Evening primrose oil enriched with gamma linolenic acid and D/L-alpha tocopherol acetate attenuated carbon tetrachloride-induced hepatic injury model in male rats via TNF-α, IL-1ß, and IL-6 pathway.

The modulatory role of primrose oil (PO) supplementation enriched with γ-linolenic acid and D/L-alpha tocopherol acetate against a carbon tetrachloride (CCl4)-induced liver damage model was assessed in this study. Twenty male Albino rats were divided into four groups. The control group received corn oil orally. The PO group received 10 mg/kg P O orally. The CCl4 group received 2 mL/kg CCl4 orally and PO/CCl4 group; received PO and 2 mL/kg CCl4 orally. The relative liver weight was recorded. Serum liver enzymes, hepatic malondialdehyde (MDA), hepatic reduced glutathione (GSH) and the expression of hepatic tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6) were assessed. The binding affinities of γ-linolenic acid and D/L-alpha tocopherol constituents with IL-1ß, IL-6 and TNF-α were investigated using molecular docking simulations. Histopathological and electron microscopic examinations of the liver were performed. The results indicated that CCl4 elevated serum liver enzyme and hepatic MDA levels, whereas GSH levels were diminished. The upregulation of IL-1ß, IL-6, and TNF-α gene expressions were induced by CCl4 treatment. The PO/CCl4-treated group showed amelioration of hepatic injury biomarkers and oxidative stress. Restoration of histopathological and ultrastructural alterations while downregulations the gene expressions of TNF-α, IL1-ß and IL-6 were observed. In conclusion, evening primrose oil enriched with γ-linolenic acid and D/L-alpha tocopherol acetate elicited a potential amelioration of CCl4-induced hepatic toxicity.

Efficacy of γ-linolenic acid, Vitis vinifera extract, and acetyl-L-carnitine combination therapy for improving arterial stiffness in Korean adults: Real-world evidence.

Atherosclerosis is associated with various cardiovascular diseases (CVDs). Measurement of arterial stiffness using pulse wave velocity (PWV) enables assessment of atherosclerosis progression in individuals. The authors screened patients with asymptomatic atherosclerosis, based on the PWV findings, to evaluate appropriate early interventions and assess the efficacy of γ-linolenic acid, Vitis vinifera extract, and acetyl-L-carnitine triple combination therapy in atherosclerosis prevention. This retrospective study analyzed the medical records of adult patients between March 2007 and April 2019, with presenting complaints of fatigue and lethargy. Among patients with vascular stiffness beyond their biological age on brachial-ankle PWV (baPWV) testing, those with ≥80% compliance for three drugs were allocated to the experimental group. Those with compliance of <80% for any one drug were allocated to the control group to assess changes in arterial stiffness, fasting plasma glucose (FPG), lipid level, and blood pressure (BP). After 1 year of triple-combination therapy, there were significant decreases in right and left baPWV (1537.16 ± 274.84 and 1519.00 ± 289.32 cm/s, respectively) as compared to baseline (1633.15 ± 271. 20 and 1598.64 ± 267.95 cm/s, respectively; p < .001). There was no difference in baPWV between sexes. Moreover, neither group showed significant changes in FPG and lipid levels. When triple-combination therapy combining γ-linolenic acid, V. vinifera extract, and acetyl-L-carnitine was administered to patients with high arterial stiffness relative to their age, as assessed by baPWV, the experimental group showed a decrease in arterial stiffness in both sexes.

γ-Linolenic Acid-Rich Oil- and Fish Oil-Induced Alterations of Hepatic Lipogenesis, Fatty Acid Oxidation, and Adipose Tissue mRNA Expression in Obese KK-A y Mice.

