BackgroundDriven by reduced nutritional intakes and metabolic alterations, malnutrition in cancer patients adversely affects quality of life, treatment tolerance and survival. We examined evidence for oral nutritional interventions during chemo(radio)therapy.DesignWe carried out a systematic review of randomized controlled trials (RCT) with either dietary counseling (DC), high-energy oral nutritional supplements (ONS) aiming at improving intakes or ONS enriched with protein and n-3 polyunsaturated fatty acids (PUFA) additionally aiming for modulation of cancer-related metabolic alterations. Meta-analyses were carried out on body weight (BW) response to nutritional interventions, with subgroup analyses for DC and/or high-energy ONS or high-protein n-3 PUFA-enriched ONS.ResultsEleven studies were identified. Meta-analysis showed overall benefit of interventions on BW during chemo(radio)therapy (+1.31 kg, 95% CI 0.24–2.38, P = 0.02, heterogeneity Q = 21.1, P = 0.007). Subgroup analysis showed no effect of DC and/or high-energy ONS (+0.80 kg, 95% CI −1.14 to 2.74, P = 0.32; Q = 10.5, P = 0.03), possibly due to limited compliance and intakes falling short of intake goals. A significant effect was observed for high-protein n-3 PUFA-enriched intervention compared with isocaloric controls (+1.89 kg, 95% CI 0.51–3.27, P = 0.02; Q = 3.1 P = 0.37). High-protein, n-3 PUFA-enriched ONS studies showed attenuation of lean body mass loss (N = 2 studies) and improvement of some quality of life domains (N = 3 studies). Overall, studies were limited in number, heterogeneous, and inadequately powered to show effects on treatment toxicity or survival.ConclusionThis systematic review suggests an overall positive effect of nutritional interventions during chemo(radio)therapy on BW. Subgroup analyses showed effects were driven by high-protein n-3 PUFA-enriched ONS, suggesting the benefit of targeting metabolic alterations. DC and/or high-energy ONS were less effective, likely due to cumulative caloric deficits despite interventions. We highlight the need and provide recommendations for well-designed RCT to determine the effect of nutritional interventions on clinical outcomes, with specific focus on reaching nutritional goals and providing the right nutrients, as part of an integral supportive care approach.

BackgroundChronic idiopathic pain syndromes are major causes of personal suffering, disability, and societal expense. Dietary n-6 linoleic acid has increased markedly in modern industrialized populations over the past century. These high amounts of linoleic acid could hypothetically predispose to physical pain by increasing the production of pro-nociceptive linoleic acid-derived lipid autacoids and by interfering with the production of anti-nociceptive lipid autacoids derived from n-3 fatty acids. Here, we used a rat model to determine the effect of increasing dietary linoleic acid as a controlled variable for 15 weeks on nociceptive lipid autacoids and their precursor n-6 and n-3 fatty acids in tissues associated with idiopathic pain syndromes.ResultsIncreasing dietary linoleic acid markedly increased the abundance of linoleic acid and its pro-nociceptive derivatives and reduced the abundance of n-3 eicosapentaenoic acid and docosahexaenoic acid and their anti-nociceptive monoepoxide derivatives. Diet-induced changes occurred in a tissue-specific manner, with marked alterations of nociceptive lipid autacoids in both peripheral and central tissues, and the most pronounced changes in their fatty acid precursors in peripheral tissues.ConclusionsThe present findings provide biochemical support for the hypothesis that the high linoleic acid content of modern industrialized diets may create a biochemical susceptibility to develop chronic pain. Dietary linoleic acid lowering should be further investigated as part of an integrative strategy for the prevention and management of idiopathic pain syndromes.

