Alcohol Consumption-Related Metabolites in Relation to Colorectal Cancer and Adenoma: Two Case-Control Studies Using Serum Biomarkers.

Alcohol is a known carcinogen that may be associated with colorectal cancer. However, most epidemiologic studies assess alcoholic beverage consumption using self-reported data, leading to potential exposure misclassification. Biomarkers of alcohol consumption may provide an alternative, complementary approach that reduces misclassification and incorporates individual differences in alcohol metabolism. Therefore, we evaluated the relationship between previously identified alcohol consumption-related metabolites and colorectal cancer and adenoma using serum metabolomics data from two studies. Data on colorectal cancer were obtained from a nested case-control study of 502 US adults (252 cases, 250 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Data on colorectal adenoma were obtained from a case-control study of 197 US adults (120 cases, 77 controls) from the Navy Colon Adenoma Study. Unconditional multivariable logistic regression models were fit to calculate odds ratios (OR) and 95% confidence intervals (CI) for eight alcohol consumption-related metabolites identified in a previous analysis: ethyl glucuronide; 4-androstene-3beta,17beta-diol disulfate 1; 5-alpha-androstan-3beta,17beta-diol disulfate; 16-hydroxypalmitate; bilirubin (E,Z or Z,E); cyclo (-leu-pro); dihomo-linoleate (20:2n6); and palmitoleate (16:1n7). We found no clear association between these alcohol consumption-related metabolites and either endpoint. However, we did observe an inverse association between cyclo (-leu-pro) and colorectal adenoma that was only observed in the highest metabolite quantile (OR 4th vs. 1st Quantile = 0.30, 95% CI: 0.12-0.78; P-trend = 0.047), but no association for colorectal cancer. In conclusion, there were no adverse associations between alcohol consumption-related metabolites and colorectal cancer or adenoma.

Oleic acid content of a meal promotes oleoylethanolamide response and reduces subsequent energy intake in humans.

Animal data suggest that dietary fat composition may influence endocannabinoid (EC) response and dietary behavior. This study tested the hypothesis that fatty acid composition of a meal can influence the short-term response of ECs and subsequent energy intake in humans. Fifteen volunteers on three occasions were randomly offered a meal containing 30 g of bread and 30 mL of one of three selected oils: sunflower oil (SO), high oleic sunflower oil (HOSO) and virgin olive oil (VOO). Plasma EC concentrations and appetite ratings over 2 h and energy intake over 24 h following the experimental meal were measured. Results showed that after HOSO and VOO consumption the circulating oleoylethanolamide (OEA) was significantly higher than after SO consumption; a concomitantly significant reduction of energy intake was found. For the first time the oleic acid content of a meal was demonstrated to increase the post-prandial response of circulating OEA and to reduce energy intake at subsequent meals in humans.

Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.

Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia.

Role of osteopathic manipulative treatment in altering pain biomarkers: a pilot study.

CONTEXT: Underlying mechanisms explaining the effects of osteopathic manipulative treatment (OMT) are poorly defined. The authors evaluate various nociceptive (pain) biomarkers that have been suggested as important mediators in this process. OBJECTIVE: To determine if OMT influences levels of circulatory pain biomarkers. METHODS: In a prospective, blinded assessment, blood was collected from 20 subjects (10 with chronic low back pain [LBP], 10 controls without chronic LBP) for 5 consecutive days. On day 4, OMT was administered to subjects 1 hour before blood collection. Blood was analyzed for levels of beta-endorphin (betaE), serotonin (5-hydroxytryptamine [5-HT]), 5-hydroxyindoleacetic acid (5-HIAA), anandamide (arachidonoylethanolamide [AEA]), and N-palmitoylethanolamide (PEA). A daily questionnaire was used to monitor confounding factors, including pain and stress levels, sleep patterns, and substance use. RESULTS: Increases from baseline in betaE and PEA levels and a decrease in AEA levels occurred immediately posttreatment. At 24 hours posttreatment, similar biomarker changes from baseline were observed. A decrease in stress occurred from baseline to day 5. The change in PEA from baseline to 24 hours posttreatment correlated with the corresponding changes in stress. Subgroup analysis showed that subjects with chronic LBP had significantly reduced 5-HIAA levels at 30 minutes posttreatment (P=.05) and 5-HT levels at 24 hours posttreatment (P=.02) when compared with baseline concentrations. The increase in PEA in subjects with chronic LBP at 30 minutes posttreatment was two times greater than the increase in control subjects. CONCLUSION: Concentrations of several circulatory pain biomarkers were altered after OMT. The degree and duration of these changes were greater in subjects with chronic LBP than in control subjects without the disorder.

