemicals that induce cytochromes that metabolize CCl4, or delay tissue regeneration when co-administered with CCl4 will potentiate its toxicity thoroughly, while appropriate CYP450 inhibitors will alleviate much of the toxicity. Oxygen partial pressure can also direct the course of CCl4 hepatotoxicity. Pressures between 5 and 35 mmHg favor lipid peroxidation, whereas absence of oxygen, as well as a partial pressure above 100 mmHg, both prevent lipid peroxidation entirely. Consequently, the location of CCl4-induced damage mirrors the oxygen gradient across the liver lobule. Mixed halogenated methanes and ethanes, found as so-called disinfection byproducts at low concentration in drinking water, elicit symptoms of toxicity very similar to carbon tetrachloride, including carcinogenicity.
Piolot, A., D. Blache, et al. (2003). "Effect of fish oil on LDL oxidation and plasma homocysteine concentrations in health." J Lab Clin Med 141(1): 41-9.
Oxidation of low-density lipoprotein (LDL) and hyperhomocysteinemia are believed to play a role in therogenesis. Whether n-3 polyunsaturated fatty acids increase LDL susceptibility to oxidation or influence homocysteine (Hcy) metabolism has long been a subject of controversy. In this study, we evaluated the effect of 8 weeks of dietary supplementation with 6 g/day of fish oil (FO; 3 g of n-3 fatty acids) on plasma lipoproteins, in vitro LDL peroxidation, antioxidant status, and plasma Hcy concentrations in 16 normolipidemic subjects. FO rapidly and significantly (P < .01) decreased plasma total and very low density lipoprotein triglyceride concentrations and had no effect on LDL or high-density-lipoprotein cholesterol. The mean lag time before onset of Cu(2+)-induced LDL oxidation, as well as plasma and LDL alpha-tocopherol and beta-carotene concentrations, was unchanged. However, changes in plasma aminothiol concentrations occurred during the study. Specifically, a progressive and significant increase in total Hcy plasma concentrations was observed (13.4% and 20% after 4 and 8 weeks, respectively; P < .01). Total glutathione concentrations were significantly higher after 8 weeks (P < .05). The tHcy increase was not associated with changes in plasma folate or vitamin B(12) concentrations. However, concentrations of plasma nitric oxide metabolites (NO(x) = NO(2) + NO(3)) were significantly higher than at baseline after 8 weeks of FO intake (74%; P < .01). Further, the changes in total Hcy and NO(x) plasma concentrations observed after 8 weeks of FO were found to be significantly correlated (r = .78, P < .001). With this study, we report for the first time the apparent interaction of n-3 fatty acids and nitric oxide on Hcy metabolism.
Ogita, H., K. Node, et al. (2003). "Eicosapentaenoic acid reduces myocardial injury induced by ischemia and reperfusion in rabbit hearts." J Cardiovasc Pharmacol 41(6): 964-9.
Intake of fish oil is known to have cardioprotective effects and reduce cardiovascular mortality. However, it is not widely recognized that eicosapentaenoic acid (EPA), one of the n-3 polyunsaturated fatty acids (PUFAs), exerts beneficial effects against myocardial ischemia/reperfusion injury. The purpose of this study is to investigate whether EPA attenuates the severity of myocardial ischemia/reperfusion injury and which cellular mechanism is involved. Rabbits were treated with or without EPA (600 mg/kg/day) for 2 weeks. Infarct size was measured in open-chest rabbits after 30-minute occlusion of the left anterior descending coronary artery (LAD) and after the subsequent 3-hour reperfusion. In several groups, NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, or charybdotoxin, a blocker of calcium-activated potassium (K(Ca)) channels, was infused intravenously beginning 20 minutes before LAD occlusion and continuing during reperfusion. Infarct size was reduced in the group treated with EPA compared with the control group (7.2 +/- 1.0% vs 24.6 +/- 2.3%; P < 0.01). The occurrence of ventricular arrhythmias in the reperfusion period tended to decrease in the EPA group. Either L-NAME or charybdotoxin partially blunted or completely abolished the infarct size-limiting effect of EPA, respectively. Eicosapentaenoic acid significantly increased the n-3:n-6 ratio of PUFA. Eicosapentaenoic acid reduces myocardial infarct size, mainly via the opening of K(Ca) channel-mediated and partially NO-mediated mechanisms in rabbit hearts.
Narayanan, B. A., N. K. Narayanan, et al. (2003). "Modulation of inducible nitric oxide synthase and related proinflammatory genes by the omega-3 fatty acid docosahexaenoic acid in human colon cancer cells." Cancer Res 63(5): 972-9.
Epidemiological and preclinical studies demonstrate that consumption of diets high in omega-3 polyunsaturated fatty acids reduces the risk of colon cancer. Inhibition of colon carcinogenesis by omega-3 polyunsaturated fatty acids is mediated through modulation of more than one signaling pathway that alters the expression of genes involved in colon cancer growth. In our earlier studies on global gene expression with cDNA microarrays, we have shown that treatment of CaCo-2 colon cancer cells with docosahexaenoic acid (DHA) down-regulated the prostaglandin family of genes, as well as cyclooxygenase 2 expression and several cell cycle-related genes, whereas it up-regulated caspases 5, 8, 9, and 10 that are associated with apoptosis. It is known that nitric oxide activates the cyclooxygenase 2 enzyme, which plays a pivotal role in the progression of colon cancer via prostaglandin synthesis and angiogenesis. The present study was undertaken to examine the multifaceted role of DHA in the expression of inducible nitric oxide synthase (iNOS) and of related proinflammatory genes, as those have been shown to play a role in tumor progression. In addition, we aimed to identify associated target genes by DNA microarray, reverse transcription-PCR analysis, and cellular localization of iNOS expression in CaCo-2 cells. Results of this study demonstrate that treatment with DHA down-regulates iNOS in parallel with a differential expression and down-regulation of IFNs, cyclic GMP, and nuclear factor kappa B isoforms. More importantly, our findings clearly demonstrate the up-regulation of cyclin-dependent kinase inhibitors p21((Waf1/Cip1)) and p27, differentiation-associated genes such as alkaline phosphatases, and neuronal differentiation factors. These finding strongly suggest that the antitumor activity of DHA may be attributed, at least in part, to an effect on iNOS regulatory genes. In addition, our results indicate the presence of specific gene expression profiles in human colon cancer that can be used as molecular targets for chemopreventive agents.
Komatsu, W., K. Ishihara, et al. (2003). "Docosahexaenoic acid suppresses nitric oxide production and inducible nitric oxide synthase expression in interferon-gamma plus lipopolysaccharide-stimulated murine macrophages by inhibiting the oxidative stress." Free Radic Biol Med 34(8): 1006-16.
