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Lipids Nov 2022α-linolenic acid (αLNA) conversion into the functionally important ω-3 polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA), and docosahexaenoic acid... (Review)
Review
α-linolenic acid (αLNA) conversion into the functionally important ω-3 polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), has been regarded as inadequate for meeting nutritional requirements for these PUFA. This view is based on findings of small αLNA supplementation trials and stable isotope tracer studies that have been interpreted as indicating human capacity for EPA and, in particular, DHA synthesis is limited. The purpose of this review is to re-evaluate this interpretation. Markedly differing study designs, inconsistent findings and lack of trial replication preclude robust consensus regarding the nutritional adequacy of αLNA as a source of EPC and DHA. The conclusion that αLNA conversion in humans is constrained is inaccurate because it presupposes the existence of an unspecified, higher level of metabolic activity. Since capacity for EPA and DHA synthesis is the product of evolution it may be argued that the levels of EPA and DHA it maintains are nutritionally appropriate. Dietary and supra-dietary EPA plus DHA intakes confer health benefits. Paradoxically, such health benefits are also found amongst vegetarians who do not consume EPA and DHA, and for whom αLNA conversion is the primary source of ω-3 PUFA. Since there are no reported adverse effects on health or cognitive development of diets that exclude EPA and DHA, their synthesis from αLNA appears to be nutritionally adequate. This is consistent with the dietary essentiality of αLNA and has implications for developing sustainable nutritional recommendations for ω-3 PUFA.
Topics: Humans; alpha-Linolenic Acid; Fatty Acids, Omega-3; Eicosapentaenoic Acid; Docosahexaenoic Acids; Fatty Acids, Unsaturated
PubMed: 35908848
DOI: 10.1002/lipd.12355 -
European Review For Medical and... Nov 2023Methotrexate (MTX) is a folic acid antagonist used in chronic inflammatory diseases and various cancer treatments. Although the main mechanism of the toxic effect of MTX...
OBJECTIVE
Methotrexate (MTX) is a folic acid antagonist used in chronic inflammatory diseases and various cancer treatments. Although the main mechanism of the toxic effect of MTX is not known, it is stated that it causes oxidative stress and inflammation. Alpha-linolenic acid (ALA) protects against oxidative stress, apoptosis, and inflammation. For this reason, we aimed to find out the useful effect of ALA on MTX-induced nephrotoxicity MATERIALS AND METHODS: The mice were divided into 4 groups randomly. The control group was treated with physiological saline solution; the ALA group was treated with ALA (200 mg/kg) by gavage; MTX-treated group received 20 mg/kg i.p. (intraperitoneal) MTX; and MTX+ALA treated group received 20 mg/kg i.p. MTX and ALA 200 mg/kg by gavage. All of the drugs were performed once a day for 9 days.
RESULTS
Alpha-linolenic acid significantly decreased oxidative stress parameters and MTX-induced inflammatory and apoptotic mediators. Furthermore, histopathological examination showed that MTX induced significant edematous damage, and ALA treatment attenuated this damage in renal tissue.
CONCLUSIONS
Our results revealed that ALA may be helpful against MTX-induced nephrotoxicity in mice via its antioxidant and anti-inflammatory properties.
Topics: Mice; Animals; Methotrexate; alpha-Linolenic Acid; Antioxidants; Oxidative Stress; Inflammation; Kidney
PubMed: 38039041
DOI: 10.26355/eurrev_202311_34479 -
Nutrients Dec 2023Oral cancer ranks sixth among Taiwan's top 10 cancers and most patients with poor prognosis acquire metastases. The essential fatty acid alpha-linolenic acid (ALA) has...
