The Effect of Very-Long-Chain n-3 Polyunsaturated Fatty Acids in the Central Nervous System and Their Potential Benefits for Treating Alcohol Use Disorder: Reviewing Pre-Clinical and Clinical Data.

Alcohol use poses a significant global health concern, leading to serious physical and socioeconomic issues worldwide. The current treatment options for problematic alcohol consumption are limited, leading to the exploration of alternative approaches, such as nutraceuticals. One promising target is very-long-chain n-3 polyunsaturated fatty acids (VLC n-3 PUFAs). This review aims to compile the most relevant pre-clinical and clinical evidence on the effect of VLC n-3 PUFAs on alcohol use disorders and related outcomes. The findings suggest that VLC n-3 PUFAs may alleviate the physiological changes induced by alcohol consumption, including neuroinflammation and neurotransmitter dysregulation. Additionally, they can reduce withdrawal symptoms, improve mood, and reduce stress level, all of which are closely associated with problematic alcohol consumption. However, more research is required to fully understand the precise mechanisms by which VLC n-3 PUFAs exert their function. Furthermore, PUFAs should not be considered a standalone solution, but as a complement to other therapeutic approaches. Although preliminary evidence supports the potential therapeutic effect of VLC n-3 PUFAs on problematic alcohol consumption, additional research is needed to validate these findings and determine the optimal use of PUFAs as part of a comprehensive approach to the treatment of alcohol use disorders.

Fatty acid profiling in the genus Pinus in relation to its chemotaxonomy and nutritional or pharmaceutical properties.

To develop and utilize the oil of Pinus seeds and explore natural resources rich in pinolenic acid (PNLA), twenty-one Pinus taxa were evaluated in a search of Δ5-unsaturated polymethylene-interrupted fatty acids (Δ5-UPIFA)-rich oils. While the fatty acid (FA) composition was determined by GC-FID and GC-MS, NMR of crude oils proved to be a fast method for establishing the ratio between Δ5-UPIFA and total FA. For all analyzed taxa, both the geographical origin and the concentration of total FA in the seeds are provided. PNLA and sciadonic acids occurred in all samples, while taxoleic and bishomopinolenic acids were present in most taxa. PNLA reached a maximum of 28.3% of total FA in P. mugo, and P. koraiensis showed the highest total FA amount (66.8 g/100 g seeds). The previously unanalyzed taxon P. ponderosa var. scopulorum can be considered a new PNLA source (17.1%). Principal Component Analysis showed that the similarities in FA profiles allow the grouping of the various taxa within Pinus subsections and confirmed the differential metabolic activities of Δ5 and Δ9 desaturase enzymes. This study showed that several underutilized Pinus taxa could be developed into renewable woody oil species, and their seeds could be used as raw materials for Δ5-UPIFA-rich oils extraction.

Buglossoides spp. seeds, a land source of health-promoting n-3 PUFA and phenolic compounds.

Ahiflower oil© is extracted from the seeds of Buglossoides arvensis, which contains high amounts of stearidonic acid (SDA, 18:4n-3), while its phenolic composition still is unreported. Moreover, several Buglossoides taxa remain unstudied and could become natural sources of SDA. In this work, seeds of several Buglossoides taxa and Ahiflower oil© were screened for fatty acids, phenolic compounds, and in vitro antiproliferative activities against colorectal cancer cells. Four flavonoids and 16 phenolic acids were identified and quantified. Among Buglossoides taxa, the highest amounts of phenolic compounds were found in samples collected in Spain, under a warm Mediterranean climate. Rosmarinic and lithospermic acids were the main phenols found in Buglossoides seeds. The MTT assay showed dose- and time-dependent inhibitory effects of B. arvensis extracts on HT-29 cancer cells, with a GI50value of ∼280 µg/mL after 72 h of cell exposure to seed extracts. The latter showed lower antiproliferative activity than that of pure phenolics due to the simultaneous presence of other compounds in the extracts, as evidenced by 1H NMR. This work constitutes the first approach to evaluate the seeds of several Buglossoides taxa as functional oils-providers to use them as functional foods.

γ-Linolenic and Stearidonic Acids from Boraginaceae of Diverse Mediterranean Origin.

