13-cis-Retinoic Acid Affects Brain Perfusion and Function: In Vivo Study

Acyl-coenzyme A synthetases (ACSs) catalyze the fundamental, initial reaction in fatty acid metabolism. "Activation" of fatty acids by thioesterification to CoA allows their participation in both anabolic and catabolic pathways. The availability of the sequenced human genome has facilitated the investigation of the number of ACS genes present. Using two conserved amino acid sequence motifs to probe human DNA databases, 26 ACS family genes/proteins were identified. ACS activity in either humans or rodents was demonstrated previously for 20 proteins, but 6 remain candidate ACSs. For two candidates, cDNA was cloned, protein was expressed in COS-1 cells, and ACS activity was detected. Amino acid sequence similarities were used to assign enzymes into subfamilies, and subfamily assignments were consistent with acyl chain length preference. Four of the 26 proteins did not fit into a subfamily, and bootstrap analysis of phylograms was consistent with evolutionary divergence. Three additional conserved amino acid sequence motifs were identified that likely have functional or structural roles. The existence of many ACSs suggests that each plays a unique role, directing the acyl-CoA product to a specific metabolic fate. Knowing the full complement of ACS genes in the human genome will facilitate future studies to characterize their specific biological functions.

Trans‐fatty acids (TFA) intake has been associated with risk factors for cardiovascular disease. However, little is known about the TFA levels in humans or about how these levels relate to other fatty acids (FA).In order to assess TFA levels in humans we have developed and validated an isotope dilution‐gas chromatography‐negative chemical ionization‐mass spectrometry method for the quantitation of 28 FA in human plasma, including 4 major TFA. We analyzed 73 convenience samples from adults. All samples contained TFA, with average levels ± standard deviation of 2.66 ± 1.29 μM for palmitelaidic acid 12.70 ± 8.31 μM for elaidic acid, 16.59 ± 11.10 μM for vaccenic acid, and 1.15 ± 0.52 μM for linoelaidic acid. The sum of all FA was 9647 ± 2913 μM. The sum of the 4 TFA accounted for 0.34 ± 0.20 % of total FA. FA values expressed as percent of total FA showed negative association between monounsaturated FA and polyunsaturated fatty acids (PUFAs), ω‐6 PUFAs, and ω‐3 PUFAs. Negative trends were also seen between certain TFA and the summed PUFAs. We have developed an analytical method that enables the assessment of major TFA and other FA in 100 μL of plasma, which allows the investigation of FA concentrations as well as differences in the composition of these FA in plasma. This method is being used to analyze samples from the National Health and Nutrition Examination Survey (NHANES).

Red blood cells from 31 healthy donors were examined for the cholesterol content, the fatty acid composition, and the susceptibility to lipid peroxidation induced by either hydrogen peroxide or phenylhydrazine. Lipid peroxidation was monitored by the release of pentane and ethane. In addition, plasma fatty acids were measured in order to find out, whether plasma and red cell fatty acids were correlated. In experiments with hydrogen peroxide, a significant positive correlation was found between the proportion of arachidonic acid (C 20:4n - 6; r = 0.57, p less than 0.01) and docosahexaenoic acid (C 22:6n - 3; r = +0.71, p less than 0.01), and the release of pentane and ethane, respectively. A significant negative correlation was found between the membrane cholesterol content and the pentane release (r -0.44, p less than 0.05). In experiments performed with phenylhydrazine, red cell membrane lipid composition did not influence the susceptibility of red cells to lipid peroxidation. A close correlation was found between plasma and red cell fatty acids (palmitic acid, r = +0.46, p less than 0.01; linoleic acid, r = +0.41, p less than 0.05; arachidonic acid, r = +0.59, p less than 0.01; docosahexaenoic acid, r = +0.67, p less than 0.01). The results demonstrated that the degree of peroxide-induced oxidation of erythrocyte lipids depends on the content of polyunsaturated fatty acids in the membrane, which on the other hand, is determined by plasma fatty acids. It is suggested that dietary variations may influence the susceptibility of red cells to lipid peroxidation.