Oral cancer ranks sixth among Taiwan's top 10 cancers and most patients with poor prognosis acquire metastases. The essential fatty acid alpha-linolenic acid (ALA) has been found to diminish many cancer properties. However, the anti-cancer activity of ALA in oral cancer has yet to be determined. We examined the mechanisms underlying ALA inhibition of metastasis and induction of apoptotic cell death in oral squamous cell carcinoma (OSCC). Migration and invasion assays confirmed the cancer cells' EMT capabilities, whereas flow cytometry and Western blotting identified molecular pathways in OSCC. ALA dramatically reduced cell growth in a concentration-dependent manner according to the findings. Low concentrations of ALA (100 or 200 μM) inhibit colony formation, the expression of Twist and EMT-related proteins, the expression of MMP2/-9 proteins, and enzyme activity, as well as cell migration and invasion. Treatment with high concentrations of ALA (200 or 400 μM) greatly increases JNK phosphorylation and c-jun nuclear accumulation and then upregulates the FasL/caspase8/caspase3 and Bid/cytochrome c/caspase9/caspase3 pathways, leading to cell death. Low concentrations of ALA inhibit SAS and GNM cell migration and invasion by suppressing Twist and downregulating EMT-related proteins or by decreasing the protein expression and enzyme activity of MMP-2/-9, whereas high concentrations of ALA promote apoptosis by activating the JNK/FasL/caspase 8/caspase 3-extrinsic pathway and the Bid/cytochrome c/caspase 9 pathway. ALA demonstrates potential as a treatment for OSCC patients.
Topics: Humans; Carcinoma, Squamous Cell; Mouth Neoplasms; Squamous Cell Carcinoma of Head and Neck; alpha-Linolenic Acid; Cytochromes c; Cell Line, Tumor; Apoptosis; Cell Proliferation; Head and Neck Neoplasms; Cell Movement; Epithelial-Mesenchymal Transition
PubMed: 38068849
DOI: 10.3390/nu15234992 -
Bioorganic & Medicinal Chemistry Apr 2018Oxidation products of the poly-unsaturated fatty acids (PUFAs) arachidonic acid, α-linolenic acid and docosahexaenoic acid are bioactive in plants and animals as shown...
Oxidation products of the poly-unsaturated fatty acids (PUFAs) arachidonic acid, α-linolenic acid and docosahexaenoic acid are bioactive in plants and animals as shown for the cyclopentenones prostaglandin 15d-PGJ and PGA, cis-(+)-12-oxophytodienoic acid (12-OPDA), and 14-A-4 neuroprostane. In this study an inexpensive and simple enzymatic multi-step one-pot synthesis is presented for 12-OPDA, which is derived from α-linolenic acid, and the analogous docosahexaenoic acid (DHA)-derived cyclopentenone [(4Z,7Z,10Z)-12-[[-(1S,5S)-4-oxo-5-(2Z)-pent-2-en-1yl]-cyclopent-2-en-1yl] dodeca-4,7,10-trienoic acid, OCPD]. The three enzymes utilized in this multi-step cascade were crude soybean lipoxygenase or a recombinant lipoxygenase, allene oxide synthase and allene oxide cyclase from Arabidopsis thaliana. The DHA-derived 12-OPDA analog OCPD is predicted to have medicinal potential and signaling properties in planta. With OCPD in hand, it is shown that this compound interacts with chloroplast cyclophilin 20-3 and can be metabolized by 12-oxophytodienoic acid reductase (OPR3) which is an enzyme relevant for substrate bioactivity modulation in planta.
Topics: Cyclopentanes; Docosahexaenoic Acids; Molecular Structure; Stereoisomerism; alpha-Linolenic Acid
PubMed: 28818464
DOI: 10.1016/j.bmc.2017.07.061 -
Journal of Thrombosis and Haemostasis :... Feb 2022Sickle cell disease (SCD) is a genetic hemoglobinopathy associated with high morbidity and mortality. The primary cause of hospitalization in SCD is vaso-occlusive...
BACKGROUND
Sickle cell disease (SCD) is a genetic hemoglobinopathy associated with high morbidity and mortality. The primary cause of hospitalization in SCD is vaso-occlusive crisis (VOC), mediated by alteration of red blood cells, platelets, immune cells and a pro-adhesive endothelium.
OBJECTIVES
We investigated the potential therapeutic use of the plant-derived omega-3 alpha-linolenic acid (ALA) in SCD.
