A Mixture of Polyunsaturated Fatty Acids ω-3 and ω-6 Reduces Melanoma Growth by Inhibiting Inflammatory Mediators in the Murine Tumor Microenvironment.

BACKGROUND: Although it has been previously demonstrated that acute inflammation can promote the tumor growth of a sub-tumorigenic dose of melanoma cells through of 5-lipoxygenase inflammatory pathway and its product leukotriene B4, and also that the peritumoral treatment with eicosapentaenoic acid and its product, leukotriene B5, reduces the tumor development, the effect of the treatment by gavage with omega-3 and omega-6 in the tumor microenvironment favorable to melanoma growth associated with acute inflammation has never been studied. METHODS: C57BL/6 mice were coinjected with 1 × 106 apoptotic cells plus 1 × 103 viable melanoma cells into the subcutaneous tissue and treated by gavage with omega-3-rich fish oil or omega-6-rich soybean oil or a mixture of these oils (1:1 ratio) during five consecutive days. RESULTS: The treatment by gavage with a mixture of fish and soybean oils (1:1 ratio) both reduced the melanoma growth and the levels of leukotriene B4 (LTB4), prostaglandin E2 (PGE2), PGE2/prostaglandin E3 (PGE3) ratio, and CXC ligand 1 (CXCL1) and increased the levels of interleukin 10 (IL-10) to IL-10/CXCL1 ratio in the melanoma microenvironment. CONCLUSION: The oral administration of a 1:1 mixture of fish oil and soybean oil was able to alter the release of inflammatory mediators that are essential for a microenvironment favorable to the melanoma growth in mice, whereas fish oil or soybean oil alone was ineffective.

L-arginine abolishes the hypothalamic serotonergic activation induced by central interleukin-1ß administration to normal rats.

IL-1ß-induced anorexia may depend on interactions of the cytokine with neuropeptides and neurotransmitters of the central nervous system control of energy balance and serotonin is likely to be one catabolic mediator targeted by IL-1ß. In the complex interplay involved in feeding modulation, nitric oxide has been ascribed a stimulatory action, which could be of significance in counteracting IL-1ß effects.The present study aims to explore the participation of the nitric oxide and the serotonin systems on the central mechanisms induced by IL-1ß and the relevance of their putative interactions to IL-1ß hypophagia in normal rats.Serotonin levels were determined in microdialysates of the ventromedial hypothalamus after a single intracerebroventricular injection of 10 ng of IL-1ß , with or without the pre-injection of 20 µg of the nitric oxide precursor L-arginine. IL-1ß significantly stimulated hypothalamic serotonin extracellular levels, with a peak variation of 130 ± 37% above baseline. IL- 1ß also reduced the 4-h and the 24-h food intakes (by 23% and 58%, respectively). The IL-1ß-induced serotonergic activation was abolished by the pre-injection of L-arginine while the hypophagic effect was unaffected.The data showed that one central effect of IL-1ß is serotonergic stimulation in the ventromedial hypothalamus, an action inhibited by nitric oxide activity. It is suggested that, although serotonin participates in IL-1ß anorexia, other mechanisms recruited by IL-1ß in normal rats are able to override the absence of the serotonergic hypophagic influence.

Soybean and fish oil mixture increases IL-10, protects against DNA damage and decreases colonic inflammation in rats with dextran sulfate sodium (DSS) colitis.

It was investigated whether dietary polyunsaturated fatty acids (PUFA) could influence colonic injury, tissue DNA damage, cytokines and myeloperoxidase activity (MPO) and plasma corticosterone in DSS-induced colitis rats. Male weaning Wistar rats were fed for 47 days with an AIN-93 diet with control (C), fish (F) or a mixture of fish and soybean oil (SF). The colitis was induced from day 36 until day 42 by 3% DSS in drinking water. On day 48, blood samples were collected for corticosterone determination. The distal colon was excised for histological analysis and to quantify the cytokine (IL-4, IL-10 and INF-gamma), MPO and DNA damage. The disease activity index (DAI) was recorded daily during colitis induction. The DAI, MPO, histological analyses showed decreases only in the SF group compared with the C group. IL-10 was increased and DNA damage was reduced in the groups F and SF, and an inverse correlation between these variables was found. There were no differences in corticosterone, IFN-gamma and IL-4 levels. Soybean and fish oil mixture may be effective in improving colonic injury and DNA damage, and it could be an important complementary therapy in UC to reduce the use of anti-inflammatory drugs and prevent colorectal cancer.

