Self-reported taste and smell alterations and the liking of oral nutritional supplements with sensory-adapted flavors in cancer patients receiving systemic antitumor treatment.

PURPOSE: Taste and smell alterations (TAs and SAs) are often reported by patients with cancer receiving systemic antitumor therapy and can negatively impact food intake and quality of life. This study aimed to examine the occurrence of TAs and SAs and investigate the impact of TAs on overall liking of oral nutritional supplements (ONS) with warming and cooling sensations. METHODS: Patients receiving systemic antitumor therapy completed a questionnaire on sensory alterations and evaluated overall liking of 5 prototype flavors of Nutridrink® Compact Protein (hot tropical ginger (HTG), hot mango (HM), cool red fruits (CRF), cool lemon (CL), and neutral (N)) on a 10-point scale via a sip test. Differences between patients with and without TAs were investigated using permutation analysis. RESULTS: Fifty patients with various cancer types and treatments were included. Thirty patients (60%) reported TAs and 13 (26%) experienced SAs. Three flavors were rated highly with a liking score > 6 (CRF 6.8 ± 1.7; N 6.5 ± 1.9; HTG 6.0 ± 2.0). Larger variation in ONS liking scores was observed in patients with TAs with or without SAs (4.5-6.9 and 4.6-7.2, respectively) vs. patients without TAs (5.9-6.5). TAs were associated with increased liking of CRF (Δ = + 0.9) and N (Δ = + 1.0) flavors. CONCLUSIONS: TAs and SAs are common in patients with cancer undergoing systemic antitumor therapy. Patients with TAs were more discriminant in liking of ONS flavors compared to patients without TAs, and sensory-adapted flavors appeared to be appreciated. The presence of TAs should be considered when developing or selecting ONS for patients with cancer. TRIAL REGISTRATION: Registration at ClinicalTrials.gov (NCT03525236) on 26 April 2018.

Dietary linoleic acid-induced alterations in pro- and anti-nociceptive lipid autacoids: Implications for idiopathic pain syndromes?

BACKGROUND: Chronic 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. RESULTS: Increasing 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. CONCLUSIONS: The 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.

Brain Arachidonic Acid Incorporation and Turnover are not Altered in the Flinders Sensitive Line Rat Model of Human Depression.

Brain serotonergic signaling is coupled to arachidonic acid (AA)-releasing calcium-dependent phospholipase A2. Increased brain serotonin concentrations and disturbed serotonergic neurotransmission have been reported in the Flinders Sensitive Line (FSL) rat model of depression, suggesting that brain AA metabolism may be elevated. To test this hypothesis, (14)C-AA was intravenously infused to steady-state levels into control and FSL rats derived from the same Sprague-Dawley background strain, and labeled and unlabeled brain phospholipid and plasma fatty acid concentrations were measured to determine the rate of brain AA incorporation and turnover. Brain AA incorporation and turnover did not differ significantly between controls and FSL rats. Compared to controls, plasma unesterified docosahexaenoic acid was increased, and brain phosphatidylinositol AA and total lipid linoleic acid and n-3 and n-6 docosapentaenoic acid were significantly decreased in FSL rats. Several plasma esterified fatty acids differed significantly from controls. In summary, brain AA metabolism did not change in FSL rats despite reported increased levels of serotonin concentrations, suggesting possible post-synaptic dampening of serotonergic neurotransmission involving AA.

The 51 kDa FADS3 is secreted in the ECM of hepatocytes and blood in rat.

The fatty acid desaturase (Fads) cluster is composed of three genes encoding for the Δ5- and Δ6-desaturases and FADS3. The two former proteins are involved in the fatty acid biosynthesis; the latter one shares a high sequence identity but has still no attributed function. In a previous work performed in rat, we described three isoforms of FADS3 expressed in a tissue-dependent manner. In the present study, we demonstrated a specific subcellular targeting depending on the isoform. In cultured hepatocytes, which mainly expressed the 51 kDa protein, FADS3 was unexpectedly present in the cytosolic fraction, but was also secreted in the extracellular matrix on fibronectin-containing fibers. The secretion pathway was investigated and we determined the presence of exosome-like vesicles on the FADS3-stained fibers. In parallel, FADS3 was detected in blood of hepatic vessel, and particularly in serum. In conclusion, this study demonstrated a very specific intra- and extracellular location of FADS3 in comparison with the Δ5- and Δ6-desaturases, suggesting a unique function for this putative desaturase, even if no activity has been yet identified neither in the extracellular matrix of hepatocytes nor in serum.

iPLA2ß knockout mouse, a genetic model for progressive human motor disorders, develops age-related neuropathology.