The physiological activity of γ-linolenic acid (GLA)-rich evening primrose oil and eicosapentaenoic and doxosahexaenoic acids-rich fish oil, which affect hepatic fatty acid oxidation and synthesis, and adipose tissue mRNA expression were compared in diabetic obese KK-A y mice. The mice were fed diets containing 100 g/kg of either palm oil (saturated fat), GLA oil, or fish oil for 21 days. These oils, compared with palm oil, greatly increased the activity and mRNA levels of hepatic fatty acid oxidation enzymes. These oils also increased the carnitine concentrations and mRNA levels of carnitine transporter (solute carrier family 22, member 5) in the liver. In general, these effects were comparable between GLA and fish oils. In contrast, GLA and fish oils, compared with palm oil, reduced the activity and mRNA levels of the proteins related to hepatic lipogenesis, except for those of malic enzyme. The reducing effect was stronger for fish oil than for GLA oil. These changes were accompanied by reductions in the triacylglycerol levels in the serum and liver. The reduction in the liver was stronger for fish oil than for GLA oil. These oils also reduced epididymal adipose tissue weight accompanied by a reduction in the mRNA levels of several proteins that regulate adipocyte functions; these effects were stronger for fish oil than for GLA oil. These oils were also effective in reducing serum glucose levels. Therefore, both fish oil and GLA-rich oil were effective at ameliorating metabolic disorders related to obesity and diabetes mellitus.

Dihomo-γ-Linolenic Acid (20:3n-6)-Metabolism, Derivatives, and Potential Significance in Chronic Inflammation.

Dihomo-γ-linolenic acid (DGLA) has emerged as a significant molecule differentiating healthy and inflamed tissues. Its position at a pivotal point of metabolic pathways leading to anti-inflammatory derivatives or via arachidonic acid (ARA) to pro-inflammatory lipid mediators makes this n-6 polyunsaturated fatty acid (PUFA) an intriguing research subject. The balance of ARA to DGLA is probably a critical factor affecting inflammatory processes in the body. The aim of this narrative review was to examine the potential roles of DGLA and related n-6 PUFAs in inflammatory conditions, such as obesity-associated disorders, rheumatoid arthritis, atopic dermatitis, asthma, cancers, and diseases of the gastrointestinal tract. DGLA can be produced by cultured fungi or be obtained via endogenous conversion from γ-linolenic acid (GLA)-rich vegetable oils. Several disease states are characterized by abnormally low DGLA levels in the body, while others can feature elevated levels. A defect in the activity of ∆6-desaturase and/or ∆5-desaturase may be one factor in the initiation and progression of these conditions. The potential of GLA and DGLA administrations as curative or ameliorating therapies in inflammatory conditions and malignancies appears modest at best. Manipulations with ∆6- and ∆5-desaturase inhibitors or combinations of long-chain PUFA supplements with n-3 PUFAs could provide a way to modify the body's DGLA and ARA production and the concentrations of their pro- and anti-inflammatory mediators. However, clinical data remain scarce and further well-designed studies should be actively promoted.

Lipidome analysis and characterization of Buglossoides arvensis acyltransferases that incorporate polyunsaturated fatty acids into triacylglycerols.

Buglossoides arvensis is a burgeoning oilseed crop that contains an unique combination of ω-3 and ω-6 polyunsaturated fatty acids (PUFA), constituting ~80-85% of seed triacylglycerols (TAGs). To uncover the critical TAG biosynthetic pathways contributing for high PUFA accumulation, we performed lipidome of developing seeds and characterized acyltransferases involved in the final step of TAG biosynthesis. During seed development, distribution of lipid molecular species in individual lipid classes showed distinct patterns from an early-stage (6 days after flowering (DAF)) to the middle-stage (12 and 18 DAF) of oil biosynthesis. PUFA-containing TAG species drastically increased from 6 to 12 DAF. The expression profiles of key triacylglycerol biosynthesis genes and patterns of phosphatidylcholine, diacylglycerol and triacylglycerol molecular species during seed development were used to predict the contribution of diacylglycerol acyltransferases (DGAT1 and DGAT2) and phospholipid: diacylglycerol acyltransferases (PDAT1 and PDAT2) to PUFA-rich TAG biosynthesis. Our analysis suggests that DGATs play a crucial role in enriching TAGs with PUFA compared to PDATs. This was further confirmed by fatty acid feeding studies in yeast expressing acyltransferases. BaDGAT2 preferentially incorporated high amounts of PUFAs into TAG, compared to BaDGAT1. Our results provide insight into the molecular mechanisms of TAG accumulation in this plant and identify target genes for transgenic production of SDA in traditional oilseed crops.