N-3 polyunsaturated fatty acids (PUFAs) are known to have anti-inflammatory effects. Excess production of nitric oxide (NO) is associated with inflammation. Therefore, we examined the effects of PUFAs on NO production and inducible NO synthase (iNOS) expression by stimulated murine macrophages. One typical n-3 PUFA docosahexaenoic acid (DHA) strongly inhibited NO production and iNOS expression in RAW264 macrophages and mouse peritoneal macrophages in a dose-dependent manner. This inhibition was accompanied by inhibiting the oxidative stress-sensitive transcription factor nuclear factor (NF)-kappaB activation. In stimulated macrophages, intracellular peroxides level was enhanced, but pretreatment of DHA dose-dependently inhibited this enhancement. These results suggest that DHA has an antioxidative effect based on the inhibition of the accumulation of intracellular peroxides, and this inhibition caused the suppression of the activation of NF-kappaB, resulting in the inhibition of NO production and iNOS expression. On the other hand, DHA treatment enhanced the level of intracellular glutathione (GSH), and this enhancement is thought to mediate the activity of DHA because lowering the GSH level by inhibiting GSH biosynthesis reversed the DHA-induced suppression of NO production, NF-kappaB activation, and the accumulation of intracellular peroxides. Our results demonstrate that DHA inhibits NO production in macrophages and this inhibition is, in part, mediated by upregulation of GSH.
Hirafuji, M., T. Machida, et al. (2003). "Cardiovascular protective effects of n-3 polyunsaturated fatty acids with special emphasis on docosahexaenoic acid." J Pharmacol Sci 92(4): 308-16.
It is widely accepted that n-3 polyunsaturated fatty acids (PUFAs) rich in fish oils protect against several types of cardiovascular diseases such as myocardial infarction, arrhythmia, atherosclerosis, or hypertension. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may be the active biological components of these effects. Although the precise cellular and molecular mechanisms underlying the beneficial effects are still uncertain, the protective effects of n-3 PUFAs are attributable to their direct effects on vascular smooth muscle cell (VSMC) functions. These n-3 PUFAs activate K(+)(ATP) channels and inhibit certain types of Ca(2+) channels, probably via at least 2 distinct mechanisms. N-3 PUFAs favorably alter the eicosanoid profile and regulate cytokine-induced expression of inducible nitric oxide synthase and cyclooxygenase-2 via mechanisms involving modulation of signaling transduction events. N-3 PUFAs also modulate VSMC proliferation, migration, and apoptosis. These recent data suggest that modulation of these VSMC functions contribute to the beneficial effects of n-3 PUFAs on various cardiovascular disorders. Furthermore, recent studies strongly suggest that DHA has more potent and beneficial effects than EPA. However, many questions about the cellular and molecular mechanisms still remain to be answered.
Das, U. N. (2003). "Can memory be improved? A discussion on the role of ras, GABA, acetylcholine, NO, insulin, TNF-alpha, and long-chain polyunsaturated fatty acids in memory formation and consolidation." Brain Dev 25(4): 251-61.
It is proposed that long-chain polyunsaturated fatty acids when given from the perinatal period will ensure proper development and growth of the brain and maintain the activity and/or concentrations of ras, nitric oxide, insulin, and various neurotransmitters and cytokines at physiological level and thus, improve memory and prevent learning deficits.
Das, U. N., E. J. Ramos, et al. (2003). "Metabolic alterations during inflammation and its modulation by central actions of omega-3 fatty acids." Curr Opin Clin Nutr Metab Care 6(4): 413-9.
PURPOSE OF REVIEW: To discuss the possible relationship between long-chain polyunsaturated fatty acids, cytokines, anandamides, nitric oxide, leptin, various neurotransmitters in the brain, and their role in anorexia of acute and chronic inflammatory conditions and cancer. RECENT FINDINGS: Recent studies have shown that long-chain polyunsaturated fatty acids, especially the omega-3 series, have antiinflammatory actions, increase the concentrations of anandamides, enhance the levels of acetylcholine and nitric oxide and modulate the concentrations and actions of various neurotransmitters, including leptin, in the brain. Patients suffering from acute and chronic inflammatory conditions have low tissue concentrations of various long-chain polyunsaturated fatty acids, and high levels of proinflammatory cytokines that can cause anorexia and decrease food intake. SUMMARY: It is suggested that supplementation of long-chain polyunsaturated fatty acids may have a role in the prevention and treatment of acute and chronic inflammatory conditions, improving anorexia associated with these conditions.
Das, U. N. (2003). "Folic acid says NO to vascular diseases." Nutrition 19(7-8): 686-92.
OBJECTIVES: The possible link between folic acid or folate and tetrahydrobiopterin (H(4)B), vitamin C, polyunsaturated fatty acids (PUFAs), and nitric oxide (NO), which may explain the beneficial actions of these nutrients in various vascular conditions, was investigated. METHODS: The literature pertaining to the actions of folic acid/folate, H(4)B, vitamin C, PUFAs, and NO was reviewed. RESULTS: Impaired endothelial NO (eNO) activity is an early marker for cardiovascular disease. Most risk factors for atherosclerosis are associated with impaired endothelium-dependent vasodilatation due to reduced NO production. Folate not only reduces plasma homocysteine levels but also enhances eNO synthesis and shows anti-inflammatory actions. It stimulates endogenous H(4)B regeneration, a cofactor necessary for eNO synthesis, inhibits intracellular superoxide generation, and thus enhances the half-life of NO. H(4)B in turn enhances NO generation and augments arginine transport into the cells. Folic acid increases the concentration of omega-3 PUFAs, which also enhance eNO synthesis. Vitamin C augments eNO synthesis by increasing intracellular H(4)B and stabilization of H(4)B. Insulin stimulates H(4)B synthesis and PUFA metabolism, suppresses the production of proinflammatory cytokine tumor necrosis factor-alpha and superoxide anion, and enhances NO generation. The ability of folate to augment eNO generation is independent of its capacity to lower plasma homocysteine levels. CONCLUSIONS: The common mechanism by which folic acid, H(4)B, vitamin C, omega-3 fatty acids, and L-arginine bring about their beneficial actions in various vascular diseases is by enhancing eNO production. Hence, it remains to be determined whether a judicious combination of folic acid, vitamins B12, B6, and C, H(4)B, L-arginine, and omega-3 fatty acids in appropriate amounts may form a novel approach in the prevention and management of various conditions such as hyperlipidemias, coronary heart disease, atherosclerosis, peripheral vascular disease, and some neurodegenerative conditions.
Das, U. N. (2003). "A perinatal strategy to prevent coronary heart disease." Nutrition 19(11-12): 1022-7.