This article is available online at http://www.jlr.org derived from the biosynthetic pathways resulting in the conversion of essential precursors to their respective elongated polyenoic products.The availability of PUFA in mammalian cells greatly depends on the activity of enzymes involved in FA metabolism. In animals and humans, the ⌬ 5-and ⌬ 6-desaturases are the pivotal enzymes introducing de novo unsaturations in the carbon chain of precursors leading to the synthesis of long-chain PUFA (LC-PUFA). These enzymes were cloned 10 years ago from mammals ( 2-5 ). In parallel, Marquardt et al. ( 6 ) described the human genomic structure of the fatty acid desaturase ( FADS ) cluster including the FADS1 and FADS2 genes coding, respectively, for the ⌬ 5-and ⌬ 6-desaturases. A third gene, named FADS3 , was identifi ed, revealing 62% and 70% nucleotide sequence identity with FADS1 and FADS2 , respectively. Further studies showed a signifi cant correlation between FADS3 polymorphism and lipid metabolism markers such as PUFA, high density-or low density-lipoprotein cholesterol, and triglyceride levels ( 7-10 ). The newly discovered gene was thereafter integrated into a serial analysis of gene expression and a DNA microarray succeeding in more physiological data. FADS3 was therefore found to be highly expressed at the implantation site of the embryo in mouse uterus ( 11 ) and downregulated during human neurogenic differentiation ( 12 ). More recently, Park et al. described, in baboon, different alternative transcripts of FADS3 generated by alternative splicing, which suggests the occurrence of multiple FADS3 gene products ( 13 ). This study also showed a different pattern of expression in response to human neuroblastoma SK-N-SH cell differentiation. All data together only concern the FADS3 gene with no description of the functional role of the putative FADS3 protein. PUFAs are key components involved in a variety of physiological functions ( 1 ). Some of them, belonging to the n-6 or n-3 families, have to be fulfi lled from the diet or This work was supported by the Région Bretagne, the Groupe Lipides et Nutrition, Valorex (Combourtillé, France), and Polaris (Pleuven, France).

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BackgroundThe polyunsaturated arachidonic and docosahexaenoic acids (AA and DHA) participate in cell membrane synthesis during neurodevelopment, neuroplasticity, and neurotransmission throughout life. Each is metabolized via coupled enzymatic reactions within separate but interacting metabolic cascades.HypothesisAA and DHA pathway genes are coordinately expressed and underlie cascade interactions during human brain development and aging.MethodsThe BrainCloud database for human non-pathological prefrontal cortex gene expression was used to quantify postnatal age changes in mRNA expression of 34 genes involved in AA and DHA metabolism.ResultsExpression patterns were split into Development (0 to 20 years) and Aging (21 to 78 years) intervals. Expression of genes for cytosolic phospholipases A2 (cPLA2), cyclooxygenases (COX)-1 and -2, and other AA cascade enzymes, correlated closely with age during Development, less so during Aging. Expression of DHA cascade enzymes was less inter-correlated in each period, but often changed in the opposite direction to expression of AA cascade genes. Except for the PLA2G4A (cPLA2 IVA) and PTGS2 (COX-2) genes at 1q25, highly inter-correlated genes were at distant chromosomal loci.ConclusionsCoordinated age-related gene expression during the brain Development and Aging intervals likely underlies coupled changes in enzymes of the AA and DHA cascades and largely occur through distant transcriptional regulation. Healthy brain aging does not show upregulation of PLA2G4 or PTGS2 expression, which was found in Alzheimer's disease.