Insight into the possible mechanism(s) involved in the antinociceptive and antineuropathic activity of Descurainia sophia L. Webb ex Prantl essential oil.

ETHNOPHARMACOLOGICAL RELEVANCE: Descurainia sophia (L.)(Brassicaceae), popularly known as "Khaksheer", is a native species widely distributed in Iran. The seeds and essential oil has been used in local traditional medicine (Persian folk ethnomedicine) to treat fever, inflammation, back pain, and headache. AIM OF THE STUDY: To investigate in vitro anti-nociceptive and antineuropathic activities of Descurainia sophia seeds essential oil (DSEO) in rats and to determine the possible mechanism(s) involved. MATERIALS AND METHODS: The antinociceptive activity of DSEO or Linolenic acid (LA) was evaluated using the formalin induced paw licking test followed by determination on the role of NO-cGMP-K+ channel pathway as well as a number of non-opioid receptor systems (vanilloid, dopamine, cannabinoid, serotonin, peroxisome proliferator activated, and adrenergic receptors) in the modulation of DSEO-induced antinociceptive activity. Additionally, the cervical spinal cord contusion (CCS) model was used to study antineuropathic potential of DSEO or LA. RESULTS: DSEO exerted significant (p < 0.05) antinociceptive activity in formalin test (both phases) and altered mechanical allodynia and hyperalgesia observed in the CCS model. Pretreatment with glibenclamide, Nω-nitro-L-arginine methyl ester, tranilast, methylene blue, SCH23390, SR141716A and SR144528 restored DSEO-induced antinociceptive activity observed in the formalin test. Furthermore, LA also reduced nociceptive responses induced in the formalin and CCS models. CONCLUSION: DSEO inhibits inflammatory mediated nociceptive response partly via the modulation of NO-cGMP-K+ channels pathway well as the activation of vanilloid, dopamine, and cannabinoid receptors, and exerts antineuropathic activity possibly via the modulation of inflammatory mediated activity. Thus, these findings confirm the Persian ethno-medicine claim on the efficacy of D. Sophia.

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.

Improved γ-Linolenic Acid Production from Cellulose in Mucor circinelloides via Coexpression of Cellobiohydrolase and Delta-6 Desaturase.

The present study was aimed at facilitating the production of γ-linolenic acid (GLA) from the cellulosic substrate with the engineered oleaginous fungus Mucor circinelloides WJ11. Here, the homologous recombination technology was used to overexpress the cellobiohydrolase (CBH2) derived from Trichoderma longibrachiatum and the original delta-6 fatty acid desaturase (D6) in M. circinelloides to construct genetically engineered strains capable of effectively using cellulose to enhance GLA synthesis. When cultivated in modified K&R medium supplemented with microcrystalline cellulose, the CBH2 and D6 coexpressing strains led to increases in the biomass (up to 12.8 g/L) and lipid yield (up to 3.7 g/L) of 87% and 2.4-fold, respectively, compared to that of the control strain. Notably, when CBH2 and D6 were coexpressed in M. circinelloides, the yield of GLA reached 608 mg/L, which was a dramatic increase of 3.9-fold compared to that of the control strain. This is the first report on promoting the GLA production from the cellulosic substrate via coexpression of CBH2 and delta-6 desaturase. This work provides a theoretical basis for efficient transformation from the cellulosic substrate to functional GLA by CBH2 and D6 coexpressing strains, which might play a positive role in promoting the sustainable development of biological industry.