I investigated whether metabolism of essential fatty acids and the concentrations of their long-chain metabolites (long-chain polyunsaturated fatty acids [LCPUFAs]) are altered in fetal or perinatal growth retardation, maternal hypercholesterolemia, low-grade systemic inflammation, insulin resistance, and atherosclerosis, conditions that predispose to the development of coronary heart disease (CHD).I critically reviewed the literature pertaining to the metabolism of essential fatty acids in CHD and conditions that predispose to it.LCPUFAs enhance endothelial nitric oxide synthesis, suppress the production of the proinflammatory cytokines tumor necrosis factor and interleukin-6, attenuate insulin resistance, and have antiatherosclerotic properties. Low-birthweight infants have decreased concentrations of LCPUFAs, especially arachidonic acid. Neonatal arachidonic acid status is related to intrauterine growth, and LCPUFAs improve fetal and postnatal growth. LCPUFAs are useful in the management of hyperlipidemia, inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, and may mediate the beneficial actions of statins. Plasma concentrations of various LCPUFAs are low in diabetes mellitus, hypertension, and CHD and in populations at high risk of CHD. Breast milk is rich in LCPUFAs, and this may explain why and how adequate (6 mo to 1 y) breast feeding protects against the development of obesity, hypertension, insulin resistance, and CHD.LCPUFAs are essential for the growth and development of the fetus and infant. LCPUFAs can prevent various conditions that predispose to the development of CHD. The low incidence of CHD seen in adequately breast-fed infants can be linked to the LCPUFA content of breast milk. Based on this evidence, I suggest that provision of LCPUFAs during critical periods of growth, especially from the second trimester of pregnancy to age 5 y, prevents CHD in adult life.
Christon, R. A. (2003). "Mechanisms of action of dietary fatty acids in regulating the activation of vascular endothelial cells during atherogenesis." Nutr Rev 61(8): 272-9.
Dietary long chain omega-3 polyunsaturated fatty acids from fish oil appear to be clearly efficient in regulating endothelial dysfunction (or activation), which is the first stage of atherogenesis. Studies on endothelial cells in vitro have shown that the main dietary PUFA and oleic acid may prevent endothelium activation either by inhibiting the expression of adhesion molecules or by improving the nitric oxide production. Saturated fatty acids and also linoleic acid do not inhibit endothelium activation. The mechanisms involved in this inhibition could be related to endothelial cell membrane characteristics or redox status. However, these findings need to be confirmed in vivo.
Beeharry, N., J. E. Lowe, et al. (2003). "Linoleic acid and antioxidants protect against DNA damage and apoptosis induced by palmitic acid." Mutat Res 530(1-2): 27-33.
Polyunsaturated fats are the main target for lipid peroxidation and subsequent formation of mutagenic metabolites, but diets high in saturated fats are more strongly associated with adverse health effects. We show that the common saturated fatty acid, palmitic acid, is a potent inducer of DNA damage in an insulin-secreting cell line, and in primary human fibroblasts. Damage is not associated with upregulation of inducible nitric oxide synthase, but is prevented by two different antioxidants, alpha-lipoic acid and 3,3'-methoxysalenMn(III) (EUK134), which also partly prevent palmitic acid-induced apoptosis and growth inhibition. Since mutagenic metabolites can be formed from peroxidation of polyunsaturated fatty acids, co-administration of palmitic and a polyunsaturated fatty acid might be particularly harmful. Palmitic acid-induced DNA damage is instead prevented by linoleic acid, which is acting here as a protective agent against oxidative stress, rather than as a source of mutagenic metabolites. These results illustrate the complexity of the relationship of dietary fat intake to genotoxicity.
Robinson, L. E., M. T. Clandinin, et al. (2002). "The role of dietary long-chain n-3 fatty acids in anti-cancer immune defense and R3230AC mammary tumor growth in rats: influence of diet fat composition." Breast Cancer Res Treat 73(2): 145-60.
We determined if long-chain n-3 fatty acids fed as part of a: (1) high polyunsaturated fat diet (currently recommended by several health agencies) or (2) low polyunsaturated fat diet (representative of that consumed by a large segment of the North American population) improved antitumor immune defense and inhibited tumor growth. Rats were fed one of four semi-purified diets (20% w/w fat) for 21 days pre- and 17 days post- R3230AC mammary tumor implantation. The polyunsaturated to saturated fatty acid (P/S) ratio was either 1 (high P/S diet) or 0.35 (low P/S diet). At each P/S ratio, diets provided long-chain n-3 fatty acids at 0 or 5% w/w of total fat. Long-chain n-3 fatty acids fed in a high P/S diet did not affect tumor growth or host immune responses. In contrast, feeding long-chain n-3 fatty acids in a low P/S diet increased natural killer cell cytotoxicity, splenocyte nitric oxide and interleukin-2 production, and the proportion of activated (CD25+) CD8+ and CD28+ cells, but did not significantly inhibit tumor growth. For both P/S diets, tumor cells from rats fed long-chain n-3 fatty acids had a higher n-3 content and n-3/n-6 ratio in phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol. Furthermore, the magnitude of increase in n-3 fatty acid incorporation into tumor phospholipids was greater when fed in a low P/S diet. We demonstrated that the dietary P/S ratio significantly influences the effect of long-chain n-3 fatty acids on host immune responses and n-3 fatty acid incorporation into tumor cells. These findings warrant further consideration when designing dietary recommendations.
Maccarrone, M., M. Bari, et al. (2002). "Endocannabinoid degradation, endotoxic shock and inflammation." Curr Drug Targets Inflamm Allergy 1(1): 53-63.
Endocannabinoids are an emerging class of lipid mediators, which include amides and esters of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG) are the main endogenous agonists of cannabinoid receptors. Endotoxic shock is a potentially lethal failure of multiple organs that can be initiated by the inflammatory agent lipopolysaccharide (LPS), present in the outer membrane of gram-negative bacteria. LPS has been recently shown to stimulate the production of AEA in rat macrophages, and of 2-AG in rat platelets. The mechanism responsible for this effect has not been elucidated. On the other hand, mast cells are multifunctional bone marrow-derived cells found in mucosal and connective tissues and in the nervous system, where they play an essential role in inflammation. As yet, little is known about endogenous modulators and mechanisms of mast cell activation. Here, we review recent literature on the role of endocannabinoids in endotoxic shock and inflammation, and report our recent research on the effects of LPS on the production of AEA and 2-AG in human lymphocytes, and on AEA degradation by a specific AEA membrane transporter (AMT) and an AEA-degrading enzyme (fatty acid amide hydrolase, FAAH). We also report the ability of the HMC-1 human mast cells to degrade AEA through a nitric oxide-sensitive AMT and a FAAH. The role of endocannabinoids in HMC-1 degranulation is discussed as well. Taken together, it can be suggested that human lymphocytes and mast cells take part in regulating the peripheral endocannabinoid system, which can affect some activities of these cells.