Calcium-independent phospholipase A2 group VIa (iPLA2ß) preferentially releases docosahexaenoic acid (DHA) from the sn-2 position of phospholipids. Mutations of its gene, PLA2G6, are found in patients with several progressive motor disorders, including Parkinson disease. At 4 months, PLA2G6 knockout mice (iPLA2ß(-/-)) show minimal neuropathology but altered brain DHA metabolism. By 1 year, they develop motor disturbances, cerebellar neuronal loss, and striatal α-synuclein accumulation. We hypothesized that older iPLA2ß(-/-) mice also would exhibit inflammatory and other neuropathological changes. Real-time polymerase chain reaction and Western blotting were performed on whole brain homogenate from 15 to 20-month old male iPLA2ß(-/-) or wild-type (WT) mice. These older iPLA2ß(-/-) mice compared with WT showed molecular evidence of microglial (CD-11b, iNOS) and astrocytic (glial fibrillary acidic protein) activation, disturbed expression of enzymes involved in arachidonic acid metabolism, loss of neuroprotective brain derived neurotrophic factor, and accumulation of cytokine TNF-α messenger ribonucleic acid, consistent with neuroinflammatory pathology. There was no evidence of synaptic loss, of reduced expression of dopamine active reuptake transporter, or of accumulation of the Parkinson disease markers Parkin or Pink1. iPLA2γ expression was unchanged. iPLA2ß deficient mice show evidence of neuroinflammation and associated neuropathology with motor dysfunction in later life. These pathological biomarkers could be used to assess efficacy of dietary intervention, antioxidants or other therapies on disease progression in this mouse model of progressive human motor diseases associated with a PLA2G6 mutation.

Trans-vaccenate is Δ13-desaturated by FADS3 in rodents.

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 (Δ5-desaturase) and FADS2 (Δ6-desaturase). Here, we show that rat FADS3 displays no common Δ5-, Δ6- or Δ9-desaturase activity but is able to catalyze the unexpected Δ13-desaturation of trans-vaccenate. Although there is no standard for complete conclusive identification, structural characterization strongly suggests that the Δ11,13-conjugated linoleic acid (CLA) produced by FADS3 from trans-vaccenate is the trans11,cis13-CLA isomer. In rat hepatocytes, knockdown of FADS3 expression specifically reduces trans-vaccenate Δ13-desaturation. Evidence is presented that FADS3 is the first "methyl-end" fatty acid desaturase functionally characterized in mammals.

The fatty acid desaturase 3 gene encodes for different FADS3 protein isoforms in mammalian tissues.

In 2000, Marquardt et al. (A. Marquardt, H. Stöhr, K. White, and B. H. F. Weber. 2000. cDNA cloning, genomic structure, and chromosomal localization of three members of the human fatty acid desaturase family. Genomics. 66: 176-183.) described the genomic structure of the fatty acid desaturase (FADS) cluster in humans. This cluster includes the FADS1 and FADS2 genes encoding, respectively, for the Delta 5- and Delta 6-desaturases involved in polyunsaturated fatty acid biosynthesis. A third gene, named FADS3, has recently been identified but no functional role has yet been attributed to the putative FADS3 protein. In this study, we investigated the FADS3 occurrence in rat tissues by using two specific polyclonal antibodies directed against the N-terminal and C-terminal ends of rat FADS3. Our results showed three potential protein isoforms of FADS3 (75 kDa, 51 kDa, and 37 kDa) present in a tissue-dependent manner. The occurrence of these FADS3 isoforms did not depend on the mRNA level determined by real-time PCR. In parallel, mouse tissues were also tested and showed the same three FADS3 isoforms but with a different tissue distribution. Finally, we reported the existence of FADS3 in human cells and tissues but different new isoforms were identified. To conclude, we showed in this study that FADS3 does exist under multiple protein isoforms depending on the mammalian tissues. These results will help further investigations to determine the physiological function of FADS3.