Omega-3 fatty acids decrease CRYAB, production of oncogenic prostaglandin E2 and suppress tumor growth in medulloblastoma.

AIMS: Medulloblastoma (MB) is one of the most common malignant central nervous system tumors of childhood. Despite intensive treatments that often leads to severe neurological sequelae, the risk for resistant relapses remains significant. In this study we have evaluated the effects of the ω3-long chain polyunsaturated fatty acids (ω3-LCPUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on MB cell lines and in a MB xenograft model. MAIN METHODS: Effects of ω3-LCPUFA treatment of MB cells were assessed using the following: WST-1 assay, cell death probes, clonogenic assay, ELISA and western blot. MB cells were implanted into nude mice and the mice were randomized to DHA, or a combination of DHA and EPA treatment, or to control group. Treatment effects in tumor tissues were evaluated with: LC-MS/MS, RNA-sequencing and immunohistochemistry, and tumors, erythrocytes and brain tissues were analyzed with gas chromatography. KEY FINDINGS: ω3-LCPUFA decreased prostaglandin E2 (PGE2) secretion from MB cells, and impaired MB cell viability and colony forming ability and increased apoptosis in a dose-dependent manner. DHA reduced tumor growth in vivo, and both PGE2 and prostacyclin were significantly decreased in tumor tissue from treated mice compared to control animals. All ω3-LCPUFA and dihomo-γ-linolenic acid increased in tumors from treated mice. RNA-sequencing revealed 10 downregulated genes in common among ω3-LCPUFA treated tumors. CRYAB was the most significantly altered gene and the downregulation was confirmed by immunohistochemistry. SIGNIFICANCE: Our findings suggest that addition of DHA and EPA to the standard MB treatment regimen might be a novel approach to target inflammation in the tumor microenvironment.

Effect of enteral immunomodulatory nutrition formula on mortality and critical care parameters in critically ill patients: A systematic review with meta-analysis.

BACKGROUND: Enteral immunomodulatory nutrition is recommended as an adjuvant therapy for patients in intensive care units (ICU), but its effectiveness is incompletely understood. AIM: The aim of this review was to examine the effect of a commonly used immunomodulatory formula-omega-3 fatty acids, γ-linolenic acid, and antioxidants-on clinical outcomes and mortality risk in critically ill patients. DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs). METHOD: PubMed, Scopus, and Institute for Scientific Information (ISI) Web of Knowledge databases were searched until 18 February 2021. RCTs that used the immunomodulatory formula in the ICU were included. RESULTS: Ten RCTs (1166 participants) were included in the meta-analysis. The immunomodulatory formula reduced the duration of ICU stay weighted mean difference [(WMD): -2.97 days; 95%CI: -5.59, -0.35)], mechanical ventilation (WMD = -2.20 days, 95%CI: -4.29, -0.10), sequential organ failure assessment and multiple organ dysfunction scores (Hedge's g: -0.42 U/L; 95% CI: -0.74, -0.11), decreased 8-day overall mortality risk (RR = 0.74, 95% CI: 0.58, 0.91), and extended the ICU-free days (WMD: 4.06 days, 95% CI: 0.02, 8.09). The improvement in respiratory function and reduction in mortality risk was more in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Furthermore, the reduction in mechanical ventilation and mortality risk was more evident in older (>60 years) vs young adults. CONCLUSION AND RELEVANCE TO CLINICAL PRACTICE: Taken together, the immunomodulatory formula may enhance clinical practice for critical care nurses, such that the prevalence and/or susceptibility to secondary conditions commonly encountered in the ICU (ie, ALI and ARDS) could be attenuated, ultimately allowing critical care nurses to focus their care on the primary reason for which a patient is in the ICU. The study protocol was registered in PROSPERO.