METHODS
Berkeley mice were fed a low- or high-ALA diet for 4 weeks, followed by analysis of liver fibrosis, endothelial activation, platelet activation and formation of platelet-neutrophils aggregates. Aggregation of platelets over collagen under flow after high-ALA was compared to a blocking P-selectin Fab.
RESULTS
Dietary high-ALA was able to reduce the number of sickle cells in blood smear, liver fibrosis, and the expression of adhesion molecules on the endothelium of aorta, lungs, liver and kidneys (VCAM-1, ICAM-1 and vWF). Specific parameters of platelet activation were blunted after high-ALA feeding, notably P-selectin exposure and the formation of neutrophil-platelet aggregates, along with a correspondingly reduced expression of PSGL-1 on neutrophils. By comparison, in vivo treatment of SCD mice with the anti-P-selectin Fab was able to similarly reduce the formation of neutrophil-platelet aggregates, but did not reduce GpIbα shedding nor the activation of the α β integrin in response to thrombin. Both ALA feeding and P-selectin blocking significantly reduced collagen-mediated cell adhesion under flow.
CONCLUSIONS
Dietary ALA is able to reduce the pro-inflammatory and pro-thrombotic state occurring in the SCD mouse model and may represent a novel, inexpensive and readily available therapeutic strategy for SCD.
Topics: Anemia, Sickle Cell; Animals; Cell Adhesion; Collagen; Diet; Mice; Platelet Activation; alpha-Linolenic Acid
PubMed: 34758193
DOI: 10.1111/jth.15581 -
The Journal of Nutrition Jun 2020The cognitive impairments that characterize Down syndrome (DS) have been attributed to brain hypocellularity due to neurogenesis impairment during fetal stages. Thus,...
BACKGROUND
The cognitive impairments that characterize Down syndrome (DS) have been attributed to brain hypocellularity due to neurogenesis impairment during fetal stages. Thus, enhancing prenatal neurogenesis in DS could prevent or reduce some of the neuromorphological and cognitive defects found in postnatal stages.
OBJECTIVES
As fatty acids play a fundamental role in morphogenesis and brain development during fetal stages, in this study, we aimed to enhance neurogenesis and the cognitive abilities of the Ts65Dn (TS) mouse model of DS by administering oleic or linolenic acid.
METHODS
In total, 85 pregnant TS females were subcutaneously treated from Embryonic Day (ED) 10 until Postnatal Day (PD) 2 with oleic acid (400 mg/kg), linolenic acid (500 mg/kg), or vehicle. All analyses were performed on their TS and Control (CO) male and female progeny. At PD2, we evaluated the short-term effects of the treatments on neurogenesis, cellularity, and brain weight, in 40 TS and CO pups. A total of 69 TS and CO mice were used to test the long-term effects of the prenatal treatments on cognition from PD30 to PD45, and on neurogenesis, cellularity, and synaptic markers, at PD45. Data were compared by ANOVAs.
RESULTS
Prenatal administration of oleic or linolenic acid increased the brain weight (+36.7% and +45%, P < 0.01), the density of BrdU (bromodeoxyuridine)- (+80% and +115%; P < 0.01), and DAPI (4',6-diamidino-2-phenylindole)-positive cells (+64% and +22%, P < 0.05) of PD2 TS mice with respect to the vehicle-treated TS mice. Between PD30 and PD45, TS mice prenatally treated with oleic or linolenic acid showed better cognitive abilities (+28% and +25%, P < 0.01) and a higher density of the postsynaptic marker PSD95 (postsynaptic density protein 95) (+65% and +44%, P < 0.05) than the vehicle-treated TS animals.
CONCLUSION
The beneficial cognitive and neuromorphological effects induced by oleic or linolenic acid in TS mice suggest that they could be promising pharmacotherapies for DS-associated cognitive deficits.
Topics: Animals; Body Weight; Brain; Cognition; Disease Models, Animal; Down Syndrome; Female; Maternal Exposure; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Neurogenesis; Oleic Acid; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; alpha-Linolenic Acid
PubMed: 32243527
DOI: 10.1093/jn/nxaa074 -
International Journal of Food Sciences... Aug 2017The pro- or anti-inflammatory bioactivity of dietary essential linoleic acid (LA) and alpha-linolenic acid (ALA) is mainly attributed to rate-limiting delta-6 desaturase...