Platelet aggregation and its relation to fatty acid composition of platelets, plasma and adipose tissue was determined in 196 randomly selected, free-living, 40-49-year-old men in two regions of Finland (east and southwest) with a nearly twofold difference in the IHD rate. There were no significant east-southwest differences in platelet aggregation induced with ADP, thrombin or epinephrine. ADP-induced platelet secondary aggregation showed significant negative associations with all C20-C22 omega 3-fatty acids in platelets (r = -0.26- -0.40) and with the platelet 20: 5 omega 3/20: 4 omega 6 and omega 3/omega 6 ratios, but significant positive correlations with the contents of 18:2 in adipose tissue (r = 0.20) and plasma triglycerides (TG) (r = 0.29). Epinephrine-induced aggregation correlated negatively with 20: 5 omega 3 in plasma cholesteryl esters (CE) (r = -0.23) and TG (r = -0.29), and positively with the total percentage of saturated fatty acids in platelets (r = 0.33), but had no significant correlations with any of the omega 6-fatty acids. Thrombin-induced aggregation correlated negatively with the omega 3/6 omega ratio in adipose tissue (r = -0.25) and the 20: 3 omega 6/20: 4 omega 6 ratio in plasma CE (r = -0.27) and free fatty acids (FFA) (r = -0.23), and positively with adipose tissue 18:2 (r = 0.23) and 20:4 omega 6 (r = 0.22) in plasma phospholipids (PL). The percentages of prostanoid precursors in platelet lipids, i.e. 20:3 omega 6, 20:4 omega 6 and 20:5 omega 3, correlated best with the same fatty acids in plasma CE (r = 0.32 - 0.77) and PL (r = 0.28 - 0.74). Platelet 20:5 omega 3 had highly significant negative correlations with the percentage of 18:2 in adipose tissue and all plasma lipid fractions (r = -0.35 - -0.44).(ABSTRACT TRUNCATED AT 250 WORDS)

Fatty acids have been linked to attention-deficit/hyperactivity disorder (ADHD), but the biological basis of this association remains unclear. This study examined dietary and plasma fatty acid profiles and fatty acid desaturase-2 (FADS2) in children with ADHD.This cross-sectional study included 85 children with ADHD and 85 controls aged 6-12 years. ADHD symptoms were assessed using the Conners' Parent Rating Scale-Revised: Short Form (CPRS-R: S). Dietary fatty acid intake was estimated from three non-consecutive 24-hour recalls. Plasma fatty acids were measured by GC-MS. Plasma FADS2 protein levels were quantified by ELISA, and FADS2 mRNA expression was assessed by real-time PCR. Principal component analysis (PCA) was used to derive fatty acid components, followed by structural equation modeling (SEM) to evaluate associations with ADHD symptom severity.Children with ADHD showed a greater relative dietary contribution of omega-6 fatty acids and total PUFAs, higher plasma LA levels and omega-6/omega-3 ratio, and lower plasma MUFAs, GLA, and docosanoic acid than controls. Plasma FADS2 protein levels were numerically higher but not significantly different, whereas relative FADS2 mRNA expression was lower in the ADHD group. In SEM, greater ADHD symptom severity was associated with a PCA-derived component characterized by higher LA and omega-6/omega-3 ratio together with lower nervonic acid.Children with ADHD differed from controls across multiple dietary, plasma, and FADS2-related fatty acid measures, particularly those related to omega-6 balance. ADHD symptom severity was also associated with a multivariable fatty acid profile.

OBJECTIVE—Neonates of women with gestational diabetes mellitus (GDM) have reduced levels of arachidonic acid (AA) (20:4 n-6) and docosahexaenoic acid (DHA) (22:6 n-3). To assess whether this is the result of impaired placental transfer or endogenous fetal metabolism, fatty acids in umbilical venous and arterial plasma were analyzed in neonates of GDM women.RESEARCH DESIGN AND METHODS—Fatty acids were analyzed by gas chromatography in the plasma of 15 subjects with GDM and 30 healthy control subjects undergoing elective cesarean section and in vein and artery cord blood collected separately.RESULTS—The percentages of AA (20:4 n-6), DHA (22:6 n-3), and total n-6 or n-3 polyunsaturated fatty acids (PUFAs) as well as total PUFAs were lower in umbilical arterial but not in venous plasma of neonates of the GDM versus the control group.CONCLUSIONS—An altered handling or metabolism of long-chain PUFAs by the fetus rather than impaired placental transfer seems to be responsible for the lower proportion of those fatty acids in the plasma of neonates of GDM mothers.

