Relationships of omega-3 and omega-6 polyunsaturated fatty acids with esophageal diseases: a two-sample Mendelian randomization analysis.

Introduction: Omega-3 polyunsaturated fatty acids (PUFAs) have been widely studied and used as nutritional supplements because of their anti-inflammatory effects. Previous studies have shown an association between polyunsaturated fatty acids such as omega-3 and omega-6 PUFAs with the development of malignant tumors. However, the relationships of omega-3 and omega-6 PUFAs with esophageal diseases have not been characterized. Methods: Mendelian randomization (MR) is a statistical method for identifying instrumental variables (IVs) from genome-wide association study (GWAS) data, and is associated with little confounding by environmental or other disease-related factors. We used genome-wide association study (GWAS) data from previously published studies on circulating concentrations of omega-3, omega-6, docosahexaenoic acid (DHA) and linoleic acid (LA), as well as esophageal cancer and other esophageal diseases, which were downloaded from the IEU OpenGwas database (https://gwas.mrcieu.ac.uk/) and the GWAS Catalog database (https://www.ebi.ac.uk/). The inverse variance-weighted approach was used as the principal analysis, and the MR-Egger and weighted median methods were used alongside. A series of sensitivity analyses were used to ensure the robustness of the causality estimates. Results: We found that the circulating omega-3 PUFAs concentration was positively associated with esophageal cancer (p = 8 × 10-4), and circulating DHA concentration (the main component of omega-3 in food), was also positively associated with esophageal cancer (p = 2 × 10-2), but no significant association was found between circulating omega-6 PUFAs and esophageal cancer (p = 0.17), and circulating LA concentration (the main component of omega-6 in food), was also no significant associated with esophageal cancer (p = 0.32). We found no significant relationships of circulating omega-3 and omega-6 PUFAs concentration with four other esophageal diseases. Conclusion: This study indicates that higher levels of circulating omega-3 PUFAs and DHA concentrations may be a risk factor for the development of esophageal cancer. Conversely, an increased omega-6/omega-3 ratio may serve as a protective factor against esophageal cancer. These findings have significant implications for the clinical application of omega-3 PUFAs and the prevention and treatment of esophageal cancer.

Omega-3 Fatty Acids and Arrhythmias.

The pro- and antiarrhythmic effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been extensively studied in preclinical and human trials. Despite early evidence of an antiarrhythmic role of n-3 PUFA in the prevention of sudden cardiac death and postoperative and persistent atrial fibrillation (AF), subsequent well-designed randomized trials have largely not shown an antiarrhythmic benefit. Two trials that tested moderate and high-dose n-3 PUFA demonstrated a reduction in sudden cardiac death, but these findings have not been widely replicated, and the potential of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to reduce arrhythmic death in combination, or as monotherapy, remains uncertain. The accumulated clinical evidence does not support supplementation of n-3 PUFA for postoperative AF or secondary prevention of AF. Several large, contemporary, randomized controlled trials of high-dose n-3 PUFA for primary or secondary cardiovascular prevention have demonstrated a small, significant, dose-dependent increased risk of incident AF compared with mineral oil or corn oil comparator. These findings were reproduced with both icosapent ethyl monotherapy and a mixed EPA+DHA formulation. The proarrhythmic mechanism of increased AF in contemporary cohorts exposed to high-dose n-3 PUFA is unknown. EPA and DHA and their metabolites have pleiotropic cardiometabolic and pro- and antiarrhythmic effects, including modification of the lipid raft microenvironment; alteration of cell membrane structure and fluidity; modulation of sodium, potassium, and calcium currents; and regulation of gene transcription, cell proliferation, and inflammation. Further characterization of the complex association between EPA, EPA+DHA, and DHA and AF is needed. Which formulations, dose ranges, and patient subgroups are at highest risk, remain unclear.

Creation of a novel zebrafish model with low DHA status to study the role of maternal nutrition during neurodevelopment.