Parenteral feeding alters the fatty acid composition of serum phospholipids of rabbits.

BACKGROUND: Cholestatic liver disease develops in 30% to 70% of neonates receiving total parental nutrition (TPN). We analyzed the fatty acid composition of serum phospholipids from control and TPN-fed rabbits to determine if TPN altered the fatty acid profile. METHODS: Eleven male New Zealand White rabbits aged 9 to 11 weeks received TPN, whereas 11 other rabbits were offered standard laboratory rabbit chow ad libitum. After 14 days on the prescribed diet, serum samples were analyzed for their phospholipid fatty acid content by gas chromatography. RESULTS: The proportions of palmitolenic (16:2n7), alpha-linolenic (18:3n3), arachidic (20:0), and eicosaenoic (20:1n9) acids were significantly lower in the serum phospholipids of the TPN-fed animals compared with the control group. The proportion of docosahexaenoic acid (22:6n3), a fatty acid that is critical to the development of the nervous system, was increased two- to threefold. CONCLUSIONS: The differences in proportions of fatty acids observed between control and TPN-fed animals indicate that a fatty acid elongation and desaturation pathways are perturbed in rabbits on TPN.

Impact of portacaval anastomosis on plasma fatty acid profile in cirrhosis: a randomized 24-month follow-up study.

BACKGROUND: Portacaval anastomosis has an hypolipemic effect in familial hypercholesterolemia and in healthy animals. In cirrhosis, it raises serum cholesterol, but there is no information on its effect upon plasma fatty acids. However, indirect data suggest that portacaval shunting might contribute to the polyunsaturated fatty acid deficit of these patients. We assessed the effect of portacaval anastomosis on plasma fatty acid profile in cirrhosis. METHODS: Forty-four Child-Pugh class A/B bleeding cirrhotics were randomized to be treated with portacaval anastomosis (n = 20) or nonsurgical therapy (n = 24). Fatty acid profile in plasma total lipids, alcohol intake, anthropometry, Child-Pugh score, serum cholesterol, triglycerides, and antioxidant micronutrients were assessed before and 3, 6, 12, 18, and 24 months after surgery or the start of nonsurgical therapy. Time course of plasma fatty acids was assessed using unbalanced repeated measures models with the above mentioned variables acting as covariates. RESULTS: No changes in the time course of percent plasma saturated, monounsaturated, and essential fatty acids were found between groups. Percent long-chain omega-6 and omega-3 polyunsaturated fatty acids decreased during follow-up in shunted patients compared with controls (p = .007 and p < .0005). However, this was not due to a true decrease in polyunsaturated fatty acid levels but to greater increases in saturated and monounsaturated fatty acid concentrations in shunted patients compared with control patients (p = .047 and p = .006). CONCLUSIONS: Portacaval anastomosis does not worsen plasma polyunsaturated fatty acid deficiency in cirrhosis. However, by increasing saturated and monounsaturated fatty acids, it further decreases plasma lipid unsaturation.

Effects of ursodeoxycholic acid treatment on essential fatty acid deficiency in patients with biliary atresia.

