Sambasiva R. Chavali

Dietary α-linolenic acid increases TNF-α, and decreases IL-6, IL-10 in response to LPS: effects of sesamin on the Δ-5 desaturation of ω6 and ω3 fatty acids in mice

Abstract Sesamin (a non-fat portion of sesame seed oil) inhibits Δ-5 desaturase activity resulting in an accumulation of dihomo-γ-linolenic acid (DGLA) which can displace arachidonic acid (AA) and decrease the formation of pro-inflammatory mediators. We investigated the effects of consumption of diets containing 0.25wt% sesamin and 15 wt% safflower oil (SO) (providing 12% of the added fat as linoleic acid) or a 15 wt% 2:1 mixture of linseed oil and SO (LOSO) (providing 6% α-linolenic acid and 6% linoleic acid) for 3 weeks on the liver membrane fatty acid composition and on the production of prostaglandin (PG) E 2 , TNF-α, IL-6 and IL 10 in mice. Consumption of sesamin-supplemented SO and LOSO diets resulted in a significant increase in the levels of 20:3ω6 (DGLA), suggesting that sesamin inhibited Δ-5 desaturation of ω6 fatty acids. In animals fed LOSO diets, the levels of α-linolenic acid, eicosapentaenoic acid (EPA) and of docosahexaenoic acid (DHA) were elevated with a concomitant decrease of arachidonic acid (AA) in the liver membrane phospholipids. Further, in animals fed LOSO diets with or without sesamin, an increase in the circulating levels of TNF-α was associated with a concomitant decrease in PGE 2 . Despite a lack of differences in the levels of AA, the PGE 2 levels were significantly lower in mice fed sesamin-supplemented SO compared to those fed SO alone. Thus, these data suggest that irrespective of the availability of a specific fatty acid as a substrate, through regulating the PGE 2 synthesis, the production of TNF-α could be modulated.

Increased survival after cecal ligation and puncture in mice consuming diets enriched with sesame seed oil.

ObjectivesLignans that present in the nonfat portion of sesame seed oil (SSO) can inhibit &Dgr;-5 desaturase activity, resulting in an increase in the accumulation of dihomo-&ggr;-linolenic acid and, subsequently, decrease the production of proinflammatory dienoic eicosanoids with a concomitant increase in the secretion of less inflammatory monoenoic eicosanoids. DesignFemale Balb/c mice were fed diets supplemented with 5wt% SSO or a physical mixture of oils (control) whose fatty acid composition resembled that of SSO for 3 wks. Measurements and Main Results During a 4-day observation period after cecal ligation and puncture, only 20% of the controls and as many as 65% in the SSO group survived. Furthermore, the levels of cytokines and dienoic eicosanoids produced in response to an intraperitoneal injection of a nonlethal dose (50 &mgr;g/mouse) of endotoxin were measured in both groups. The interleukin (IL)-10 levels were markedly higher in mice fed SSO diets compared with the controls. However, the plasma concentrations of prostaglandin E1 + 2, tumor necrosis factor-&agr;, IL-6, and IL-12 did not differ significantly between the two groups of mice. ConclusionsBecause the fatty acid composition is almost similar between the two diets, sesamin, sesamol and other lignans in SSO appear to be responsible for an increase in survival after cecal ligation and puncture and also for an increase in the IL-10 levels in response to a nonlethal dose of endotoxin in mice.

Effect of a fish oil structured lipid-based diet on prostaglandin release from mononuclear cells in cancer patients after surgery.

BACKGROUND The authors compared the effect on eicosanoid production (prostaglandin E2 [PGE2], 6-keto PGF 1 alpha, and thromboxane B2) from peripheral blood mononuclear cells (PBMC) of feeding an enteral diet containing a fish oil/medium-chain triglyceride structured lipid (FOSL-HN) vs an isonitrogenous, isocaloric formula (O-HN) in patients undergoing major abdominal surgery for upper gastrointestinal malignancies. A previous study, which used the same formulas and experimental design, suggested improved renal and liver function as well as a reduced number of gastrointestinal and infectious complications with the use of fish oil structured lipids. This study sought to investigate the potential mechanism for these effects by assessing eicosanoid production from PBMC with the two diets. METHODS This prospective, blinded, randomized trial was conducted in 20 patients who were jejunally fed either FOSL-HN or O-HN for 7 days. Serum chemistries, hematology, urinalysis, gastrointestinal complications, liver and renal function, and eicosanoid production from isolated PBMC, either unstimulated or stimulated with endotoxin, were measured at endotoxin baseline and on day 7. Comparisons were made in 10 and 8 evaluable patients based a priori on the ability to reach a tube feeding rate of > 40 mL/h. RESULTS Patients receiving FOSL-HN experienced no untoward side effects compared with patients given O-HN and demonstrated the same general trend toward improved hepatic, renal and immune function found in the previous study. There was a significant reduction in PGE2 (p < .03) and 6-keto PGF 1 alpha (p < .01) production from PBMC with endotoxin stimulation in patients receiving FOSL-HN. CONCLUSIONS The results of early enteral feeding with FOSL-HN after surgery in this follow-up study provide further support to claims of safety, tolerance, and improved physiologic function. There was an associated reduction in eicosanoid production from PBMCs, which is presumed to be the principal mechanism for these effects.