The pro- or anti-inflammatory bioactivity of dietary essential linoleic acid (LA) and alpha-linolenic acid (ALA) is mainly attributed to rate-limiting delta-6 desaturase (D6D) activity. The aim of this study was to analyze mechanisms of D6D-substrates ALA, LA and D6D-product gamma-linolenic acid (GLA) under D6D-deficient conditions. Fatty acid profiles (GC-MS), D6D gene expression (real-time RT-PCR) and NFκB activity (luciferase assay) were assessed in HEK293 cells. FADS2 gene expression was approved being marginal. Incubation with ALA or LA did not increase D6D products but their elongase products C20:3n-3 and C20:2n-6. Bypassing the D6D, GLA elevated C20:3n-6 and C20:4n-6. LA significantly increased (+18% at 60 μM; p < .001), ALA reduced (-32% at 100 μM; p < .001) and GLA did not specifically change NFκB activity. Our data indicate that D6D might not be essential for the distinct effects of LA and ALA on NFκB activity.
Topics: Fatty Acid Desaturases; Gene Expression Regulation; HEK293 Cells; Humans; NF-kappa B; Transfection; Tumor Necrosis Factor-alpha; alpha-Linolenic Acid
PubMed: 27960561
DOI: 10.1080/09637486.2016.1265918 -
Methods in Molecular Biology (Clifton,... 2024Alzheimer's disease (AD) is characterized by the abnormal accumulation of disordered protein, that is, extracellular senile plaques of amyloid-β (Aβ) and intracellular...
Alzheimer's disease (AD) is characterized by the abnormal accumulation of disordered protein, that is, extracellular senile plaques of amyloid-β (Aβ) and intracellular neurofibrillary tangles of Tau. Tau protein has gained the attention in recent years owing to the ability to propagate in a "prion-like" nature. The disordered protein Tau possesses a high positive charge, which allows its binding to anionic proteins and factors. The native disorder of proteins attends the β-sheet structure from its random-coiled conformation upon charge compensation by various polyanionic agents such as heparin, RNA, etc. Anionic lipids such as arachidonic acid (AA) and oleic acid (OA) are also one of the factors which can induce aggregation of Tau in physiological conditions. The free units of Tau protein can bind to lipid membranes through its repeat domain (RD), the anionic side chains of the membrane lipids induce aggregation of Tau by reducing the activation barrier. In this study, we investigated the role of α-linolenic acid (ALA) as an inducing agent for Tau aggregation in vitro conditions. Omega-3 fatty acids bear a capacity to reduce the pathology of Tau by downregulating the Tau phosphorylation pathway. We have studied by using various biochemical or biophysical methods the potency of ALA as an aggregating agent for Tau. We have implemented different techniques such as SDS-PAGE, transmission electron microscopy, CD spectroscopy to evaluated higher-order aggregates of Tau upon induction by ALA.
Topics: Humans; tau Proteins; alpha-Linolenic Acid; Alzheimer Disease; Amyloid beta-Peptides; Neurofibrillary Tangles
PubMed: 38512668
DOI: 10.1007/978-1-0716-3629-9_11 -
Pest Management Science Jun 2022α-linolenic acid is an essential unsaturated fatty acid in organisms. However, there is a large gap between α-linolenic acid accumulation and its synthesis mechanism...
Fatty acid synthases and desaturases are essential for the biosynthesis of α-linolenic acid and metamorphosis in a major mulberry pest, Glyphodes pyloalis walker (Lepidoptera: Pyralidae).
BACKGROUND
α-linolenic acid is an essential unsaturated fatty acid in organisms. However, there is a large gap between α-linolenic acid accumulation and its synthesis mechanism in insects. Fatty acid synthases (FASs) and desaturases (Desats) are vital enzymes required for the synthesis of unsaturated fatty acids.