Serum Nonesterified Fatty Acids and Incident Stroke: The CHS.

Background Significant associations between total nonesterified fatty acid (NEFA) concentrations and incident stroke have been reported in some prospective cohort studies. We evaluated the associations between incident stroke and serum concentrations of nonesterified saturated, monounsaturated, polyunsaturated, and trans fatty acids. Methods and Results CHS (Cardiovascular Health Study) participants (N=2028) who were free of stroke at baseline (1996-1997) and had an archived fasting serum sample were included in this study. A total of 35 NEFAs were quantified using gas chromatography. Cox proportional hazards regression models were used to evaluate associations of 5 subclasses (nonesterified saturated, monounsaturated, omega (n)-6 polyunsaturated, n-3 polyunsaturated, and trans fatty acids) of NEFAs and individual NEFAs with incident stroke. Sensitivity analysis was conducted by excluding cases with hemorrhagic stroke (n=45). A total of 338 cases of incident stroke occurred during the median 10.5-year follow-up period. Total n-3 (hazard ratio [HR], 0.77 [95% CI, 0.61-0.97]) and n-6 (HR, 1.32 [95% CI, 1.01-1.73]) subclasses of NEFA were negatively and positively associated with incident stroke, respectively. Among individual NEFAs, dihomo-γ-linolenic acid (20:3n-6) was associated with higher risk (HR, 1.29 [95% CI, 1.02-1.63]), whereas cis-7-hexadecenoic acid (16:1n-9c) and arachidonic acid (20:4n-6) were associated with a lower risk (HR, 0.67 [95% CI, 0.47-0.97]; HR, 0.81 [95% CI. 0.65-1.00], respectively) of incident stroke per standard deviation increment. After the exclusion of cases with hemorrhagic stroke, these associations did not remain significant. Conclusions A total of 2 NEFA subclasses and 3 individual NEFAs were associated with incident stroke. Of these, the NEFA n-3 subclass and dihomo-γ-linolenic acid are diet derived and may be potential biomarkers for total stroke risk.

Serum Levels of Dihomo-Gamma (γ)-Linolenic Acid (DGLA) Are Inversely Associated with Linoleic Acid and Total Death in Elderly Patients with a Recent Myocardial Infarction.

Dihomo-gamma-linolenic acid (DGLA) is an n-6 polyunsaturated fatty acid (PUFA) derived from linoleic acid (LA). The LA:DGLA ratio reflects conversion from LA to DGLA. Low levels of DGLA in serum have been related to poor outcome in myocardial infarction (MI) patients. Aims: To assess the association of DGLA and LA:DGLA with total death as a primary aim and incident cardiovascular events as a secondary objective. Methods: Baseline samples from 1002 patients, aged 70 to 82 years, included 2-8 weeks after an MI and followed for 2 years, were used. Major adverse clinical events (MACE) consisted of nonfatal MI, unscheduled coronary revascularization, stroke, hospitalization for heart failure or all-cause death. Cox regression analysis was used to relate serum n-6 PUFA phospholipid levels (%wt) to the risk of MACE, adjusting for the following: (1) age, sex and body mass index (BMI); (2) adding baseline cod liver oil supplementation; (3) adding prevalent hypertension, chronic kidney disease and diabetes mellitus. Results: Median DGLA level in serum phospholipids was 2.89 (Q1-Q3 2.43-3.38) %wt. DGLA was inversely related to LA and LA:DGLA ratio. There were 208 incident cases of MACE and 55 deaths. In the multivariable analysis, the hazard ratio (HR) for the total death in the three higher quartiles (Q2-4) of DGLA as compared to Q1 was 0.54 (0.31-0.95), with p = 0.03 (Model-1), 0.50 (0.28-0.91), with p = 0.02 (Model-2), and 0.47 (0.26-0.84), with p = 0.012 (Model-3), and non-significant for MACE. Risk of MACE (Model 3) approached borderline significance for LA:DGLA in Q2-4 vs. Q1 [HR 1.42 (1.00-2.04), p = 0.052]. Conclusions: Low levels of DGLA were related to a high LA:DGLA ratio and risk of total death in elderly patients with recent MI.