Docosahexaenoic acid (DHA), a dietary omega-3 fatty acid, is a major building block of brain cell membranes. Offspring rely on maternal DHA transfer to meet their neurodevelopmental needs, but DHA sources are lacking in the American diet. Low DHA status is linked to altered immune responses, white matter defects, impaired vision, and an increased risk of psychiatric disorders during development. However, the underlying cellular mechanisms involved are largely unknown, and advancements in the field have been limited by the existing tools and animal models. Zebrafish are an excellent model for studying neurodevelopmental mechanisms. Embryos undergo rapid external development and are optically transparent, enabling direct observation of individual cells and dynamic cell-cell interactions in a way that is not possible in rodents. Here, we create a novel DHA-deficient zebrafish model by 1) disrupting elovl2, a key gene in the DHA biosynthesis pathway, via CRISPR-Cas9 genome editing, and 2) feeding mothers a DHA-deficient diet. We show that low DHA status during development is associated with a small eye morphological phenotype and demonstrate that even the morphologically normal siblings exhibit dysregulated gene pathways related to vision and stress response. Future work using our zebrafish model could reveal the cellular and molecular mechanisms by which low DHA status leads to neurodevelopmental abnormalities and provide insight into maternal nutritional strategies that optimize infant brain health.

The efficacy and acceptability of anti-inflammatory omega-3 polyunsaturated fatty acid supplements in sepsis management: a network meta-analysis of randomized controlled trials.

Sepsis is a critical medical condition associated with high mortality for patients. Current pharmacological strategies for sepsis management or prevention had not achieved satisfactory results. The omega-3 fatty acids, with anti-inflammatory benefits, are considered to be promising agents for sepsis management/prevention. The aim of this network meta-analysis (NMA) is to compare the efficacy of various dosages and formulations of fish oil supplements for sepsis management and sepsis prevention. The current NMA consisted of two parts: (1) sepsis management and (2) sepsis prevention. The PubMed, ClinicalKey, Embase, ProQuest, Cochrane CENTRAL, ScienceDirect, Web of Science, and ClinicalTrials.gov databases were systematically searched to date of February 22nd, 2024 for relevant randomized controlled trials (RCTs). RCTs were eligible for inclusion if they enrolled participants with a diagnosis of sepsis or who with high risk for sepsis. All NMA procedures were conducted under the frequentist model. The primary outcomes assessed are (1) mortality rate in sepsis treatment or (2) incidence of sepsis in sepsis prevention. Our NMA, based on 28 RCTs and 1718 participants (mean age=51.6 years, mean female proportion=35.6 %), showed that (1) high dose parenteral fish oil supplement yield the lowest mortality rate in sepsis management in adult patients, and (2) high dose enteral fish oil supplement yield the lowest incidence of sepsis in pediatric patients. This study provides compelling evidence that high-dose fish oil supplements provide beneficial effects for both sepsis management and sepsis prevention. Our findings provide a preliminary rationale for future large-scale RCTs to investigate the role of fish oil supplementation in sepsis management or prevention.

Omega-3 supplementation changes the physical properties of leukocytes but not erythrocytes in healthy individuals: An exploratory trial.

n3-PUFA impact health in several ways, including cardiovascular protection and anti-inflammatory effects, but the underlying mechanisms are not fully understood. In this exploratory study involving 31 healthy subjects, we aimed to investigate the effects of 12 weeks of fish-oil supplementation (1500 mg EPA+DHA/day) on the physical properties of multiple blood cell types. We used deformability cytometry (DC) for all cell types and Laser-assisted Optical Rotational Red Cell Analysis (Lorrca) to assess red blood cell (RBC) deformability. We also investigated the correlation between changes in the physical properties of blood cells and changes in the Omega-3 Index (O3I), defined as the relative content of EPA+DHA in RBCs. Following supplementation, the mean±SD O3I increased from 5.3 %±1.5 % to 8.3 %±1.4 % (p < 0.001). No significant changes in RBC properties were found by both techniques. However, by DC we observed a consistent pattern of physical changes in lymphocytes, neutrophils and monocytes. Among these were significant increases in metrics correlated with the cells' deformability resulting in less stiff cells. The results suggest that leukocytes become softer and have an increased ability to deform under induced short-term physical stress such as hydrodynamic force in the circulation. These changes could impact immune function since softer leukocytes can potentially circulate more easily and could facilitate a more rapid response to systemic inflammation or infection. In conclusion, fish-oil supplementation modulates some physical properties of leukocyte-subfractions, potentially enhancing their biological function. Further studies are warranted to explore the impact of n3-PUFA on blood cell biology, particularly in disease states associated with leukocyte dysregulation.