Thirty Boraginaceae species from different tribes were evaluated in a search of γ-linolenic (GLA, 18:3n-6) and stearidonic acid (SDA, 18:4n-3)-rich oils. The high GLA percentages were found in the seed oils of Symphytum bulbosum and S. tuberosum subsp. tuberosum (27.6 and 27.2 % of total fatty acids (FA)), which are unusually high values for GLA-oils in the current literature. On the whole seed, noticeable GLA percentages were found in S. grandiflorum, S. tuberosum subsp. tuberosum and Borago officinalis (7.43, 4.90, and 4.51 g/100 g, respectively). The main SDA-taxa detected in this study were Buglossoides arvensis, B. incrassata and Glandora oleifolia (21.3, 18.9, and 16.3 % of total fatty acids). On total seed weight, Glandora rosmarinifolia showed the highest SDA content (3.57 g/100 g). Finally, the higher FA contents were found in S. grandiflorum and Paramoltkia doerfleri seeds (35.2 and 37.0 g/100 g, respectively). Principal component analysis showed that similarities in FA profiles allow grouping species as botanical criteria for Boraginaceae tribes do, while the FA groupings confirm the metabolic activities of desaturase and elongase enzymes. Data on the FA composition of the seed oils analyzed here suggest their potential use as functional foods and can be considered as novel sources of SDA and GLA.

Adding a purple corn extract in rats supplemented with chia oil decreases gene expression of SREBP-1c and retains Δ5 and Δ6 hepatic desaturase activity, unmodified the hepatic lipid profile.

Flavonoids upregulate gene expression of PPAR-α and underregulate the gene expression of SREBP-1c, and their intake increases the plasmatic concentration of n-3 LC-PUFAs. However, the biological mechanisms underlying these effects have not been elucidated. In this work, the effect of oral supplementation of ALA from chia (Salvia hispanica L.) seed oil and anthocyanins from a purple corn extract (PCE) on gene expression of SREBP-1c, PPAR-α and Δ5 and Δ6 desaturases (Δ5D and Δ6D), the activity of these enzymes in the liver as well as the hepatic lipid profile were evaluated in thirty-six female Sprague Dawley rats whose diet was supplemented with olive oil (OL), chia oil (CH), olive oil and PCE (OL + PCE) or chia oil and PCE (CH + PCE). Gene expression of PPAR-α was significantly higher when supplemented with CH and CH + PCE, SREBP-1c gene expression was higher when supplemented with chia oil. CH supplementation enhanced Δ5D expression whereas no significant differences between treatments were observed concerning Δ6D gene expression. Activities of both desaturases were increased by including olive oil (OL + PCE and OL), and they were found to be higher in CH + PCE respect to CH for both enzymes. The ALA and n-3 LCPUFAs hepatic content was higher with CH, decreasing the levels of AA and n-6 LCPUFAs. It is concluded that the joint action of flavonoids such as anthocyanins and ALA show an anti-adipogenic effect. Desaturase activity was inhibited by ALA and kept by the anthocyanins from PCE, thus anthocyanins would exert a protective effect on the desaturase activity but they would not affect on its gene expression, however, high doses of ALA increased the production of its metabolites, masking the effect of PCE.

Iron-induced pro-oxidant and pro-lipogenic responses in relation to impaired synthesis and accretion of long-chain polyunsaturated fatty acids in rat hepatic and extrahepatic tissues.

OBJECTIVES: Iron is involved in processes involving oxygen transfer and utilization. Excess iron is linked to cardiovascular diseases and some types of cancer. Iron overload is associated with oxidative stress development, and may have important interactions with lipid metabolism in the liver favoring the development and progression of non-alcoholic fatty liver disease. The aim of the study described here was to assess the effect of high intake of iron on oxidative stress-related parameters, lipid metabolism, and levels of long-chain polyunsaturated fatty acids (LCPUFAs) in liver and other tissues of the rat. METHODS: Male Wistar rats (21 d old) were fed an iron-rich diet (200 mg iron/kg diet, IRD) versus a control diet (50 mg iron/kg diet; CD) for 21 d. Samples of erythrocytes, liver, adipose tissue, brain, heart, and testicles were evaluated for fatty acid composition and hepatic biochemical and oxidative stress parameters, Δ-6 and Δ-5 desaturase activities, SREBP-1c and PPAR-α mRNA expression and DNA-binding capacity, and lipolytic, lipogenic, and antioxidant enzymatic activities. RESULTS: The IRD caused liver steatosis and increased activity of plasma transaminases, with higher oxidative stress status in plasma and liver. Liver Δ-6 and Δ-5 desaturase exhibited decreased activity, but enhanced expression in response to the IRD compared with the CD, with lower levels of ω-3 and ω-6 LCPUFAs and higher expression and DNA binding of SREBP-1c, whereas expression and DNA-binding activity of PPAR-α were diminished. CONCLUSIONS: IRD induced oxidative stress and a reduction in the desaturation capacity of the liver, with LCPUFA depletion in the different tissues studied, thus promoting a pro-steatotic condition in the liver.