Insight into the Secondary Metabolites of Geum urbanum L. and Geum rivale L. Seeds (Rosaceae).

The present study aimed at the identification and quantitation of phenolic compounds, fatty acids, and further characteristic substances in the seeds of Geum urbanum L. and Geum rivale L. For this purpose, individual components of extracts recovered with MeOH, CH2Cl2, and by cold-pressing, respectively, were characterized by HPLC-DAD/ESI-MSn and GC/MS and compared with reference compounds. For both Geum species, phenolic compounds, such as flavonoids and gallic acid derivatives, and triterpenes, such as saponins and their aglycones, were detected. Surprisingly, both Geum species revealed the presence of derivatives of the triterpenoid aglycons asiatic acid and madecassic acid, which were characterized for the first time in the genus Geum. Furthermore, the fatty acids of both species were characterized by GC-MS after derivatization. Both species showed a promising fatty-acid profile in terms of nutritional properties because of high proportions of unsaturated fatty acids. Linoleic acid and linolenic acid were most abundant, among other compounds such as palmitic acid and stearic acid. In summary, the present study demonstrates the seeds of G. urbanum and G. rivale to be a valuable source of unsaturated fatty acids and bioactive phenolics, which might be exploited for nutritional and cosmetic products and for phytotherapeutic purposes.

Gamma-linolenic Acid from Fifty-seven Ribes Species and Cultivars.

γ-linolenic acid (GLA, 18:3n-6) is a bioactive fatty acid (FA) that exerts several healthy actions; however, its occurrence is restricted to a few oils. The goal of this study was to detect GLA-rich Ribes species and cultivars (cv), and to achieve this the seeds of 7 Ribes taxa and 50 Ribes cv were surveyed for FA profiles. The highest GLA percentages were found in R. nigrum cv 'Plotnokistnaya', 'Volshebnica', 'Atlant' and 'Nara' (22.6, 22.1, 20.9, and 20.0% of total FA, respectively) and also in R. komarovii (19.6%) and R. nigrum var. sibiricum (18.3%). Stearidonic acid (SDA, 18:4n-3) had the highest values in both R. rubrum 'Konstantinovskaya' and R. niveum 'Smolyaninovskaya' (4.8%). GLA content ranged from 0.4 in some R. rubrum cv and R. niveum 'Smolyaninovskaya' to 3.5 g/100 g seeds in R. nigrum 'Plotnokistnaya'. Principal component analysis (PCA) was performed using PUFA profiles, which allowed grouping Ribes sections as well as black currant cv derived from different pedigree within the section Coreosma. All taxa and cv checked here are valuable by-product sources, given the high GLA percentages contained in their seed oils. Such cv could be used for healthy oils production, as well as for breeding to obtain new cv with improved GLA concentrations.

γ-Linolenic Acid Prevents Lipid Metabolism Disorder in Palmitic Acid-Treated Alpha Mouse Liver-12 Cells by Balancing Autophagy and Apoptosis via the LKB1-AMPK-mTOR Pathway.