The aim of the study was to evaluate the safety and efficacy of fish oil-containing (FO) lipid emulsions that are rich in ω-3 fatty acids for parenteral nutrition in preterm neonates by using data retrieved from randomized controlled trials. We performed a meta-analysis of 8 randomized controlled trials representing 483 premature neonates to compare FO with control (CO) lipid emulsions. This meta-analysis revealed that the levels of ω-3 fatty acids in the form of docosahexaenoic acid, eicosapentaenoic acid, and arachidonic acid (% of total fatty acids) in plasma were statistically higher in FO groups (mean difference [MD] -0.7%, 95% confidence interval [CI] -1.05 to -0.36, P < 0.001; MD -1.31%, 95% CI -1.40 to -1.21, P < 0.001). The differences were found in red blood cell (RBC) membranes. The levels of arachidonic acid (% of total fatty acids) as ω-6 fatty acid in plasma and red blood cell membranes were significantly lower in FO groups (MD 1.27%, 95% CI 1.12-1.42, P < 0.001) (MD 0.92%, 95% CI 0.12-1.72, P = 0.02). The mean body weight, serum level of bilirubin, triglycerides or C-reactive protein, all-cause mortality, and rate of lipid emulsion-associated complications were, however, not different between FO and CO groups. The level of docosahexaenoic acid is efficiently improved by FO lipid emulsions. The changes observed in eicosapentaenoic acid and arachidonic acid, and the associated safety issue, however, remain to be clarified. Any clinical benefit or detrimental effect of using FO in premature neonates cannot be demonstrated by the present study.

The release of fatty acids and glycerol from adipose tissue of obese diabetics and obese controls has been studied in relation to the fall in plasma fatty acids during a glucose tolerance test. Adipose tissue was taken at zero-time and lh after an oral glucose load (50g). Obese diabetics released more fatty acids from adipose tissue than obese controls (p < 0.001), whereas glycerol release was similar in the two groups. The percent reduction in release of fatty acids from adipose tissue of obese diabetics during a G. T. T. was significantly less than obese controls (p < 0.02), as was the percent fall in plasma fatty acids (p < 0.02), whereas the percent reduction in glycerol release from adipose tissue was similar in the two groups. In addition the percent fall in plasma fatty acids during a G.T.T. correlated with the percent reduction in release of fatty acids from adipose tissue (p<0.05), but not with release of glycerol; and the increment in plasma insulin from zero-time to lh during a G.T.T. correlated with the percent reduction in fatty acid release from adipose tissue (p<0.01). Finally, the plasma insulin at lh of a G.T.T. correlated inversely with the release of fatty acids from adipose tissue (p<0.05), but not with the release of glycerol. The data is consistent with the view that the plasma fatty acids fall during a G.T.T. due to re-esterification of fatty acids rather than due to an antilipolytic action of insulin.

BackgroundProinflammatory biomarkers levels are increased among patients with cardiovascular disease, and it is known that both the presence of insulin resistance and diet may influence those levels. However, these associations are not well studied among patients with established cardiovascular disease. Our objective is to compare inflammatory biomarker levels among cardiovascular disease secondary prevention patients with and without insulin resistance, and to evaluate if there is any association between plasma fatty acid levels and inflammatory biomarker levels among them.MethodsIn this cross-sectional sub-study from the BALANCE Program Trial, we collected data from 359 patients with established cardiovascular disease. Plasma fatty acids and inflammatory biomarkers (interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12, high sensitive C-reactive protein (hs-CRP), adiponectin, and tumor necrosis factor (TNF)-alpha) were measured. Biomarkers and plasma fatty acid levels of subjects across insulin resistant and not insulin resistant groups were compared, and general linear models were used to examine the association between plasma fatty acids and inflammatory biomarkers.ResultsSubjects with insulin resistance had a higher concentration of hs-CRP (p = 0.002) and IL-6 (p = 0.002) than subjects without insulin resistance. Among subjects without insulin resistance there was a positive association between stearic fatty acid and IL-6 (p = 0.032), and a negative association between alpha-linolenic fatty acid and pro-inflammatory biomarkers (p < 0.05). Among those with insulin resistance there was a positive association between monounsaturated fatty acids and arachidonic fatty acid and adiponectin (p < 0.05), and a negative association between monounsaturated and polyunsaturated fatty acids and pro-inflammatory biomarkers (p < 0.05), as well as a negative association between polyunsaturated fatty acids and adiponectin (p < 0.05). Our study has not found any association between hs-CRP and plasma fatty acids.ConclusionsSubjects in secondary prevention for cardiovascular disease with insulin resistance have a higher concentration of hs-CRP and IL-6 than individuals without insulin resistance, and these inflammatory biomarkers are positively associated with saturated fatty acids and negatively associated with unsaturated fatty acids.