Kulkarni, P., J. Cai, et al. (2002). "Lipids and nitric oxide in porcine retinal and choroidal blood vessels." J Ocul Pharmacol Ther 18(3): 265-75.
Lipid profiles of porcine retina, and retinal and choroidal vessels were analyzed using the gas chromatography/mass spectrometry (GC/MS) technique. The retina and both isolated retinal and choroidal vessels contained saturated fatty acid stearic acid and polyunsaturated fatty acids, including arachidonic (C20:4, AA), a precursor for vasoactive prostaglandin (PG-2) series, and W-6 docosahexaenoic acids (C22:6, DHA). However, eicosapentaenoic acid (C20:5, EPA), a precursor for PG-3 series, was not detected in these vessels. When stearic acid was used for normalization of tissue sample, the retina contained relatively higher amounts of DHA than AA, retinal vessels had equal amounts of AA and DHA, while choroidal vessels contained higher amounts of AA than DHA. We also examined the endogenous synthesis of vasoactive endothelial-derived factors like PGs and nitric oxide (NO). Since vasoactive angiotensin II (Ang II) releases these products from blood vessels, this polypeptide was used in a porcine retinal circulation model. The porcine retinal central artery was perfused with oxygenated/heparinized physiological salt solution at 37 degrees C. Changes in A1 and A2 arteriolar diameters induced by Ang II were determined in the absence and presence of the nitric oxide synthase inhibitor, l-NO Arginine (LNOA), and cyclooxygenase inhibitor, flurbiprofen (FB). The central retinal artery designated as the first order arteriole A1 and subsequent branch was defined as A2. Luminal diameters of Al and A2 arterioles were 35 +/- 2 am and 10 +/- 1 microm, respectively. Topical Ang II (10(-10) M-10(-6) M) caused small vasoconstrictions in a dose-dependent manner. This response was enhanced after inhibition of PG synthesis by (10-6 M) FB. Ang II induced-constrictions were further enhanced in the presence of NO synthase inhibitor, LNOA (10(-7) M). There was slightly more increase in Ang II-induced vasoconstrictions in the presence of both NO and PG inhibitors, suggesting that NO may cause release of PGs from these vessels. This study demonstrates that the porcine retinal arterioles have the ability to regulate vasoconstriction responses induced by Ang II by synthesis and release of endogenous vasodilating PGs and NO (especially NO); and these substances may play a vital role in porcine retinal circulation.
Das, U. N. (2002). "Estrogen, statins, and polyunsaturated fatty acids: similarities in their actions and benefits-is there a common link?" Nutrition 18(2): 178-88.
OBJECTIVES: To investigate whether there is any common link between estrogen, statins, and polyunsaturated fatty acids (PUFAs), which have similar actions and benefits. METHODS: To critically review the literature pertaining to the actions of estrogen, statins, and various PUFAs. RESULTS: Estrogen, statins, and PUFAs enhance nitric oxide synthesis, suppress the production of proinflammatory cytokines such as tumor necrosis factor(alpha), interleukin-1, interleukin-2, and interleukin-6, show antioxidant-like and antiatherosclerotic properties, have neuroprotective actions, and by themselves or their products inhibit tumor cell proliferation and improve osteoporosis. Estrogen, statins, and PUFAs not only have similar actions but also appear to interact with each other. For instance, the binding of estrogen to its receptor on the cell membrane may be determined by its lipid content, statins and PUFAs inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, statins influence the metabolism of PUFAs, and PUFA deficiency enhances 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Statins and PUFAs inhibit tumor cell proliferation, suppress ras activity, and may prevent neurodegeneration and improve cognitive functions such as learning and memory. This suggests that PUFAs might be mediators of the actions of statins. Estrogen boosts cognitive performance in women after menopause and may protect against Alzheimer's disease. CONCLUSIONS: The common link between estrogen, statins, and PUFAs may be nitric oxide. Hence, a combination(s) of estrogen or its derivatives, statins, and various PUFAs may form a novel approach in the management of various conditions such as hyperlipidemias, coronary heart disease, atherosclerosis, osteoporosis, cancer, neurodegenerative conditions, and to improve memory.
Das, U. N. (2002). "Is type 2 diabetes mellitus a disorder of the brain?" Nutrition 18(7-8): 667-72.
I propose that type 2 diabetes mellitus is due to damage to neurons in the ventromedial hypothalamus or to a defect in the action or properties of insulin or insulin receptors in the brain. These neuronal abnormalities are probably secondary to a marginal deficiency of long-chain polyunsaturated fatty acids during the critical periods of brain growth and development. Hence, supplementation of adequate amounts of long-chain polyunsaturated fatty acids during the third trimester of pregnancy to 2 y postterm can prevent or postpone the development of diabetes mellitus.
Sikka, S. C. (2001). "Relative impact of oxidative stress on male reproductive function." Curr Med Chem 8(7): 851-62.
Impairment of normal spermatogenesis and sperm function are the most common causes of male factor infertility. Abnormal sperm function is difficult to evaluate and treat. There is a lack of understanding of the factors contributing to normal and abnormal sperm function leading to infertility. Many recent studies indicate that oxygen-derived free radicals induce damage to spermatozoa. The excessive generation of these reactive oxygen species (superoxide, hydroxyl, nitric oxide, peroxide, peroxynitrile) by immature and abnormal spermatozoa and by contaminating leukocytes associated with genitourinary tract inflammation have been identified with idiopathic male infertility. Mammalian spermatozoa membranes are rich in polyunsaturated fatty acids. This makes them very susceptible to oxygen-induced damage, which is mediated by lipid peroxidation. In a normal situation, the antioxidant mechanisms present in the reproductive tissues and their secretions are likely to quench these reactive oxygen species (ROS) and protect against oxidative damage to gonadal cells and mature spermatozoa. During chronic disease states, aging, toxin exposure, or genitourinary infection/inflammation, these cellular antioxidant mechanisms downplay and create a situation called oxidative stress. Thus, a balance between ROS generation and antioxidant capacity plays a critical role in the pathophysiology of disease state. Recent efforts towards the development of new reliable assays to evaluate this oxidative stress status have resulted in the establishment of ROS-TAC score. Such assessment of oxidative stress status (OSS) may help in designing newer modes of male factor infertility treatment by suitable antioxidants.
Kuroda, R., K. Hirata, et al. (2001). "Unsaturated free fatty acids inhibit Ca2+ mobilization and NO release in endothelial cells." Kobe J Med Sci 47(5): 211-9.