Supplementation with Docosahexaenoic Acid and Extra Virgin Olive Oil Prevents Liver Steatosis Induced by a High-Fat Diet in Mice through PPAR-α and Nrf2 Upregulation with Concomitant SREBP-1c and NF-kB Downregulation.

SCOPE: Nonalcoholic fatty liver disease is the most common cause of liver disease, for which there is no validated drug therapy at present time. In this respect, the PUFA docosahexaenoic acid (DHA; C22:6 n-3) modulate lipid metabolism in the liver, and extra virgin olive oil (EVOO) has hepatoprotective effects. METHODS AND RESULTS: The effect of combined DHA (C22:6 n-3) and EVOO administration to mice on oxidative stress and metabolic disturbances induced by high-fat diet (HFD) is evaluated. Male C57BL/6J mice are fed with a control diet (10% fat, 20% protein, and 70% carbohydrates) or an HFD (60% fat, 20% protein, and 20% carbohydrates) for 12 weeks. Animals are supplemented with DHA (50 mg/kg/day), EVOO (50 mg/kg/day), or DHA + EVOO through oral route. DHA + EVOO cosupplementation results in greater protection (p < 0.05) over that elicited by DHA or EVOO supply alone, when compared to the damage induced by HFD. DHA + EVOO significantly reduces hepatic steatosis, oxidative stress, systemic inflammation, and insulin resistance. CONCLUSION: Synergistic beneficial effects of DHA + EVOO supplementation are associated with the activation/inactivation of key transcription factors involved in the above-mentioned processes. Data presented indicate that dietary supplementation with DHA + EVOO drastically reduces the development of nonalcoholic fatty liver disease.

Hydroxytyrosol prevents reduction in liver activity of Δ-5 and Δ-6 desaturases, oxidative stress, and depletion in long chain polyunsaturated fatty acid content in different tissues of high-fat diet fed mice.

BACKGROUND: Eicosapentaenoic acid (EPA, C20:5n-3), docosahexaenoic acid (DHA, C22:6n-3) and arachidonic acid (AA, C20:4n-6) are long-chain polyunsaturated fatty acids (LCPUFAs) with relevant roles in the organism. EPA and DHA are synthesized from the precursor alpha-linolenic acid (ALA, C18:3n-3), whereas AA is produced from linoleic acid (LA, C18:2n-6) through the action of Δ5 and Δ6-desaturases. High-fat diet (HFD) decreases the activity of both desaturases and LCPUFA accretion in liver and other tissues. Hydroxytyrosol (HT), a natural antioxidant, has an important cytoprotective effects in different cells and tissues. METHODS: Male mice C57BL/6 J were fed a control diet (CD) (10% fat, 20% protein, 70% carbohydrates) or a HFD (60% fat, 20% protein, 20% carbohydrates) for 12 weeks. Animals were daily supplemented with saline (CD) or 5 mg HT (HFD), and blood and the studied tissues were analyzed after the HT intervention. Parameters studied included liver histology (optical microscopy), activity of hepatic desaturases 5 and 6 (gas-liquid chromatography of methyl esters derivatives) and antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase by spectrophotometry), oxidative stress indicators (glutathione, thiobarbituric acid reactants, and the antioxidant capacity of plasma), gene expression assays for sterol regulatory element-binding protein 1c (SREBP-1c) (qPCR and ELISA), and LCPUFA profiles in liver, erythrocyte, brain, heart, and testicle (gas-liquid chromatography). RESULTS: HFD led to insulin resistance and liver steatosis associated with SREBP-1c upregulation, with enhancement in plasma and liver oxidative stress status and diminution in the synthesis and storage of n-6 and n-3 LCPUFAs in the studied tissues, compared to animals given control diet. HT supplementation significantly reduced fat accumulation in liver and plasma as well as tissue metabolic alterations induced by HFD. Furthermore, a normalization of desaturase activities, oxidative stress-related parameters, and tissue n-3 LCPUFA content was observed in HT-treated rats over control animals. CONCLUSIONS: HT supplementation prevents metabolic alterations in desaturase activities, oxidative stress status, and n-3 LCPUFA content in the liver and extrahepatic tissues of mice fed HFD.