To assess the modifications of the main fatty acids (FA) in plasma and red blood cells during pregnancy. A longitudinal study of 36 normal pregnant women was carried out with 3 cut-off points: first trimester, second trimester and third trimester. 14 FA in plasma and erythrocyte phospholipids were measured using capillary gas chromatography. Measurements were expressed in percentages and in absolute values. In plasma there was a significant increase in the proportion of saturated FA and a decrease in the proportion of long chain polyunsaturated fatty acids (PUFA) both in the omega 6 (omega 6) and omega 3 (omega 3) series. On the other hand, in erythrocyte phospholipids there was a decrease in the proportion of eicosapentaenoic acid and an increase in that of docosahexaenoic acid. In the omega 6 series, dihomo-gamma-linolenic acid increased, whereas the omega 6 docosapentaenoic acid decreased. There was a significant decrease in the proportion of omega 3 PUFA in plasma from the first to the third trimester. Thus, it is suggested that the omega 3 PUFA intake during pregnancy should be increased in the last trimester.

Since 1982, oral isotretinoin has been indicated for the treatment of severe nodular-cystic acne, but indications for its use have expanded significantly in recent decades. Dermatologists around the world have begun to actively use isotretinoin for moderate and even mild forms of acne, for acne that is resistant to standard treatment methods, as well as if the patient has a tendency to scar formation, which indirectly confirms that most often the benefits obtained from the use of the drug are significantly higher than the possible risk of side effects. Despite 38 years of experience with isotretinoin, currently some dermatologists unreasonably avoid prescribing the drug. Analysis of the literature and our own experience show that this attitude to acne therapy with systemic isotretinoin is usually associated with insufficient or inadequate awareness of doctors and patients. The most common reason why systemic isotretinoin therapy is not prescribed is fear of the risk of side effects during treatment.Therefore, the aim of the work was to determine the profile and frequency of side effects in acne treatment with systemic isotretinoin. For this purpose, we retrospectively analyzed 76 outpatient records of patients receiving systemic isotretinoin in the complex therapy of acne. Among the patients there were 51 women aged 13 to 42 years and 25 men aged 14 to 39 years. Roaccutane (F. Hoffmann-La Roche Ltd, Switzerland) was used as a systemic therapy for acne. The regimen of therapy with Roaccutane was as follows: for the first 2 months — 0.3—0.4 mg per 1 kg of body weight per day, then with normal biochemical parameters of liver, kidney function, lipid and carbohydrate metabolism, the daily dose increased to 0.5—0.7 mg per 1 kg of the patient’s body weight until a cumulative dose of 120 mg per kg of body weight is reached. In all patients who received Roaccutane for the treatment of acne, side effects were well tolerated, easily corrected and sometimes required only a temporary reduction in its daily dose. Changes in the biochemical blood test were transient: the indicators were restored to normal values after the end of the course of therapy.

It is unknown whether a novel small-quantity lipid-based nutrient supplement (SQ-LNS) containing alpha-linolenic (ALA) and linoleic acids impacts maternal plasma lipids and fatty acid status. We measured plasma fatty acids (wt%) and lipid concentrations at 36 wk gestation and breast milk fatty acids (wt%) at 6 months postpartum in a subsample of women enrolled in a randomized controlled trial studying the effects of SQ-LNS on birth outcomes and child growth. Women≤20 wk gestation in Ghana (n=1,320) and Malawi (n=1,391) were assigned to receive daily either: 1) iron-folic acid (pregnancy); 2) multiple micronutrients (pregnancy and lactation); or 3) SQ-LNS (pregnancy and lactation). At 36 wk, plasma ALA levels were higher in those receiving SQ-LNS. SQ-LNS increased breast milk ALA in Ghana but not Malawi. There was no effect on plasma lipids or other selected fatty acids. SQ-LNS may impact plasma and breast milk ALA levels depending on the population.