RESULTS
The pupae of Glyphodes pyloalis (Lepidoptera: Pyralidae), which is a destructive pest of mulberry trees, contain the highest level of α-linolenic acid compared to other life-history stages. To further explore the synthesis mechanism of α-linolenic acid in G. pyloalis pupae, we constructed a pupal transcriptome dataset and identified 106 genes related to fatty acid metabolism from it. Among these, two fatty acid synthases (GpylFAS) and five desaturases (GpylDesat) were identified. A qRT-PCR validation revealed that GpylFAS1 and GpylDesat1, 2, 3, 5 were expressed highest at pupal stages. Furthermore, the content of α-linolenic acid decreased significantly after silencing GpylFAS1 and GpylDesat5, respectively. Besides, knocking down GpylFAS1 or GpylDesat5 resulted in more malformed pupae and adults, as well as lower emergence rates. Meanwhile, silencing GpylFAS1 or GpylDesat5 affected the expressions of the other GpylFASs and GpylDesats.
CONCLUSION
The present results illustrate the pivotal function of FASs and Desats in α-linolenic acid biosynthesis and metamorphosis in insects. Our research also broadens the sources of unsaturated fatty acids, especially for α-linolenic acid from insects, and provides novel insights for the management of mulberry insect pests from the perspective of utilization rather than control. © 2022 Society of Chemical Industry.
Topics: Animals; Fatty Acid Desaturases; Fatty Acid Synthases; Morus; Moths; Pupa; alpha-Linolenic Acid
PubMed: 35362207
DOI: 10.1002/ps.6895 -
Cell Cycle (Georgetown, Tex.) May 2022Obesity is associated with elevated levels of free fatty acids (FFAs). Excessive saturated fatty acids (SFAs) exhibit significant deleterious cytotoxic effects in many...
Obesity is associated with elevated levels of free fatty acids (FFAs). Excessive saturated fatty acids (SFAs) exhibit significant deleterious cytotoxic effects in many types of cells. However, the effects of palmitic acid (PA), the most common circulating SFA, on cell cycle progression in neuronal cells have not been well-examined. The aim of this study was to examine whether PA affects the proliferation and cell cycle progression in mouse neuroblastoma Neuro-2a (N2a) cells. Our studies found that 200 µM PA significantly decreased DNA synthesis and mitotic index in N2a cells as early as 4 h following treatment. 24 h treatment with 200 µM PA significantly decreased the percentage of diploid (2 N) cells while dramatically increasing the percentage of tetraploid (4 N) cells as compared to the BSA control. Moreover, our studies found that 24 h treatment with 200 µM PA increased the percentage of binucleate cells as compared to the BSA control. Our studies also found that unsaturated fatty acids (UFAs), including linoleic acid, oleic acid, α-linolenic acid, and docosahexaenoic acid, were able to abolish PA-induced decrease of 2 N cells, increase of 4 N cells, and accumulation of binucleate cells. Taken together, these results suggest that PA may affect multiple aspects of the cell cycle progression in N2a cells, including decreased DNA synthesis, G2/M arrest, and cytokinetic failure, which could be abolished by UFAs. 4-PBA, 4-Phenylbutyric Acid; ALA, α-linolenic acid; BrdU, 5-bromo-2'-deoxyuridine; DAPI, 4',6-diamidino-2-phenylindole; ER, endoplasmic reticulum; FFA, free fatty acids; FITC, fluorescein isothiocyanate; LA, linoleic acid; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; N2a, Neuro-2a; NAC, N-acetyl cysteine; OA, oleic acid; PA, palmitic acid; pHH3, Phosphorylation of histone H3; PI, propidium iodide; SFA, saturated fatty acids; PUFA, polyunsaturated fatty acids; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; UFA, unsaturated fatty acids.
Topics: Animals; Apoptosis; Cell Line, Tumor; Cytokinesis; DNA; Fatty Acids; Fatty Acids, Nonesterified; Fatty Acids, Unsaturated; G2 Phase Cell Cycle Checkpoints; Linoleic Acids; Mice; Oleic Acids; Palmitic Acid; alpha-Linolenic Acid
PubMed: 35171079
DOI: 10.1080/15384101.2022.2040769