To assess whether ursodeoxycholic acid (UDCA) treatment has any beneficial effect on essential fatty acid (EFA) deficiency in patients who have had a Kasai operation for extrahepatic atresia (EBA), responses of serum fatty acids to UDCA administration (15 mg/kg/d) were investigated in eight jaundice-free patients and in eight patients with jaundice (serum total bilirubin > or = 1.0 mg/dL). All patients were also given taurine supplementation (100 mg/kg/d). Serum fatty acid composition was determined before and 6 months after UDCA treatment. Serum total bile acid concentration and serum total bilirubin value, as a part of conventional liver function tests, were measured before and during UDCA therapy. Before UDCA treatment, the concentrations of linoleic acid and arachidonic acid were significantly lower (P > .05 for the former; P > .01 for the latter) in both the jaundice and jaundice-free groups than in the controls. After 6 months of treatment, the linoleic acid concentration significantly increased (P > .05), to the normal range, in the jaundice-free group, but not in the jaundice group. The arachidonic acid concentration did not increase significantly in either group. The serum total bile acid concentration was lower in six of the eight jaundice-free patients and in four of the eight jaundice patients. The serum total bilirubin value decreased in six of the eight jaundice-free patients and in four of the eight jaundice patients; however, the degree of improvement was not statistically significant in either group. No side effects developed, and there were no changes in blood chemistry values unrelated to liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Short report: zinc sulphate supplementation corrects abnormal erythrocyte membrane long-chain fatty acid composition in patients with Crohn's disease.

Patients with Crohn's disease may become zinc-deficient and, in such patients, an altered metabolism of radiolabelled long-chain fatty acids has been reported. We have investigated the possible reversal by zinc supplementation of altered long-chain fatty acid profiles of red cells in Crohn's disease. Twenty patients with long-standing Crohn's disease in clinical remission received 200 mg of zinc sulphate daily for 6 weeks. Phospholipid fatty acid profiles of washed red cells were analysed before and after zinc treatment and compared to those of 20 unsupplemented healthy controls. Plasma zinc levels in Crohn's were 72 +/- 8 micrograms/dL before zinc treatment and increased to 114 +/- 10 micrograms/dl after the therapy. Prior to zinc supplementation, the percentage of palmitic, stearic and oleic acids was significantly higher in Crohn's disease, while linoleic, arachidonic and n-3 fatty acids were reduced in Crohn's disease compared to healthy controls. Zinc supplementation abolished these pre-treatment differences in red-cell long-chain fatty acid profiles but did not affect plasma fatty acid values. Further studies are needed to clarify whether these fatty acid changes can be related to the clinical course of the disease.

Effects of intravenous methyl palmoxirate on the turnover and oxidation of fatty acids in conscious dogs.

Methyl palmoxirate (MP) is a member of a class of hypoglycemic agents that inhibit fatty acid oxidation in vitro. The studies presented here were undertaken to determine the effects of intravenous (IV) MP on tracer-determined rates of fatty acid oxidation and systemic adipose tissue lipolysis in dogs. MP (40 mg/kg) was administered IV to five mongrel dogs using a primed continuous infusion of [1-14C]palmitate to determine palmitate kinetics. Palmitate concentration and rate of appearance decreased rapidly (from 155 +/- 25 to 47 +/- 6 mumol/L and 2.9 +/- 0.5 to 0.9 +/- 0.2 mumol.kg-1.min-1, respectively, at 15 minutes, both P less than .05). Palmitate oxidation also decreased, from 1.5 +/- 0.4 to 0.3 +/- 0.1 mumol.kg-1.min-1, P less than .05. Oxidative clearance decreased by approximately 50% 90 minutes after MP administration (P less than .05). Fractional oxidation of palmitate also decreased by approximately 40% (P less than .05). Plasma insulin increased from 45 +/- 6 to 240 +/- 93 pmol/L at 15 minutes (P less than .05). Plasma glucose decreased over the course of study by approximately 20% (P less than .05). In summary, MP has a specific inhibitory effect on plasma free fatty acid (FFA) oxidation in dogs, confirming previous in vitro observations in an in vivo model. In addition, it has a potent antilipolytic effect when administered IV, an effect likely mediated by stimulation of insulin secretion. The observation that systemic FFA oxidation was only partially suppressed at this relatively high dose of MP is consistent with previous studies suggesting that MP may exert its major effect in the liver, and may be less potent in extrahepatic tissues.

Impaired triacylglycerol catabolism in hypertriglyceridemia of the diabetic, cholesterol-fed rabbit: a possible mechanism for protection from atherosclerosis.