Glycosaminoglycans affect the action of human plasma kallikrein on kininogen hydrolysis and inflammation.

Human plasma kallikrein (huPK) is a serine proteinase involved in many biological processes including those of the kallikrein-kinin system. The action of huPK on kininogen results in bradykinin (BK) release, a potent mediator of inflammatory responses. BK generation may be influenced by several agents, and the aim of this work was to investigate the effect of glycosaminoglycans (GAGs) on human high-molecular-weight kininogen (HK) hydrolysis by huPK and on inflammation. huPK was pre-incubated in the absence and presence of different GAGs, followed by the addition of kininogen. Bradykinin released at different times was measured by radioimmunoassay, and KM and kcat were calculated. Tuna and bovine dermatan sulfates, the most potent GAGs studied, reduced by 80% and 68%, respectively, the catalytic efficiency of huPK (control = 4. x 10(4) M(-1) s(-1) in BK release. The effect of bovine dermatan sulfate (BDS) on inflammatory response was studied in rat paw edema induced by carrageenin and hourly determined (1-4 h) by plethysmography. BDS significantly reduced the inflammatory response in the first and second hours of measurements (24% and 28%, respectively), p < 0.05. GAGs were shown to reduce bradykinin release "in vitro" and in an inflammation model. This reduction may play a role in the control or maintenance of some pathological and physiological processes.

Diets rich in polyunsaturated fatty acids: effect on hepatic metabolism in rats.

OBJECTIVE: We investigated the effect of diets rich in omega-6 and omega-3 fatty acids on hepatic metabolism. METHODS: Male Wistar rats, just weaned, were fed ad libitum for 8 wk with one of the following diets: rat chow (C), rat chow containing 15% (w/w) soybean oil (S), rat chow containing 15% (w/w) fish oil (F), and rat chow containing 15% soy bean and fish oil (SF; 5:1, w/w). Casein was added to the fatty diets to achieve the same content of protein (20%) as the control chow. The rats were killed by decapitation, and the hepatic tissue was removed and weighed. Tissue lipid, glycogen, and protein content, in vivo lipogenesis rate, and adenosine triphosphate citrate lyase and malic enzyme activities were evaluated. Plasma total lipids, triacylglycerol, and cholesterol concentrations were assessed. RESULTS: Body weight gain was higher in F and SF than in C and S rats. Liver weight, lipid content, and lipogenesis rate increased in F and SF rats, although adenosine triphosphate citrate lyase activity decreased. Glycogen concentration decreased in S, F, and SF rats compared with C rats. Plasma total lipids and triacylglycerol concentrations were lower in F and SF than in C rats. Total and high-density lipoprotein cholesterol (HDL-C) plasma levels decreased in F rats, with maintenance of the total:HDL-C ratio. In SF rats, an increase in HDL-C led to a lower total:HDL-C ratio. CONCLUSIONS: These results indicated that an enrichment of the diet with omega-3 polyunsaturated fatty acids produces hypolipidemia but may cause changes in liver metabolism that favor lipid deposition. They also suggested that the addition of a small amount of eicosapentaenoic and docosahexaenoic polyunsaturated fatty acids to an omega-6-rich diet further improve the circulating lipid profile, in comparison with an omega-3-rich diet, but it does not prevent excess liver lipid accumulation.

Participation of corticosteroids and effects of indomethacin on the acute inflammatory response of rats fed n-6 or n-3 polyunsaturated fatty acid-rich diets.