Dietary consumption patterns in breast cancer survivors: Pilot evaluation of diet, supplements and clinical factors.

PURPOSE: Adherence to dietary intake guidelines is recommended for optimal nutrition and outcomes in breast cancer survivors. The purpose of this study was to examine dietary quality in a cohort of breast cancer survivors related to current guidelines, guiding further education-based research. METHODS: This exploratory evaluation examined compliance with current dietary guidelines. Data collected included demographics, medical histories and repeated, three-day 24-h dietary recalls. Women with early-stage breast cancer (n = 97) who completed breast cancer treatment between 6 and 24 months were recruited. Descriptive statistics and frequencies were calculated for demographic and lifestyle characteristics, reported fish consumption, body mass index categories, supplement consumption, and adequacy of macronutrient and micronutrient consumption (classified as below, meeting, or exceeding needs). RESULTS: In this cohort, 28.9% were classified as overweight and 35% were obese. The mean dietary macronutrient consumption was 44.3% (±8.9%) carbohydrates, 36.6% (±7.3%) fat, and 17.3% (±4.7%) protein. Additionally, 32.3% participants consumed >45 g sugar/d. The mean n-6 to n-3 ratio was 8.0 (±3.3):1. Further, 38% of survivors reported consuming less than 1 serving of fish per week. Participants consumed between 0 and 1.03 servings of fish per day, with an average consumption of 0.16 (±0.26) servings per day and 61.5% (n = 59) consuming 0 servings per day. The mean daily combined dietary and supplement consumption of multiple micronutrients was below the Recommended Daily Allowance for Vitamin D (30%), Calcium (52.6%), Magnesium (42.1%), and Vitamin E (80%). CONCLUSION: Breast cancer survivors 0.5-2 years post-treatment are not meeting recommended nutrition consumption guidelines for a number of nutrients. Findings suggested that nutrition therapy targeting weight loss through reduced sugar, total and saturated fat, while increasing foods rich in omega-3, and ensuring adequate micronutrient consumption would promote better nutritional consumption patterns and improve overall health during survivorship.

A plasma lipid signature in acute human traumatic brain injury: Link with neuronal injury and inflammation markers.

Traumatic brain injury (TBI) leads to major membrane lipid breakdown. We investigated plasma lipids over 3 days post-TBI, to identify a signature of acute human TBI and assess its correlation with neuronal injury and inflammation. Plasma from patients with TBI (Abbreviated Injury Scale (AIS)3 - serious injury, n = 5; AIS4 - severe injury, n = 8), and controls (n = 13) was analysed for lipidomic profile, neurofilament light (NFL) and cytokines, and the omega-3 index was measured in red blood cells. A lipid signature separated TBI from controls, at 24 and 72 h. Major species driving the separation were: lysophosphatidylcholine (LPC), phosphatidylcholine (PC) and hexosylceramide (HexCer). Docosahexaenoic acid (DHA, 22:6) and LPC (0:0/22:6) decreased post-injury. NFL levels were increased at 24 and 72 h post-injury in AIS4 TBI vs. controls. Interleukin (IL-)6, IL-2 and IL-13 were elevated at 24 h in AIS4 patients vs. controls. NFL and IL-6 were negatively correlated with several lipids. The omega-3 index at admission was low in all patients (controls: 4.3 ± 1.1% and TBI: 4.0 ± 1.1%) and did not change significantly over 3 days post-injury. We have identified specific lipid changes, correlated with markers of injury and inflammation in acute TBI. These observations could inform future lipid-based therapeutic approaches.