The etiology of the hypertriglyceridemia in alloxan-diabetic rabbits was studied by two independent methods. Production and removal rates of VLDL triacylglycerol were measured in diabetic rabbits by injection of [3H]palmitate-labelled VLDL. Similarly, triacylglycerol total removal rates were determined in non-diabetic rabbits which were infused with Intralipid to mimic the plasma triacylglycerol concentrations of diabetic rabbits. Compared to nondiabetic rabbits, triacylglycerol removal rats were decreased in diabetic rabbits, particularly at higher levels of plasma triacylglycerol. During cholesterol and triacylglycerol supplementation of the diet, post-heparin plasma lipoprotein lipase activity of diabetic rabbits with severe hypertriglyceridemia averaged 36% of that of nondiabetics, suggesting an impaired triacylglycerol removal capacity. Furthermore, plasma triacylglycerol was inversely related to post-heparin plasma lipoprotein lipase activity among diabetic rabbits. VLDL triacylglycerol production increased with increasing plasma triacylglycerol concentration among diabetic cholesterol-fed rabbits with moderately severe hypertriglyceridemia, but reached an apparent plateau among rabbits with plasma triacylglycerol concentrations from approx. 2000-9000 mg/dl. Thus, severe hypertriglyceridemia in this model of insulin deficiency can be attributed only partially to VLDL hypersecretion, whereas a removal defect, resulting in saturation of the triacylglycerol removal mechanism, appears to be largely responsible. The impaired removal of plasma triacylglycerol is also related to the presence of cholesterol predominantly in lipoproteins of increased size. The data support the hypothesis that protection against atherosclerosis in cholesterol-fed diabetic rabbits results from exclusion of very large cholesterol-containing lipoproteins from the arterial wall.

Effects of linoleic acid and mitogenic stimulation on the fatty acid composition of human lymphocytes.

Perturbation of the fatty acid composition of human lymphocytes in vitro was investigated by addition of linoleic acid complexed to bovine serum albumin (BSA-LA) and by mitogenic stimulation with phytohaemagglutinin (PHA). BSA-LA resulted in a 45% increase in linoleic acid in phosphatidylethanolamine (PE) and over 100% in phosphatidylcholine (PC) in peripheral blood cells. Supplementation with BSA-LA in PHA-stimulated lymphocytes produced even greater changes: 100% increase in linoleic acid content for PE and over 300% for PC. There was a large decrease in oleic acid: 40% for PE and almost 100% in PC. Significant decreases in arachidonic acid occurred in both phospholipid fractions. PHA alone also altered membrane phospholipid fatty acid composition, with reductions in palmitic, stearic and linoleic acid for PE and increases in oleic acid and arachidonic acid (almost 100%). For PC, there were large decreases in stearic (40%), linoleic (30%) and arachidonic (40%) acids, together with an increase in oleic acid (65%). Cells supplemented with linoleic acid grown in the presence of PHA, compared with those grown in linoleic acid-supplemented medium alone, showed a 40% decrease in palmitic acid and a 55% increase in arachidonic acid in PE. For PC, there were large decreases in stearic acid (40%) and arachidonic acid (57%). Antibody-induced redistribution of surface molecules ('capping') was inhibited by some 14% after incubation with BSA-LA. However, no consistent alterations in PHA-induced cell proliferation were observed. These data suggest that profound alterations of membrane fatty acid composition occur spontaneously during the mitotic cycle, and may be further induced by experimental manipulation, without gross perturbation of cell function.

Essential fatty acid deficiency in premature infants.

To better characterize essential fatty acid (EFA) deficiency in neonates, we assessed 63 premature infants by serial determinations of plasma fatty acids for the level of linoleic acid, the presence of an abnormal trienoic acid (5,8,11-eicosatrienoic acid [20:3 omega 9]), and the ratio of this compound to arachidonic acid, ie, the triene-tetraene ratio. The data indicated that at age 7 d, 67% of these infants had low plasma linoleic acid levels, 62% showed readily detectable 20:3 omega 9, and 44% had a high triene-tetraene ratio. Infants fed by age 2 d had a normal mean linoleate level at 7 d and none showed detectable 20:3 omega 9 by 10 d. In contrast, infants who were not fed until 7 d showed a very high incidence of abnormal fatty acid status. By maintaining a daily record of linoleate intake, we calculated from regression models that the average amount required to achieve normal fatty acid nutrition was 1.19 g.kg-1.d-1.

The effects of essential fatty acid supplementation by Efamol in hyperactive children.