Circulating free fatty acids (FFAs) are elevated in various disorders like states of insulin resistance, and an increase of FFAs has been reported to be associated with endothelial dysfunction. To investigate the effect of FFAs on vascular endothelial cells, we measured nitric oxide (NO) release and intracellular free calcium concentration ([Ca2+]i ) in cultured bovine aortic endothelial cells (BAECs). Monounsaturated FFAs such as oleic acid (OA) and polyunsaturated FFAs such as linoleic acid (LA) dose-dependently (10-100 Emol/L) inhibited NO release from BAECs stimulated by adenosine 5'-(3-O-thio)triphosphate (ATP AS) whereas saturated FFAs such as palmitic acid had no effect on NO release. ATP AS induced a biphasic increase in [Ca2+]i, which consisted of a rapid increase followed by a sustained increase. OA and LA inhibited ATP AS-induced Ca2+ release from intracellular Ca2+ stores and increase in Ca2+ influx from extracellular space. In addition, OA and LA rapidly decreased sustained increase in [Ca2+]i induced by ATP AS when OA or LA was added after stimulation with ATP AS. Impaired Ca2+ mobilization by unsaturated FFAs (UFFAs) was completely reversed by treatment with bovine serum albumin (1 mg/ml) indicating that inhibitory effect of FFAs was not caused by cytotoxic effect. In spite of this inhibitory effect of UFFAs, neither OA nor LA had any effect on phosphoinositide hydrolysis evoked by ATP AS. From these results, elevated UFFA may contribute to impaired NO production through inhibition of receptor-mediated Ca2+ mobilization and Ca2+ influx in pathological conditions such as multiple risk factor syndrome and insulin resistance.
Jagla, A. and J. Schrezenmeir (2001). "Postprandial triglycerides and endothelial function." Exp Clin Endocrinol Diabetes 109(4): S533-47.
Several studies support the association between postprandially elevated triglyceride levels and atherosclerosis. Histological and cell culture investigations revealed, that triglyceride rich postprandial lipoproteins are taken up by macrophages and smooth muscle cells and are detectable as part of foam cells in vascular lesions. Remnant particles, generated by lipolysis of postprandial lipoproteins in vitro and fatty acids increase the permeability of the endothelium and are cytotoxic for endothelial cells. Besides these morphological changes of cells, lipoproteins have been shown to exert effects on cellular functions like the expression of membrane proteins and the production or release of several bioactive substances regulating communication with blood cells and other cell systems of the vascular wall, blood pressure and hemostasis. This review concentrates on the influence of postprandial lipoproteins on factors involved in the interaction of endothelial cells with blood leukocytes and factors mediating blood pressure regulation. Increased expression of adhesion molecules has been detected immunehistochemically in atherosclerotic plaques in animals and humans. It was demonstrated that patients with elevated triglyceride levels have increased levels of soluble adhesion molecules. Furthermore, postprandial lipoproteins were shown to induce membrane expression of adhesion molecules. This effect seems to be at least in part mediated by the oxidative modification of the particles. Accordingly chylomicrons separated after ingestion of safflower oil, rich in polyunsaturated linoleic acid, induced higher adhesion molecule expression at higher oxidant concentration compared with chylomicrons separated after ingestion of olive oil, rich in monounsaturated oleic acid. Several authors described effects of fatty acids on the expression of adhesion molecules. On the one hand, they may exert stimulatory effects as such, on the other hand cytokine induced adhesion molecule expression may be enhanced by certain fatty acids and inhibited by others, implying an interference with signal transduction processes. Effects of lipoproteins on vasoactive substances seem to be implicated in endothelial dysfunction, too. The endothelium-derived relaxing factor nitric oxide (NO) has gained increasingly attention in the last two decades and is regarded as protective against hypertension and atherosclerosis. It was demonstrated that chylomicrons and their remnants inhibited endothelium-dependent relaxations in isolated aortas. Vasodilatatory responses and nitric oxide metabolism were shown to be affected by the amount and composition of dietary fat. Cell culture experiments revealed modulation of NO release by certain fatty acids. Plasma levels of endothelin-1, a strong vasoconstrictor, have been shown to be increased in patients with type 2 diabetes and metabolic syndrome, respectively. Postprandially elevated triglycerides increased endothelin-levels in addition to insulin in patients with metabolic syndrome. In summary, there is evidence that the association between postprandial triglycerides and the metabolic syndrome is driven by direct influences on endothelial functions because plasma triglyceride levels are associated with levels of humoral risk markers of endothelial origin, and postprandial lipoproteins stimulate the release and/or expression of endothelial mediators in vitro, which induce atherogenesis and hypertension.
Das, U. N. (2001). "Essential fatty acids as possible mediators of the actions of statins." Prostaglandins Leukot Essent Fatty Acids 65(1): 37-40.
Statins and polyunsaturated fatty acids have similar actions: both enhance endothelial nitric oxide synthesis, inhibit the production of pro-inflammatory cytokines, lower cholesterol levels, prevent atherosclerosis and are of benefit in coronary heart disease, stroke and osteoporosis. Statins enhance the conversion of linoleic acid and eicosapentaenoic acid to their long chain derivatives. Animals with essential fatty acid deficiency show an increase in HMG-CoA reductase activity, which reverts to normalcy following topical application of linoleic acid. Similarly to statins, polyunsaturated fatty acids also inhibit HMG-CoA reductase activity. In view of the similarity in their actions and as statins influence essential fatty acid metabolism, it is suggested that essential fatty acids and their metabolites may serve as second messengers of the actions of statins.
Das, U. N. (2001). "Hypothesis: can glucose-insulin-potassium regimen in combination with polyunsaturated fatty acids suppress lupus and other inflammatory conditions?" Prostaglandins Leukot Essent Fatty Acids 65(2): 109-13.
In systemic lupus erythematosus, plasma concentrations of tumor necrosis factor alpha (TNF alpha) and other pro-inflammatory cytokines are elevated and those of transforming growth factor beta (TGF beta) are decreased. TNF alpha prevents lupus nephropathy whereas increased concentration of TGF beta causes glomerulosclerosis. Insulin inhibits TNF alpha and enhances TGF beta production, augments nitric oxide synthesis and blocks superoxide anion generation. Polyunsaturated fatty acids (PUFAs) also have actions similar to insulin. Hence, it is suggested that a combination of insulin (in the form of glucose-insulin-potassium) and PUFAs may be of benefit in lupus and other inflammatory conditions.
Das, U. N. (2001). "Is obesity an inflammatory condition?" Nutrition 17(11-12): 953-66.