Linoleic acid (LA, 18:2n-6) is a precursor to arachidonic acid (AA, 20:4n-6), which can be converted by brain lipoxygenase and cyclooxygenase (COX) enzymes into various lipid mediators involved in the regulation of brain immunity. Brain AA metabolism is activated in rodents by the bacterial endotoxin, lipopolysaccharide (LPS). This study tested the hypothesis that dietary LA lowering, which limits plasma supply of AA to the brain, reduces LPS-induced upregulation in brain AA metabolism. Male Fischer CDF344 rats fed an adequate LA (5.2 % energy (en)) or low LA (0.4 % en) diet for 15 weeks were infused with LPS (250 ng/h) or vehicle into the fourth ventricle for 2 days using a mini-osmotic pump. The incorporation rate of intravenously infused unesterified 14C-AA into brain lipids, eicosanoids, and activities of phospholipase A2 and COX-1 and 2 enzymes were measured. Dietary LA lowering reduced the LPS-induced increase in prostaglandin E2 concentration and COX-2 activity (P < 0.05 by two-way ANOVA) without altering phospholipase activity. The 14C-AA incorporation rate into brain lipids was decreased by dietary LA lowering (P < 0.05 by two-way ANOVA). The present findings suggest that dietary LA lowering reduced LPS-induced increase in brain markers of AA metabolism. The clinical utility of LA lowering in brain disorders should be explored in future studies.

This article is available online at http://www.jlr.org "methyl-end" FA desaturases. Therefore, linoleic acid and ␣ -linolenic acid must be provided by the diet ( 3 ). These dietary essential FAs then serve as precursors for longer PUFAs of the n-6 and n-3 series, including arachidonic acid (20:4 n-6) and docosahexaenoic acid (22:6 n-3) required for many important physiological functions in humans ( 4,5 ). In this PUFA biosynthesis, only "front-end" desaturases ( ⌬ 5-and ⌬ 6-desaturases) are involved to introduce new double bonds between the preexisting double bonds and the carboxyl end of FAs ( 6 ).In 2000, the genomic structure of the fatty acid desaturase (FADS) cluster, located on chromosome 11 in humans, was reported ( 7 ). This cluster includes the FADS1 and FADS2 genes that code, respectively, for the well-known ⌬ 5-and ⌬ 6-desaturases involved in PUFA biosynthesis ( 8-10 ). A third gene was identifi ed on this cluster with high degree of nucleotide sequence homology with both FADS1 (62%) and FADS2 (70%) and was therefore named FADS3. Since its fi rst description in humans ( 7 ), FADS3 has been identifi ed in rats ( 11 ), baboons ( 12 ), mice ( 3 ), and many other mammals showing a similar nucleotide sequence and intron/exon organization ( 12 ). When analyzing the peptide sequence deduced from the FADS3 nucleotide sequence, FADS3 protein was identifi ed as a putative desaturase, according to its similarity with FADS1 and FADS2. Indeed, the predicted structure of FADS3 is composed of an N-terminal cytochrome b5-like domain characterized by a HPGG motif shown to be essential for the ⌬ 6-desaturase activity of FADS2 ( 13 ) QIEHH in the rat) characteristic of front-end-desaturases ( 14 ). According to its amino acid sequence, FADS3 was thereafter supposed to Abstract Fatty acid desaturases play critical roles in regulating the biosynthesis of unsaturated fatty acids in all biological kingdoms. As opposed to plants, mammals are so far characterized by the absence of desaturases introducing additional double bonds at the methyl-end site of fatty acids. However, the function of the mammalian fatty acid desaturase 3 (FADS3) gene remains unknown. This gene is located within the FADS cluster and presents a high nucleotide sequence homology with FADS1 ( ⌬ 5-desaturase) and FADS2 ( ⌬ 6-desaturase). Here, we show that rat FADS3 displays no common ⌬ 5-, ⌬ 6-or ⌬ 9-desaturase activity but is able to catalyze the unexpected ⌬ 13-desaturation of trans -vaccenate. Although there is no standard for complete conclusive identifi cation, structural characterization strongly suggests that the ⌬ 11,13-conjugated linoleic acid (CLA) produced by FADS3 from trans -vaccenate is the trans 11, cis 13-CLA isomer. In rat hepatocytes, knockdown of FADS3 expression specifically reduces trans -vaccenate ⌬ 13-desaturation. Evidence is presented that FADS3 is the fi rst "methyl-end" fatty acid desaturase functionally characterized in mammals. FA desaturases introduce double bonds between defi ned carbons of the fatty acyl chain and catalyze ...

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