Dietary Linoleic Acid Lowering Reduces Lipopolysaccharide-Induced Increase in Brain Arachidonic Acid Metabolism.

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.

Low-dose aspirin (acetylsalicylate) prevents increases in brain PGE2, 15-epi-lipoxin A4 and 8-isoprostane concentrations in 9 month-old HIV-1 transgenic rats, a model for HIV-1 associated neurocognitive disorders.

BACKGROUND: Older human immunodeficiency virus (HIV)-1 transgenic rats are a model for HIV-1 associated neurocognitive disorders (HAND). They show behavioral changes, neuroinflammation, neuronal loss, and increased brain arachidonic acid (AA) enzymes. Aspirin (acetylsalicylate, ASA) inhibits AA oxidation by cyclooxygenase (COX)-1 and COX-2. HYPOTHESIS: Chronic low-dose ASA will downregulate brain AA metabolism in HIV-1 transgenic rats. METHODS: Nine month-old HIV-1 transgenic and wildtype rats were given 42 days of 10mg/kg/day ASA or nothing in drinking water; eicosanoids were measured using ELISAs on microwaved brain extracts. RESULTS: Brain 15-epi-lipoxin A4 and 8-isoprostane concentrations were significantly higher in HIV-1 transgenic than wildtype rats; these differences were prevented by ASA. ASA reduced prostaglandin E2 and leukotriene B4 concentrations in HIV-1 Tg but not wildtype rats. Thromboxane B2, 15-HETE, lipoxin A4 and resolvin D1 concentrations were unaffected by genotype or treatment. CONCLUSION: Chronic low-dose ASA reduces AA-metabolite markers of neuroinflammation and oxidative stress in a rat model for HAND.

Coordination of gene expression of arachidonic and docosahexaenoic acid cascade enzymes during human brain development and aging.

BACKGROUND: The 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. HYPOTHESIS: AA and DHA pathway genes are coordinately expressed and underlie cascade interactions during human brain development and aging. METHODS: The 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. RESULTS: Expression 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. CONCLUSIONS: Coordinated 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.

Transient postnatal fluoxetine leads to decreased brain arachidonic acid metabolism and cytochrome P450 4A in adult mice.

Fetal and perinatal exposure to selective serotonin (5-HT) reuptake inhibitors (SSRIs) has been reported to alter childhood behavior, while transient early exposure in rodents is reported to alter their behavior and decrease brain extracellular 5-HT in adulthood. Since 5-HT2A/2C receptor-mediated neurotransmission can involve G-protein coupled activation of cytosolic phospholipase A2 (cPLA2), releasing arachidonic acid (ARA) from synaptic membrane phospholipid, we hypothesized that transient postnatal exposure to fluoxetine would alter brain ARA metabolism in adult mice. Brain ARA incorporation coefficients k* and rates Jin were quantitatively imaged following intravenous [1-(14)C]ARA infusion of unanesthetized adult mice that had been injected daily with fluoxetine (10mg/kg i.p.) or saline during postnatal days P4-P21. Expression of brain ARA metabolic enzymes and other relevant markers also was measured. On neuroimaging, k* and Jin was decreased widely in early fluoxetine- compared to saline-treated adult mice. Of the enzymes measured, cPLA2 activity was unchanged, while Ca(2+)-independent iPLA2 activity was increased. There was a significant 74% reduced protein level of cytochrome P450 (CYP) 4A, which can convert ARA to 20-HETE. Reduced brain ARA metabolism in adult mice transiently exposed to postnatal fluoxetine, and a 74% reduction in CYP4A protein, suggest long-term effects independent of drug presence in brain ARA metabolism, and in CYP4A metabolites. These changes might contribute to reported altered behavior following early SSRI in rodents.