Decreased Production of lnterleukin-1-Beta, Prostaglandin-E2 and Thromboxane-B2, and Elevated Levels of lnterleukin-6 and -10 Are Associated with Increased Survival during Endotoxic Shock in Mice Consuming Diets Enriched with Sesame Seed Oil Supplemented with Quil-A Saponin

Sesamin, present in sesame seed oil (SSO), can inhibit delta-5-desaturase activity and cause accumulation of dihomo-gamma-linolenic acid (DGLA), which displaces arachidonic acid, and subsequently decrease production of dienoic eicosanoids. The effects of diets containing both SSO and Quil A, a saponin that emulsifies fats and potentiates the immune responses, were also studied. A mixture of oils having a fatty-acid composition similar to that of SSO served as a control diet. The levels of docosapentaenoic acid in mice fed Quil-A-supplemented diets and of DGLA in those fed SSO diets were markedly higher in the liver. These changes were associated with a significant reduction in the plasma prostaglandin-E(1+2) and thromboxane-B2 levels in response to an intraperitoneal injection of a lethal dose of lipopolysaccharide (LPS) endotoxin (LD50 20 mg/kg). The levels of interleukin (IL-)6 were elevated and those of IL-1beta were decreased in mice consuming Quil-A-supplemented diets. The IL-10 levels that were elevated in all mice after LPS exposure, remained higher (even at 9 h) only in those fed Quil-A-supplemented diets, but declined rapidly in others. During a 48-hour observation period following LPS injection, all control animals died, and survival was 40% in the SSO group, and 27 and 50%, respectively, in those fed Quil-A-supplemented control and SSO diets. These data suggest that SSO and Quil A when present in the diet exerted cumulative effects that resulted in a decrease in the levels of dienoic eicosanoids with a reduction in IL-1beta and a concomitant elevation in the levels of IL-10 that were associated with a marked increase in survival in mice.

Dietary fish oil and cytokine and eicosanoid production during human immunodeficiency virus infection

BACKGROUND Dietary fish oil (FO) has been shown to modulate the immune system. The purpose of this study was to explore the effects of FO supplementation on the production of dienoic eicosanoids and cytokines in patients with human immunodeficiency virus (HIV) infection. METHODS This was a randomized, prospective, double-blind study that included homosexual males with HIV infection. Patients were asked to consume voluntarily five food bars daily containing FO (n = 10) or safflower oil (SO) (n = 9) for 6 weeks. At baseline and week 6, plasma was obtained to measure incorporation of omega-3 fatty acids. At baseline, week 3, and week 6, measurements were made of changes in dienoic eicosanoids and cytokines from lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMC) or spontaneously releasing cells. RESULTS In the FO group but not the SO group, there was increased incorporation of the omega-3 fatty acid docosahexaenoic acid (DHA) into the phospholipids of the fatty acids of the plasma. In the FO group, there was a significant decrease (p = .01) in 6-keto prostaglandin (PG) F1 alpha released from PBMC. There was a significant increase (p = .01) in interleukin (IL)-6 released from the PBMC in the FO group between baseline and week 3 and between week 3 and week 6. At week 6, there was significantly more IL-6 (p = .01) released from the PBMC in the FO group compared with the SO group. There was no change in CD4 cell counts by analysis of variance. CONCLUSIONS The FO-containing food bars were well tolerated and allowed incorporation of omega-3 fatty acids to occur. Despite evidence of significant metabolic effects on eicosanoid and cytokine production, widespread clinical use of FO for HIV-infected patients is not warranted without further study, particularly given the trend toward a decline in CD4 cell numbers at this dose and with this type of fish oil.

Increased production of TNF-α and decreased levels of dienoic eicosanoids, IL-6 and IL-10 in mice fed menhaden oil and juniper oil diets in response to an intraperitoneal lethal dose of LPS

Eicosapentaenoic acid (EPA) and the non-methylene interrupted fatty acids (NMIFA) displace arachidonic acid (AA: 20:4omega6 -5,8,11,14) in the membrane phospholipids. Unlike EPA (20:5omega3 -5,8,11,14,17), the NMIFA (20:3omega6 -5,11,14 and 20:4omega3 -5,11,14,17) lacking the delta-8 double bond are not substrates for the formation of eicosanoids. For 20 days, the mice were fed diets containing 5wt% dietary fats from various sources. The magnitudes in the production of eicosanoids and cytokines produced in response to an intraperitoneal injection of endotoxin in mice fed menhaden fish oil (MO) diets enriched with EPA were compared with those maintained on juniper oil (JO) containing NMIFA or on safflower oil (SO), a major source of the AA precursor, linoleic acid. The levels of PGE2, 6-keto-PGF1alpha and TXB2 were markedly lower (P < 0.01) in animals fed either MO or JO diets compared to the controls. The plasma levels of tumor necrosis factor (TNF)-alpha were significantly higher (P < 0.05) with a concomitant decrease of interleukin (IL)-6 and of IL-10 in mice fed MO or JO diets (P < 0.01) compared to those fed SO diet. These data suggest that the effects of consuming NMIFA of JO despite their inability to form eicosanoids are similar to those of feeding EPA which forms biologically active alternate metabolites.