Obesity may be a low-grade systemic inflammatory disease. Overweight and obese children and adults have elevated serum levels of C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and leptin, which are known markers of inflammation and closely associated with cardiovascular risk factors and cardiovascular and non-cardiovascular causes of death. This may explain the increased risk of diabetes, heart disease, and many other chronic diseases in the obese. The complex interaction between several neurotransmitters such as dopamine, serotonin, neuropeptide Y, leptin, acetylcholine, melanin-concentrating hormone, ghrelin, nitric oxide, and cytokines and insulin and insulin receptors in the brain ultimately determines and regulates food intake. Breast-feeding of more than 12 mo is associated with decreased incidence of obesity. Breast milk is a rich source of long-chain polyunsaturated fatty acids (LCPUFAs) and brain is especially rich in these fatty acids. LCPUFAs inhibit the production of proinflammatory cytokines and enhance the number of insulin receptors in various tissues and the actions of insulin and several neurotransmitters. LCPUFAs may enhance the production of bone morphogenetic proteins, which participate in neurogenesis, so these fatty acids might play an important role in brain development and function. It is proposed that obesity is a result of inadequate breast feeding, which results in marginal deficiency of LCPUFAs during the critical stages of brain development. This results in an imbalance in the structure, function, and feedback loops among various neurotransmitters and their receptors, which ultimately leads to a decrease in the number of dopamine and insulin receptors in the brain. Hence, promoting prolonged breast feeding may decrease the prevalence of obesity. Exercise enhances parasympathetic tone, promotes antiinflammation, and augments brain acetylcholine and dopamine levels, events that suppress appetite. Acetylcholine and insulin inhibit the production of proinflammatory cytokines and provide a negative feedback loop for postprandial inhibition of food intake, in part, by regulating leptin action. Statins, peroxisome proliferator-activated receptor-gamma binding agents, non-steroidal antiinflammatory drugs, and infant formulas supplemented with LCPUFAs, and LCPUFAs themselves, which suppress inflammation, may be beneficial in obesity.
Darlington, L. G. and T. W. Stone (2001). "Antioxidants and fatty acids in the amelioration of rheumatoid arthritis and related disorders." Br J Nutr 85(3): 251-69.
The generation of reactive oxygen species (free radicals) is an important factor in the development and maintenance of rheumatoid arthritis in humans and animal models. One source of free radicals is nitric oxide produced within the synoviocytes and chondrocytes and giving rise to the highly toxic radical peroxynitrite. Several cytokines, including tumour necrosis factor-alpha (TNFalpha) are involved in the formation of free radicals, partly by increasing the activity of nitric oxide synthase. Indeed, nitric oxide may mediate some of the deleterious effects of cytokines on bone resorption. Aspirin, tetracyclines, steroids and methotrexate can suppress nitric oxide synthase. Dietary antioxidants include ascorbate and the tocopherols and beneficial effects of high doses have been reported especially in osteoarthritis. There is also evidence for beneficial effects of beta-carotene and selenium, the latter being a component of the antioxidant enzyme glutathione peroxidase. The polyunsaturated fatty acids (PUFA) include the n-3 compounds, some of which are precursors of eicosanoid synthesis, and the n-6 group which can increase formation of the pro-inflammatory cytokines TNFalpha and interleukin-6, and of reactive oxygen species. Some prostaglandins, however, suppress cytokine formation, so that n-3 PUFA often oppose the inflammatory effects of some n-6-PUFA. gamma-linolenic acid (GLA) is a precursor of prostaglandin E1, a fact which may account for its reported ability to ameliorate arthritic symptoms. Fish oil supplements, rich in n-3 PUFA such as eicosapentaenoic acid have been claimed as beneficial in rheumatoid arthritis, possibly by suppression of the immune system and its cytokine repertoire. Some other oils of marine origin (e.g. from the green-lipped mussel) and a range of vegetable oils (e.g. olive oil and evening primrose oil) have indirect anti-inflammatory actions, probably mediated via prostaglandin E1. Overall, there is a growing scientific rationale for the use of dietary supplements as adjuncts in the treatment of inflammatory disorders such as rheumatoid arthritis and osteoarthritis.
Chang, Y. H., S. T. Lee, et al. (2001). "Effects of cannabinoids on LPS-stimulated inflammatory mediator release from macrophages: involvement of eicosanoids." J Cell Biochem 81(4): 715-23.
Delta(9)-Tetrahydrocannabinol (Delta(9)-THC) is the major psychoactive component of marijuana and elicits pharmacological actions via cannabinoid receptors. Anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG) are endogenous ligands for cannabinoid receptors, which because of their structural similarities to arachidonic acid (AA), AEA, and 2-AG could serve as substrates for lipoxygenases and cyclooxygenases (COXs) that metabolize polyunsaturated fatty acids to potent bioactive molecules. In this study, we have compared the effects of Delta(9)-THC, AEA, 2-AG, and another cannabinoid agonist, indomethacin morpholinylamide (IMMA), on lipopolysaccharide (LPS)-induced NO, IL-6, and PGE(2) release from J774 macrophages. Delta(9)-THC, IMMA, and AEA diminish LPS-induced NO and IL-6 production in a concentration-dependent manner. 2-AG inhibits the production of IL-6 but slightly increases iNOS-dependent NO production. Delta(9)-THC and IMMA also inhibit LPS-induced PGE(2) production and COX-2 induction, while AEA and 2-AG have no effects. These discrepant results of 2-AG on iNOS and COX-2 induction might be due to its bioactive metabolites, AA and PGE(2), whose incubation cause the potentiation of both iNOS and COX-2 induction. On the contrary, the AEA metabolite, PGE(2)-ethanolamide, influences neither the LPS-induced NO nor IL-6 production. Taken together, direct cannabinoid receptor activation leads to anti-inflammatory action via inhibition of macrophage function. The endogenous cannabinoid, 2-AG, also serves as a substrate for COX-catalyzing PGE(2) production, which in turn modulates the action of CB2.
Caplan, M. S., T. Russell, et al. (2001). "Effect of polyunsaturated fatty acid (PUFA) supplementation on intestinal inflammation and necrotizing enterocolitis (NEC) in a neonatal rat model." Pediatr Res 49(5): 647-52.
Inasmuch as long-chain polyunsaturated fatty acids (PUFA, metabolites of the essential n-3 and n-6 fatty acids) are known to modulate inflammation, we hypothesized that supplementation of formula with these compounds would prevent necrotizing enterocolitis (NEC) and intestinal inflammation in our neonatal rat model. Newborn rats were stressed with asphyxia and formula feeding, and randomly assigned to control formula, control with PUFA supplementation, and PUFA with nucleotides. Animals were followed for 72--96 h and assessed for death, gross and histologic NEC, intestinal apoptosis, endotoxemia, and intestinal mRNA synthesis of phospholipase A(2)-II (rate-limiting enzyme for platelet activating factor production), platelet activating factor receptor, and inducible nitric oxide synthase. We found that PUFA reduced the incidence of death and NEC compared with the other groups (NEC 8 of 24 versus 17 of 24 control and 13 of 23 PUFA + nucleotides, p < 0.05). Furthermore, PUFA reduced plasma endotoxemia at 48 h (25 +/- 4 EU/mL versus 276 +/- 39 EU/mL in control and 170 +/- 28 EU/mL in PUFA + nucleotide), intestinal phospholipase A(2)-II expression at 24 h, and platelet activating factor receptor expression at 48 h. Formula supplementation had no effect on apoptosis of intestinal epithelium or intestinal inducible nitric oxide synthase expression. Addition of nucleotides with PUFA abrogated the beneficial effects of PUFA on intestinal inflammation. We conclude that PUFA reduces the incidence of NEC and intestinal inflammation in a neonatal rat model.