We have previously shown that both n-3 (fish oil) and n-6 (soybean oil) PUFA-rich diets reduce carrageenan-induced paw edema in rats. The present study evaluated the role of corticosteroids, and the effect of indomethacin on this response. Basal (pre-carrageenan) levels of corticosterone were elevated in both lipid diets compared to the chow diet. During inflammation, corticosterone levels increased to a similar extent in the chow and lipid diets. With 2.0 mg/kg indomethacin, edema was reduced in the chow diet and the n-3 diet, while it was not changed in the n-6 diet. In contrast, the 16.6 mg/kg dose of indomethacin induced a mild increase in edema in the chow diet but a pronounced edema increase in the lipid diets. The increase in corticosterone levels induced by carrageenan was either reduced (chow) or completely abolished (lipids) by the treatment with the higher dose of indomethacin, compared to both the control (untreated) group, and the lower dose of indomethacin. These data indicate that both acute inflammation and the response to an antiinflammatory drug were attenuated by n-3 or n-6 PUFA-rich diets. They also showed that indomethacin can have anti- or proinflammatory properties reflecting the extent of the corticosterone inhibition by indomethacin.

Fatty acids in plasma, white and red blood cells, and tissues after oral or intravenous administration of fish oil in rats.

BACKGROUND & AIMS: The importance of route of administration of omega-3 (n-3) polyunsaturated fatty acids (PUFA) (oral vs intravenous (iv)) is not clear. We determined the relative concentrations of fatty acids in plasma phosphatidylcholine (PC), red blood cells (RBC), white blood cells (WBC) and several tissues after short-term oral or iv administration of soybean oil (SO) or fish oil (FO). METHODS: Wistar rats (n = 6/group) received saline, FO, or SO by gavage or saline, FO based-lipid emulsion (FLE), or SO based-lipid emulsion (SLE) iv. The oils were provided at 0.2 g/kg/day for three consecutive days. The animals were sacrificed 24 h after the last administration, blood was collected for plasma, WBC and RBC separation and tissues removed. Fatty acids were analysed by gas chromatography. RESULTS: FO resulted in higher eicosapentaenoic acid (EPA) in plasma PC and liver than the control. FLE resulted in higher EPA, docosahexaenoic acid (DHA) and total n-3 PUFA in plasma PC, WBC and liver than both the control and SLE groups. EPA, DHA and total n-3 PUFA were higher in the heart with FLE compared with SLE. Individual and total n-3 PUFA were higher in plasma PC, WBC, liver and heart with FLE than with FO given by gavage. CONCLUSION: Short-term iv administration of n-3 PUFA appears to be more effective at increasing EPA and DHA status in plasma, WBC, liver and heart than oral administration. This might be important for rapid treatment with n-3 PUFA.

Acupuncture reduces immune-mediated pulmonary inflammatory lesions induced in rats.

INTRODUCTION: The aim of this report was to experimen-tally demonstrate the biological actions of acupuncture in an animal model of immune-mediated inflammation associated with a deposition of collagen. MATERIALS AND METHODS: Male Wistar rats were sensitized by a subcu-taneous implant of heat-solidified hen egg-white and divided into 4 groups: acupuncture, sham acupuncture, immobilized, and control. Acupuncture was initiated the day after sensitization and repeated twice a week for 3 weeks. The dorsal acupoints chosen were GV-14 and BL-13, the ventral acupuncture points were LU-1, CV-17, ST-36 and SP-6. The dorsal points were stimulated manually and the ventral ones by electroacupuncture. On day 14, animals were challenged through the tail vein with Sepharose(R)beads coupled with ovalbumin. One week later, animals were bled, plasma corticoster-one concentrations were measured and the lungs were removed for histological evaluation. RESULTS: Measurement of the areas of pulmonary lesion on hematoxylin-eosin stained slides showed a significant decrease (p < 0.05) in the inflammatory infiltrate in the acupuncture group, compared to the other 3 groups. Utilization of Litt and Picrosirius staining methods, in order to better visualize the infiltrate of eosinophils and the deposition of collagen, respectively, showed that both were much less intense in the acupuncture group. Corticosterone plasma levels were similar in all groups. CONCLUSION: Point-specific acupuncture treatment effectively reduced the inflammatory process and the deposition of collagen around ovalbumin-Sepharose beads intravenously embolized to the lungs of rats previously sensitized with the same protein that was administered subcutaneously.