Effects of continuous tube feeding of dietary fat emulsions on eicosanoid production and on fatty acid composition during an acute septic shock in rats.

The effects of a short-term (5 days) continuous intragastric tube feeding of diets containing n - 6 polyunsaturated fatty acids (PUFA) from safflower oil (SO) or n - 3 PUFA from menhaden oil (MO) on the production of proinflammatory mediators, and on the number of animals surviving after an intravenous injection of lipopolysaccharide (LPS) were investigated in rats. The phospholipid fatty acid composition of cell membranes from several organs and of plasma were also analyzed. No marked differences in the number of animals surviving or in the production of tumor necrosis factor-alpha were observed between the 2 groups of animals. However, 90 min after LPS exposure the plasma levels of prostaglandin (PG) E2 and 6-keto-PGF1 alpha decreased significantly (40% and 60%, respectively) for the group of rats fed MO diet compared to those fed SO diet (P < 0.05). Following continuous infusion of liquid MO diet, the amount of arachidonic acid (AA) detected was significantly lower in plasma (23%), spleen (43%), lungs (41%), and liver (38%), but was unchanged in the heart tissues. The percent of eicosapentaenoic acid (EPA) incorporated into phospholipids of plasma, spleen, lungs, liver, and heart were 7.6, 4.4, 2.1, 7.2, and 1.1%, respectively. These data indicate that after continuous MO feeding, a significant decrease in the production of proinflammatory eicosanoids was associated with a marked reduction in AA content. Further, these data suggest that nutritional intervention may have a therapeutic potential to ameliorate clinical symptoms due to excessive productions of eicosanoids during acute septic complications.

Effect of prostaglandin E2 and other intracellular cyclic AMP elevating agents on the mitogen induced mouse splenocyte proliferation in a serum free culture condition.

Prostaglandins (PGs) play an important role in the regulation of the hosts immune responses to infection and inflammation. However, the mechanisms through which the PGs regulate immune functions are not well known. In the present study, we investigated the T cell specific mitogen Concanavalin A (Con A) induced mouse splenocyte proliferation in a serum free condition in vitro in the presence of absence of different doses of PGE2, indomethacin, cholera toxin and forskolin. The Con A induced splenocyte proliferative responses were significantly inhibited following the addition of PGE2 and were markedly enhanced in the presence of indomethacin (PG synthase inhibitor). As with PGE2, both cholera toxin and forskolin, which increase intracellular cyclic AMP by activating stimulatory GTP binding protein (Gs protein) and adenylate cyclase respectively, inhibited splenocyte proliferation in a dose dependent manner. These data indicate that PGE2 down regulated mitogen induced splenocyte proliferation and that blocking the production of endogenous PGs potentiated T-cell mitogen response. Further, these findings suggest that PGE2 regulation of splenocyte proliferation is due to increasing intracellular cAMP through G protein transmembrane regulation of adenylate cyclase. This study also provided a defined experimental model to investigate mechanisms of the regulation of cellular function through the exogenous and endogenous mediators such as PGs and their intracellular signal transductions.

Resting Energy Expenditure, Caloric Intake, and Short-Term Change in HIV Infection and AIDS C. GRUNFELD, M. PANGE, L. SHIMIZU, ET AL American Journal of Clinical Nutrition 55:455-460, 1992

Patients with AIDS often develop malignancies and secondary infections that cause weight loss. To examine the etiology of this weight loss, the investigators examined patients with HIV, AIDS, and AIDS plus secondary infection (AIDS-SI) for resting energy expenditure (REE), caloric intake, and short-term weight change over a 28-day period. Although caloric intake during that period for HIV positive and AIDS patients was similar to that of control subjects, it was 36% lower for AIDS-SI patients. The HIV positive and AIDS subjects showed no short-term change in weight, whereas the AIDS-SI subjects demonstrated a 5% weight loss. The HIV positive, AIDS, and AIDS-SI groups exhibited an increase over controls in REE of 11%, 25%, and 29%, respectively. Thus, the AIDS-SI patients consumed 17% fewer calories than would be needed to support the elevated REE, which accounted for the weight loss over the 28 days. Consequently, a hypermetabolic effect caused by the existence of a secondary infection coupled with the HI...