Quantitative methods for calculation of regional cerebral blood flow with technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO) have been proposed. These methods are very labour intensive and therefore are not useful in routine clinical practice. We describe a simple alternative method, using calibrated point sources as a scaling factor, whereby the tomographic slices are displayed as regional 99mTc-HMPAO brain uptake per cm3 brain tissue in 10(-6) of the injected lipophilic dose. The method was validated on Jaszczak and Hoffman phantoms using a three-detector system with HR parallel and HR fan-beam collimators. Under the optimal conditions described in this paper, the measured to real activity ratio was 1.00 (SD = 0.06). The reproducibility of the cerebellar uptake in a group of ten normal volunteers and five patients was studied. Intra-individually a mean deviation of 12.6% was observed for the total group. For those persons with a heart rate difference of less than 5 units between the two studies, a mean deviation of 7.2% was obtained. Quantitative 99mTc-HMPAO brain uptake images can be useful for longitudinal studies, especially for follow-up, activation and pharmacological studies.

The effects of altering dietary carbohydrates and lipids to oocyte donors during superovulation and ovum pickup (OPU) on in vitro embryo production was reported previously (Adamiak et al. 2004 Reprod. Dev. Fert. 16, 193–194). Here we report the effects of these dietary treatments on the fatty acid (FA) composition of plasma, granulosa cells (GCs), and cumulus–oocyte complexes (COCs) from the 32 heifers used in that study. Blood samples were collected by jugular venipuncture. COCs and GCs were harvested from each heifer by OPU as described previously but were pooled between pairs of heifers within treatment to provide adequate material for FA analysis. Both GCs and COCs were washed twice in PBS supplemented with 0.3% (w/v) BSA (FA-free) before being transferred into 2 : 1 (v/v) chloroform : methanol solution for FA extraction. FA composition was determined using gas chromatography as described previously (Reis et al. 2002, Theriogenology 57, 507). Data were analyzed by ANOVA. Total plasma FA content averaged 1.12 μg/mL and was unaffected by body condition score (BCS). Low BCS heifers had more saturated (54.0 ± 1.76 vs. 49.2 ± 1.74%) and monounsaturated (22.4 ± 1.08 vs. 18.2 ± 0.69%) FA, but less polyunsaturated FA (PUFA) (23.7 ± 1.75 vs. 32.8 ± 2.21%) in plasma than moderate BCS heifers (P &lt; 0.01). Animals fed high relative to low fiber diets had greater plasma FA (1.3 ± 0.15 vs. 1.0 ± 0.12 μg/mL) and PUFA (31.2 ± 2.56 vs. 25.3 ± 2.19%), but less monounsaturated FA (18.8 ± 1.04 vs. 21.5 ± 1.09%) (P &lt; 0.01). Dietary protected lipid (Ca soaps of FA) increased plasma FA (1.6 ± 0.07 vs. 0.6 ± 0.04 μg/mL) and PUFA (30.0 ± 1.92 vs. 26.4 ± 3.03%) (P &lt; 0.05), but reduced plasma saturated FA (48.9 ± 1.12 vs. 54.2 ± 2.14%; P &lt; 0.01) in the animals fed high compared to low fiber diets, respectively. In contrast to their effects in plasma, BCS and diet had little effect on FA composition of GCs and COCs. Although low BCS and dietary lipids both increased FA in COCs (78.3 ± 2.01 vs. 69.2 ± 2.80, P &lt; 0.01; and 77.1 ± 2.96 vs. 70.5 ± 2.26 ng/COC; P &lt; 0.05, respectively), neither factor significantly altered the FA composition of COCs. Across treatments, the FA composition of GCs and COCs differed markedly from that of plasma (Table 1), confirming the presence of a selective uptake mechanism in the follicle that can moderate dietary induced fluctuations in FA supply from peripheral circulation. Table 1. Concentrations of fatty acids in plasma, GCs, and COCs expressed as mean percentages (w/w) of total fatty acids This work was supported by Defra and The Perry Foundation.

Molecular approach of gossypol-induced reproductive toxicity in male rabbits. Changes in seminal plasma amino acids and fatty acids