The Impact of Dietary Unsaturated Fat or the Mediterranean Diet on Women Diagnosed With Breast Cancer: A Systematic Review.

This review explores the multifaceted relationship between dietary factors and breast cancer outcomes, focusing on unsaturated fats, the Mediterranean diet (MD), and other nutritional components. Breast cancer remains a significant global health concern, with lifestyle factors like diet playing a pivotal role in prevention and management. The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Articles written in English and released between 2019 and 2024 were acceptable. We used pertinent search terms such as "unsaturated fats", "Mediterranean diet", "breast cancer", and "nutrition" to perform searches in PubMed, PubMed Central (PMC), EBSCOhost, and grey literature such as Google Scholar. After screening, 11 of the 479 original papers were chosen and included in the final review. These include cross-sectional analysis and systematic review, cohort study, narrative review, systematic review and meta-analysis, case-control study, randomized controlled trials (RCTs), and cross-sectional study. Key findings suggest that adherence to the MD correlates with improved quality of life measures and reduced mortality rates among women with breast cancer, particularly in older age groups. The diet's emphasis on antioxidant-rich foods, anti-inflammatory compounds, and healthy fats contributes to these observed benefits. Specific unsaturated fats, notably omega-3 polyunsaturated fatty acids (PUFAs) like docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), demonstrate anti-cancer properties by modulating cancer cell behavior and enhancing treatment responses. Biomarkers associated with the MD, such as ß-carotene and lycopene, serve as indicators of dietary compliance and potential risk reduction. Furthermore, components found in olive oil, including polyphenols and monounsaturated fatty acids, exhibit promising effects in preventing breast cancer by exerting antioxidant and anti-proliferative actions. Other dietary factors like calcium, legumes, fruits, and vegetables also play a role in reducing breast cancer risk and improving survival rates. This review underscores the importance of dietary interventions in optimizing outcomes for breast cancer patients and highlights the need for further research to elucidate underlying mechanisms and refine dietary recommendations.

Dietary modulation of Lung Lipids Influences Inflammatory Responses to Inhaled Ozone.

The pulmonary system represents a unique lipidomic environment as it contains cellular membrane bound lipid species and a specialized reservoir of lipids in the airway epithelial lining fluid. As a major initial point of defense, airway lipids react to inhaled contaminants such as volatile organic compounds, oxides of nitrogen, or ozone (O3), creating lipokine signaling that is crucial for both the initiation and resolution of inflammation within the lung. Dietary modulation of eicosanoids has gained increased attention in recent years for improvements to cardiovascular health. The current study sought to examine how dietary supplementation with eicosanoid precursors (i.e., oils rich in saturated or polyunsaturated fatty acids) might alter the lung lipid composition and subsequently modify the inflammatory response to ozone inhalation. Our study demonstrated that mice fed a diet high in saturated fatty acids resulted in diet-specific changes to lung lipid profiles and increased cellular recruitment to the lung following ozone inhalation. Bioinformatic analysis revealed an ozone-dependent upregulation of several lipid species, including phosphoserine 37:5. Pathway analysis of lipid species revealed the process of lateral diffusion of lipids within membranes to be significantly altered due to ozone exposure. These results show promising data for influencing pulmonary lipidomic profiles via diet, which may provide a pragmatic therapeutic approach to protect against lung inflammation and damage following pulmonary insult.

Omega-3 Reverses the Metabolic and Epigenetically Regulated Placental Phenotype acquired from Pre-conceptional and Peri-conceptional Exposure to Air Pollutants.