Excessive fat deposition is the main character in nonalcoholic fatty liver disease (NAFLD), while γ-linolenic acid (GLA) is a polyunsaturated fatty acid that can reduce lipid deposition. This study investigated the effect and regulatory mechanism of GLA (100 µM) on lipid metabolism in alpha mouse liver 12 (AML-12) cells treated by 400 µM palmitic acid (PA). GLA reduced lipid content and increased fatty acid ß oxidation, as indicated by decreasing triglyceride and cholesterol contents and increasing mRNA and protein expressions of CPT1α and PPARα. GLA relieved oxidative stress caused by PA, upregulated mRNA levels of superoxide dismutase and glutathione peroxidase, and decreased reactive oxygen species content. GLA reduced apoptosis, as indicated by decreases in the BAX/BCL2 expression level and apoptosis percentage. GLA activated autophagy, autophagosome-lysosome fusion, and LKB1-AMPK-mTOR signaling and upregulated mRNA and protein expressions of Beclin-1, autophagy-related 5, and liver kinase B1 (LKB1). These effects of GLA on lipid metabolism disorders of PA-treated hepatocytes were reversed by autophagy inhibitor 3MA and AMPK inhibitor compound C, confirming our conclusions. Overall, GLA can protect AML-12 cells from lipid metabolism disorder caused by PA via balancing autophagy and apoptosis mediated by the LKB1-AMPK-mTOR pathway. Consequently, GLA, as a dietary supplement, can help to prevent and treat NAFLD by regulating lipid metabolism and autophagy.

Iminodibenzyl redirected cyclooxygenase-2 catalyzed dihomo-γ-linolenic acid peroxidation pattern in lung cancer.

Cyclooxygenase-2 (COX-2) is up-regulated by redox imbalance and is considered a target for cancer therapy. The rationale of the COX-2 inhibitor lies in suppressing COX-2 catalyzed peroxidation of omega-6 polyunsaturated fatty acids (PUFAs), which are essential and pervasive in our daily diet. However, COX-2 inhibitors fail to improve cancer patients' survival and may lead to severe side effects. Here, instead of directly inhibiting COX-2, we utilize a small molecule, iminodibenzyl, which could reprogram the COX-2 catalyzed omega-6 PUFAs peroxidation in lung cancer by inhibiting delta-5-desaturase (D5D) activity. Iminodibenzyl breaks the conversion from dihomo-γ-linolenic acid (DGLA) to arachidonic acid, resulting in the formation of a distinct byproduct, 8-hydroxyoctanoic acid, in lung cancer cells and solid tumors. By utilizing COX-2 overexpression in cancer, the combination of DGLA supplementation and iminodibenzyl suppressed YAP1/TAZ pathway, decreasing the tumor size and lung metastasis in nude mice and C57BL/6 mice. This D5D inhibition-based strategy selectively damaged lung cancer cells with a high COX-2 level, whereas it could avoid harassing normal lung epithelial cells. This finding challenged the COX-2 redox basis in cancer, providing a new direction for developing omega-6 (DGLA)-based diet/regimen in lung cancer therapy.

Increased pro-inflammatory cytokines in ovary and effect of γ-linolenic acid on adipose tissue inflammation in a polycystic ovary syndrome model.

Polycystic Ovary Syndrome (PCOS), a major endocrine disorder, affects the reproductive function of a woman, along with an association with metabolic conditions like insulin resistance and inflammation. The inflammatory nature of PCOS is much debated over, owing to numerous cases of elevation in cytokine levels. Studies have shown the beneficiary effect of Gamma-Linolenic acid (GLA) in reducing inflammation related to many conditions such as atopic dermatitis, rheumatoid arthritis, arterial disease, obesity, and even PCOS. The study aims at assessing the expression of inflammatory cytokines in the ovary and Peri-ovarian adipose tissue (POAT) of the Dehydroepiandrosterone (DHEA) induced PCOS rat model. Further, this study also evaluates the effect of γ-linolenic Acid (GLA) on these cytokines in POAT. Female Wistar rats were subcutaneously injected with 60 mg/kg DHEA daily for 28 days. These PCOS-induced rats were then orally administered with 50 mg/kg GLA for 14 days. The gene expression of cytokines was assessed by Real Time-PCR. The study showed an increase in the expression of cytokines in the ovary and POAT of the DHEA group. This suggests the role of ovarian adipose in adding to the pro-inflammatory state of PCOS. Moreover, the administration of GLA to the PCOS-induced rats resulted in a reduction of cytokine expression from the POAT, indicating that the compound was successful in reducing the associated inflammation. The study throws light on the possibility of using GLA as a supplementary or naturalistic alternative in ameliorating ovarian adipose-associated inflammation that accompanies PCOS.