Buonocore, G., S. Perrone, et al. (2001). "Free radicals and brain damage in the newborn." Biol Neonate 79(3-4): 180-6.
Newborns and particularly preterm infants are at high risk of oxidative stress and they are very susceptible to free radical oxidative damage. Indeed, there is evidence of an imbalance between antioxidant- and oxidant-generating systems which causes oxidative damage. The brain may be especially at risk of free radical-mediated injury because neuronal membranes are rich in polyunsaturated fatty acids and because the human newborn has a relative deficiency of brain superoxide dismutase and glutathione peroxidase. The brain of the term fetus is at higher risk of oxidative stress than that of the preterm fetus, as a consequence of its higher concentration of polyunsaturated fatty acids and the maturity of the N-methyl-D-aspartate receptor system at term. There seems to be a maturation-dependent window of vulnerability to free radical attack during oligodendrocyte development. Early in its differentiation, the oligodendrocyte may be vulnerable because of active acquisition of iron for differentiation at a time of relative delay in the development of certain key antioxidant defenses in the brain. Excess free iron and deficient iron-binding and -metabolizing capacity are additional features favoring oxidant stress in premature infants. Free radicals may be generated by different mechanisms, such as ischemia-reperfusion, neutrophil and macrophage activation, Fenton chemistry, endothelial cell xanthine oxidase, free fatty acid and prostaglandin metabolism and hypoxia. Reactive oxidant production by these different mechanisms contributes in a piecewise manner to the pathogenesis of perinatal brain injury.
Abeywardena, M. Y. and R. J. Head (2001). "Dietary polyunsaturated fatty acid and antioxidant modulation of vascular dysfunction in the spontaneously hypertensive rat." Prostaglandins Leukot Essent Fatty Acids 65(2): 91-7.
Two currently available edible oils-olive and canola-and two oil blends of plant origin having different n-3/n-6 polyunsaturated fatty acid (PUFA) ratios were evaluated for their ability to modify vascular dysfunction in the spontaneously hypertensive rat (SHR). Synthetic diets supplemented with test oils (5% w/w) were fed for 12 weeks, and segments of thoracic aorta used to assess vascular function. Vessels from the SHR displayed a spontaneous constrictor response after the inhibition of endothelial cell nitric oxide (NO) with N(omega)-nitro-L-arginine (NOLA). Dietary alpha -linoleate enrichment led to a reduction (P<0.05) in this abnormality with a dietary n-3/n-6 PUFA ratio of 1.0 (blend-1) yielding the best outcome. Relaxation to acetylcholine (ACh) was unaffected by dietary lipid supplementation. NOLA treated rings also displayed contractions to ACh that were abolished by indomethacin, thromboxane antagonists SQ29548, picotamide and flavonoids kaempferol and quercetin. In contrast, alpha-tocopherol, rutin and the lipoxygenase inhibitor esculetin resulted in only partial (30-55%) inhibition, and were ineffective against the NOLA-induced contraction suggesting the operation of different biochemical mechanisms in mediating the spontaneous and Ach-induced contractions. Results implicate plant-based oils and antioxidants as potential modulators of vascular function.
Abeywardena, M. Y. and R. J. Head (2001). "Longchain n-3 polyunsaturated fatty acids and blood vessel function." Cardiovasc Res 52(3): 361-71.
The cardiovascular health benefits of longchain n-3 polyunsaturated fatty acids (PUFAs) have been reported to exert at several different cellular control mechanisms. These include, effects on lipoprotein metabolism, haemostatic function, platelet/vessel wall interactions, anti-arrhythmic actions and also inhibition of proliferation of smooth muscle cells and therefore growth of the atherosclerotic plaque. Fish oil feeding has also been found to result in moderate reductions in blood pressure and to modify vascular neuroeffector mechanisms. The majority of such cardiovascular benefits of n-3 PUFAs are likely to be mediated in the vascular wall and at the vascular endothelium level, since this monolayer of cells plays a central role in the regulation and maintenance of cardiovascular homeostasis and function. While these processes include endothelium-derived vasorelaxant and vasoconstrictor compounds, the vascular endothelium also plays host to many receptors, binding proteins, transporters and signalling mechanisms. Accordingly, endothelial dysfunction, which underlies many cardiovascular disease conditions, can trigger acute vascular events including vasospasm, thrombosis or restenosis leading to ischaemia. The longchain n-3 PUFAs have been reported to possess several properties that may positively influence vascular function. These include favourable mediator profiles (nitric oxide, eicosanoids) that influence vascular reactivity, change in vascular tone via actions on selective ion channels, and maintenance of vascular integrity. In addition to direct effects on contractility, n-3 PUFAs may affect vascular function, and the process of atherogenesis, via inhibition of vascular smooth muscle cell proliferation at the gene expression level, and by modifying expression of inflammatory cytokinesis and adhesion molecules. Collectively, these properties are consistent with pleiotropic actions of longchain n-3 PUFAs, and may explain the beneficial cardiovascular protection of this family of fatty acids that have been clearly evident through epidemiological data as well from more recent large-scale clinical trials.
Sasaki, T., Y. Kanke, et al. (2000). "Dietary n-3 polyunsaturated fatty acid and status of immunocompetent cells involved in innate immunity in female rats." Ann Nutr Metab 44(1): 38-42.
The aim of this study was to estimate the contributions of dietary n-3 polyunsaturated fatty acid (PUFA), a representative dietary immunosuppressant, to the activity of both alveolar macrophages (AM) and natural killer (NK) cells, and compare them to those of n-6 PUFA. Twelve 5-week-old female Sprague-Dawley rats were divided into two dietary groups, one fed a 10% fat diet for 9 weeks enriched with n-3 PUFA (n-3 diet) and the other an n-6 PUFA (n-6 diet). AM reduced the release of nitric oxide, monocyte chemoattractant protein 1 and tumor necrosis factor alpha in the rats fed the n-3 diet, compared with rats fed the n-6 diet. NK cell activity was reduced by consumption of the n-3 diet. This study suggests that consumption of n-3 PUFA can ameliorate pulmonary inflammatory disorders which are affected by the reduction of not only proinflammatory cytokines but also chemokine released from AM.