Thirty-one children, selected for marked inattention and overactivity, were studied in a double-blind, placebo-controlled crossover study of essential fatty acid (EFA) supplementation. Subjects received the active treatment and placebo conditions for 4 weeks each and were assessed on a variety of cognitive, motor, and standardized rating scale measures. EFA supplementation (evening primrose oil; Efamol) resulted in significantly lower levels of palmitoleic acid (a nonessential fatty acid) and higher concentrations of dihomogammalinolenic acid, an EFA previously found to be deficient in some hyperactive children. Supplementation was also associated with significant changes on two performance tasks and with significant improvement to parent ratings on the subscales designated as Attention Problem and Motor Excess of the Revised Behavior Problem Checklist. However, a variety of eight other psychomotor performance tests and two standardized teacher rating scales failed to indicate treatment effects. When the experiment-wise probability level was set at .05, only 2 of 42 variables showed treatment effects. Baseline EFA concentrations appeared to be unrelated to treatment response. It was concluded that EFA supplementation, as employed here, produces minimal or no improvements in hyperactive children selected without regard to baseline EFA concentrations.

Comparison of fatty acid composition of plasma lipid fractions in well-nourished Nigerian and German infants and toddlers.

The dietary intake of essential fatty acids is reflected by the plasma lipid composition. Only scanty data is available on the pattern of plasma fatty acids in young children and the influence of different environments. We analyzed the fatty acid composition of plasma sterolesters, triglycerides, and phospholipids in well-nourished-appearing children from Benin City, Nigeria (n = 8; aged 14.1 +/- 7.2 months) and Düsseldorf, FRG (n = 17; aged 15.2 +/- 5.1 months). The Nigerian group tended to have bigger proportions of the essential omega-6-fatty acids, linoleic acid, and its metabolites, and by far higher values for long-chain omega-3-fatty acids, which are considered to be protective against atherogenesis. The saturated and nonessential monoenoic fatty acids tended to be lower in the Nigerian children, and the ratio of polyunsaturated to saturated fatty acids was higher. We conclude that the quality of dietary fat in the German children was worse and may imply an increased risk for development of atherosclerosis.

Abnormal lung surfactant related to essential fatty acid deficiency in a neonate.

A low-birth-weight infant, suffering from chronic bronchopulmonary dysplasia following hyaline membrane disease and recurrent episodes of necrotizing enterocolitis, developed biochemical evidence of essential fatty acid (EFA) deficiency in the plasma. Fatty acid composition of phosphatidylcholine and phosphatidylglycerol in the lung lavage fluid was abnormal. Plasma changes included a decrease in the level of linoleic acid and an increased level of palmitic, palmitoleic, oleic, and 5,8,11-eicosatrienoic acid to arachidonic acid being greater than 0.4:1. A lower than normal level of palmitic acid and an increased level of palmitoleic and oleic acids were seen in pulmonary sufactant phospholipid components. Upon treatment and recovery from EFA deficiency, the fatty acid pattern both in plasma and surfactant phospholipids returned to normal along with clinical improvement. An association between EFA deficiency and altered fatty acid composition of pulmonary surfactant phospholipids is suggested.

Biochemical abnormalities in Batten's syndrome.

The present data indicate that a group of ten patients with Batten's syndrome showed reduced activity of erythrocyte glutathione (GSH) peroxidase (Px) (glutathione: H2O2 oxidoreductase, EC 1.1.1.9.) using H2O2 as peroxide donor. Assay of erythrocyte GSHPx using H2O2, cumene hydroperoxide and t-butyl hydroperoxide as donors also makes it possible biochemically to divide Batten's syndrome into two types: (1) one type with decreased values when H2O2 and cumene hydroperoxide are used, and (2) one type with increased values when t-butyl hydroperoxide is used. Furthermore an increased content of palmitic, oleic and of eicosatrienoic acid but decreased linoleic acid content was found in serum from patients with Batten syndrome. An inverse relationship between erythrocyte GSHPx and serum eicosatrienoic acid was found in the patients. Finally normal selenium levels were found in erythrocytes, but decreased values were traced in whole blood. In normal human beings a connection was found between the erythrocyte selenium content and GSHPx activity assayed by cumene hydroperoxide as a peroxide donor.