Supplementation with antioxidant-rich extra virgin olive oil prevents hepatic oxidative stress and reduction of desaturation capacity in mice fed a high-fat diet: Effects on fatty acid composition in liver and extrahepatic tissues.

OBJECTIVE: The aim of this study was to assess the effect of dietary supplementation with extra virgin olive oil (EVOO) in mice on the reduction of desaturase and antioxidant enzymatic activities in liver, concomitantly with long-chain polyunsaturated fatty acids (LCPUFA) profiles in liver and extrahepatic tissues induced by a high-fat diet (HFD). METHODS: Male mice C57 BL/6 J were fed with a control diet (CD; 10% fat, 20% protein, 70% carbohydrates) or an HFD (60% fat, 20% protein, 20% carbohydrates) for 12 wk. Animals were supplemented with 100 mg/d EVOO with different antioxidant contents (EVOO I, II, and III). RESULTS: After the intervention, blood and several tissues were analyzed. Dietary supplementation with EVOO with the highest antioxidant content and antioxidant capacity (EVOO III) significantly reduced fat accumulation in liver and the plasmatic metabolic alterations caused by HFD and produced a normalization of oxidative stress-related parameters, desaturase activities, and LCPUFA content in tissues. CONCLUSIONS: Data suggest that dietary supplementation with EVOO III may prevent oxidative stress and reduction of biosynthesis and accretion of ω-3 LCPUFA in the liver of HFD-fed mice.

Vegetable oils rich in alpha linolenic acid increment hepatic n-3 LCPUFA, modulating the fatty acid metabolism and antioxidant response in rats.

Alpha-linolenic acid (C18:3 n-3, ALA) is an essential fatty acid and the metabolic precursor of long-chain polyunsaturated fatty acids (LCPUFA) from the n-3 family with relevant physiological and metabolic roles: eicosapentaenoic acid (C20:5 n-3, EPA) and docosahexaenoic acid (C22:6 n-3, DHA). Western diet lacks of suitable intake of n-3 LCPUFA and there are recommendations to increase the dietary supply of such nutrients. Seed oils rich in ALA such as those from rosa mosqueta (Rosa rubiginosa), sacha inchi (Plukenetia volubis) and chia (Salvia hispanica) may constitute an alternative that merits research. This study evaluated hepatic and epididymal accretion and biosynthesis of n-3 LCPUFA, the activity and expression of Δ-5 and Δ-6 desaturase enzymes, the expression and DNA-binding activity of PPAR-α and SREBP-1c, oxidative stress parameters and the activity of antioxidative enzymes in rats fed sunflower oil (SFO, 1% ALA) as control group, canola oil (CO, 10% ALA), rosa mosqueta oil (RMO, 33% ALA), sacha inchi oil (SIO, 49% ALA) and chia oil (ChO, 64% ALA) as single lipid source. A larger supply of ALA increased the accretion of n-3 LCPUFA, the activity and expression of desaturases, the antioxidative status, the expression and DNA-binding of PPAR-α, the oxidation of fatty acids and the activity of antioxidant enzymes, whereas the expression and DNA-binding activity of SREBP-1c transcription factor and the biosynthetic activity of fatty acids declined. Results showed that oils rich in ALA such as SIO and ChO may trigger metabolic responses in rats such as those produced by n-3 PUFA.

Acyl migration evaluation in monoacylglycerols from Echium plantagineum seed oil and Marinol.

Production of 2-monoacylglycerols (2-MAGs) by selective hydrolysis of the triacylglycerols (TAGs) of Echium plantagineum seed oil and Marinol and further purification was carried out. Three purification methods, including silica gel column chromatography, liquid-liquid extraction and low-temperature crystallization were assayed. Partial acyl migration during the purification step is always observed. Acyl migration rates were similar both for the column chromatography and for the liquid-liquid extraction methods, and resulted in 1-MAG/2-MAG ratios higher than 1.0. Fatty acid (FA) profiles of 2-MAGs after enzyme hydrolysis showed that the major FAs were stearidonic acid (56.9% of total FA in 2-position) and docosahexaenoic acid (63.6% of total FA in 2-position) for E. plantagineum seed oil and Marinol, respectively.