Borage Oil Enhances Lamellar Body Content and Alters Fatty Acid Composition of Epidermal Ceramides in Essential Fatty Acid-Deficient Guinea Pigs.

Borage oil [BO: 40.9% linoleic acid (LNA) and 24.0% γ-linolenic acid (GLA)] reverses disrupted epidermal lipid barrier in essential fatty acid deficiency (EFAD). We determined the effects of BO on lamellar body (LB) content and LNA and GLA incorporation into epidermal ceramide 1 (CER1) and epidermal ceramide 2 (CER2), major barrier lipids. EFAD was induced in guinea pigs by a diet of 6% hydrogenated coconut oil (HCO) for 10 weeks (group HCO) or 8 weeks followed by 6% BO for 2 weeks (group HCO + BO). LB content and LNA and GLA incorporation into CER1 were higher in group HCO + BO than in group HCO. Small but significant levels of LNA, GLA, and their C20-metabolized fatty acids [dihomo-γ-linolenic acid (DGLA) and arachidonic acid (ARA)] were incorporated into CER2, where ARA was detected at a level lower than LNA, but DGLA incorporation exceeded that for GLA in group HCO + BO. Dietary BO enhanced LB content and differential incorporation of GLA into CER1 and DGLA into CER2.

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.

DGLA from the Microalga Lobosphaera Incsa P127 Modulates Inflammatory Response, Inhibits iNOS Expression and Alleviates NO Secretion in RAW264.7 Murine Macrophages.

Microalgae have been considered as a renewable source of nutritional, cosmetic and pharmaceutical compounds. The ability to produce health-beneficial long-chain polyunsaturated fatty acids (LC-PUFA) is of high interest. LC-PUFA and their metabolic lipid mediators, modulate key inflammatory pathways in numerous models. In particular, the metabolism of arachidonic acid under inflammatory challenge influences the immune reactivity of macrophages. However, less is known about another omega-6 LC-PUFA, dihomo-γ-linolenic acid (DGLA), which exhibits potent anti-inflammatory activities, which contrast with its delta-5 desaturase product, arachidonic acid (ARA). In this work, we examined whether administrating DGLA would modulate the inflammatory response in the RAW264.7 murine macrophage cell line. DGLA was applied for 24 h in the forms of carboxylic (free) acid, ethyl ester, and ethyl esters obtained from the DGLA-accumulating delta-5 desaturase mutant strain P127 of the green microalga Lobosphaera incisa. DGLA induced a dose-dependent increase in the RAW264.7 cells' basal secretion of the prostaglandin PGE1. Upon bacterial lipopolysaccharide (LPS) stimuli, the enhanced production of pro-inflammatory cytokines, tumor necrosis factor alpha (TNFα) and interleukin 1ß (IL-1ß), was affected little by DGLA, while interleukin 6 (IL-6), nitric oxide, and total reactive oxygen species (ROS) decreased significantly. DGLA administered at 100 µM in all forms attenuated the LPS-induced expression of the key inflammatory genes in a concerted manner, in particular iNOS, IL-6, and LxR, in the form of free acid. PGE1 was the major prostaglandin detected in DGLA-supplemented culture supernatants, whose production prevailed over ARA-derived PGE2 and PGD2, which were less affected by LPS-stimulation compared with the vehicle control. An overall pattern of change indicated DGLA's induced alleviation of the inflammatory state. Finally, our results indicate that microalgae-derived, DGLA-enriched ethyl esters (30%) exhibited similar activities to DGLA ethyl esters, strengthening the potential of this microalga as a potent source of this rare anti-inflammatory fatty acid.