Manjari, V. and U. N. Das (2000). "Effect of polyunsaturated fatty acids on dexamethasone-induced gastric mucosal damage." Prostaglandins Leukot Essent Fatty Acids 62(2): 85-96.
BACKGROUND: Increased dietary intake of polyunsaturated fatty acids (PUFAs) is known to be associated with a decrease in the incidence of peptic ulcer disease possibly due to increase in the synthesis of prostaglandins. But, it is also likely that conversion of PUFAs to PGs may not always be required for gastric mucosal protection. Present study was designed to study the role of PUFAs in pathobiology of steroid induce gastric damage in rats. METHODS: Wistar rats were treated with 5 mg/kg bodyweight of dexamethasone to induce gastric mucosal ulcers. Effects of PUFAs was studied by supplementation of Fish oil (rich in n-3 EPA and DHA) and AA rich oil. Famotidine was used as a positive control. Generation of lipid peroxides, nitric oxide and the activity of anti-oxidant enzymes were also studied. RESULTS: Dexamethasone induced ulceration was associated with changes in the phospholipid fatty acid profile, levels of lipid peroxidation products, nitric oxide and activity of anti-oxidant enzymes. The fatty acid profile showed an increase in LA and a decrease in other PUFAs like GLA, AA, EPA and DHA. When PUFAs were supplemented in the form of Fish oil and AA rich oil or when the animals were treated with H2-blocker, famotidine, there was a decrease in the incidence of ulceration in the animals associated with near normalization of changes in the phospholipid fatty acid profile. The levels of lipid peroxides, nitric oxide, and anti-oxidant activity also reverted to control values. CONCLUSIONS: Dexamethasone induced gastric ulceration was prevented by PUFAs. This is supported by the results of our earlier study where in it was noted that in patients with DU plasma lipid peroxides, nitric oxide and phospholipid fatty acid pattern and red cell antioxidant activity were altered similar to those seen in dexamethasone treated group of the present study. These abnormalities, similar to the PUFA treated groups of the present study, reverted to normalcy following treatment of the patients with lansoprazole, a proton pump inhibitor. Further, PUFAs are known to inhibit the growth of Helicobacter pylori in vitro. Hence, it is concluded that PUFAs, free radicals, nitric oxide and anti-oxidants play a significant role in the pathobiology of peptic ulcer.
Ferrara, L. A., A. S. Raimondi, et al. (2000). "Olive oil and reduced need for antihypertensive medications." Arch Intern Med 160(6): 837-42.
BACKGROUND: The blood pressure (BP) effects of changing the total fat intake and saturated-unsaturated fat ratio are still controversial, despite evidence that saturated fat-enriched diets are associated with higher BP levels. This double-blind, randomized crossover study evaluated a possible difference between antihypertensive effects of monounsaturated (MUFA) (extra-virgin olive oil) and polyunsaturated fatty acids (PUFA) (sunflower oil). METHODS: Twenty-three hypertensive patients were assigned randomly to MUFA or PUFA diet for 6 months and then crossed over to the other diet; effects were evaluated on the basis of daily antihypertensives needed. RESULTS: Diets high in MUFA and PUFA differed from the habitual diet for reduced total and saturated fats, whereas they differed from each other for MUFA (17.2% vs 10.5%) and PUFA content (3.8% vs 10.5%). Resting BP was significantly lower (P = .05 for systolic BP; P = .01 for diastolic BP) at the end of the MUFA diet compared with the PUFA diet. Blood pressure responses during sympathetic stimulation with the cold pressor test and isometric exercise were similar. Daily drug dosage was significantly reduced during the MUFA but not the PUFA diet (-48% vs - 4%, P<.005). All patients receiving the PUFA diet required antihypertensive treatment, whereas 8 of those receiving the MUFA diet needed no drug therapy. CONCLUSIONS: A slight reduction in saturated fat intake, along with the use of extra-virgin olive oil, markedly lowers daily antihypertensive dosage requirement, possibly through enhanced nitric oxide levels stimulated by polyphenols.
Das, U. N. (2000). "Free radicals, cytokines and nitric oxide in cardiac failure and myocardial infarction." Mol Cell Biochem 215(1-2): 145-52.
Myocardial infarction is the most common cause of congestive cardiac failure. Free radicals, cytokines, nitric oxide (NO) and antioxidants play a major role both in atherosclerosis and myocardial damage and preservation. In the early stages of atherosclerosis, neutrophils and monocytes infiltrate the intima and generate free radicals which damage the endothelial cells. As a result, production of NO and prostacyclin by the endothelial cells declines, which have cardioprotective actions. This also has relevance to the beneficial action of aspirin since, it can modulate both prostanoid and L-arginine-NO systems and NF-kB translocation. In both acute myocardial infarction and chronic congestive cardiac failure, the plasma levels of various inflammatory mediators such as interleukins and tumour necrosis factor-alpha (TNFalpha) are elevated. TNFalpha, produced by the inflammatory cells and the myocardium, can suppress myocardial contractility and induce the production of free radicals, which in turn can further damage the myocardium. Transforming growth factor beta (TGFbeta), polyunsaturated fatty acids and the glucose-insulin-potassium regimen can antagonize the harmful actions of TNFalpha and protect the myocardium. This explains why efforts made to reduce the levels of pro-inflammatory cytokines have beneficial action and preserve the myocardium.
Balazy, M. (2000). "Trans-arachidonic acids: new mediators of inflammation." J Physiol Pharmacol 51(4 Pt 1): 597-607.
Inflammation and many other pathological processes lead to increased production of free radicals that target critical macromolecules such as proteins, DNA and lipids. Structural modifications of these molecules, induced by free radicals, typically result in alterations of vital biochemical processes. Hydroxyl radical-initiated lipid peroxidation is known to generate a variety of toxic oxidized lipids, many of which originate from polyunsaturated fatty acids esterified to cellular membrane phospholipids. Recent interests have focused on a group of lipids known as isoeicosanoids that are formed from peroxidation of arachidonic acid, and share structural similarity to enzymatically-derived prostaglandins and leukotrienes. However, little is known about lipid peroxidation processes initiated by nitrogen free radicals. NO2 is a toxic free radical and an abundant urban air pollutant, which is also generated in vivo from oxidations of nitric or nitrite and decomposition of peroxynitrite. The NO2-induced lipid peroxidation mechanisms involving arachidonic acid have not been characterized. Described here is the isomerization of arachidonic acid, a new process induced by NO2, which leads to a mixture of trans-arachidonic acids. We observed that the levels of trans-arachidonic acids in rat plasma increased following infusion of bacterial endotoxin; therefore, the isomerization of arachidonic acid is likely to occur in vivo by a mechanism involving NO2.