Air pollution is detrimental to pregnancy adversely affecting maternal and child health. Our objective was to unravel epigenetic mechanisms mediating the effect of pre-conception, periconception, and gestational exposure to inhaled air pollutants (AP) upon the maternal and placental-fetal phenotype and explore the benefit of an omega-3 rich dietary intervention. To this end, we investigated intra-nasal instilled AP during 8 weeks of preconception, periconception, and gestation (G; D0 to 18) upon GD16-19 maternal mouse metabolic status, placental nutrient transporters, placental-fetal size, and placental morphology. Pre-pregnant mice were glucose intolerant and insulin resistant, while pregnant mice were glucose intolerant but displayed no major placental macro-nutrient transporter changes, except for an increase in CD36. Placentas revealed inflammatory cellular infiltration with cellular edema, necrosis, hemorrhage, and an increase in fetal body weight. Upon examination of placental genome-wide epigenetic processes of DNA sequence specific 5'-hydroxymethylation (5'-hmC) and 5'-methylation (5'-mC) upon RNA sequenced gene expression profiles, revealed changes in key metabolic, inflammatory, transcriptional, and cellular processing genes and pathways. An omega-3 rich anti-inflammatory diet from preconception (8 weeks) through periconception and gestation (GD0-18), ameliorated all these maternal and placental-fetal adverse effects. We conclude that pre-conceptional, periconceptional and gestational exposures to AP incite a maternal inflammatory response resulting in features of pre-existing maternal diabetes mellitus with injury to the placental-fetal unit. DNA 5'-mC more than 5'-hmC mediated AP induced maternal inflammatory and metabolic dysregulation which together alter placental gene expression and phenotype. A dietary intervention partially reversing these adversities provides possibilities for a novel nutrigenomic therapeutic strategy.

Short-term dietary changes are reflected in the cerebral content of adult ring-billed gulls.

Omega-3 long-chain polyunsaturated fatty acids (n3-LCPUFAs) are produced primarily in aquatic ecosystems and are considered essential nutrients for predators given their structural role in vertebrates' cerebral tissues. Alarmingly, with urbanization, many aquatic animals now rely on anthropogenic foods lacking n3-LCPUFAs. In this study undertaken in Newfoundland (Canada), we tested whether recent or longer term diet explains the cerebral fatty acid composition of ring-billed gulls (Larus delawarensis), a seabird that now thrives in cities. During the breeding season, cerebral levels of n3-LCPUFAs were significantly higher for gulls nesting in a natural habitat and foraging on marine food (mean ± s.d.: 32 ± 1% of total identified fatty acids) than for urban nesters exploiting rubbish (27 ± 1%). Stable isotope analysis of blood and feathers showed that urban and natural nesters shared similar diets in autumn and winter, suggesting that the difference in cerebral n3-LCPUFAs during the breeding season was owing to concomitant and transient differences in diet. We also experimentally manipulated gulls' diets throughout incubation by supplementing them with fish oil rich in n3-LCPUFAs, a caloric control lacking n3-LCPUFAs, or nothing, and found evidence that fish oil increased urban nesters' cerebral n3-LCPUFAs. These complementary analyses provide evidence that the brain of this seabird remains plastic during adulthood and responds to short-term dietary changes.

Understanding the Role of Polyunsaturated Fatty Acids in the Development and Prevention of Cancer.

Polyunsaturated fatty acids (PUFAs), notably omega-3 (n-3) and omega-6 (n-6), have received much attention owing to their multifaceted effects not only in the management of diverse pathological conditions but also in the maintenance of overall health of an individual. A disproportionately high n-6 to n-3 ratio contributes to the development of various disorders including cancer, which ranks as a leading cause of death worldwide with profound social and economic burden. Epidemiological studies and clinical trials combined with the animal and cell culture models have demonstrated the beneficial effects of n-3 PUFAs in reducing the risk of various cancer types including breast, prostate and colon cancer. The anti-cancer actions of n-3 PUFAs are mainly attributed to their role in the modulation of a wide array of cellular processes including membrane dynamics, apoptosis, inflammation, angiogenesis, oxidative stress, gene expression and signal transduction pathways. On the contrary, n-6 PUFAs have been shown to exert pro-tumor actions; however, the inconsistent findings and controversial data emphasize upon the need to further investigation. Nevertheless, one of the biggest challenges in future is to optimize the n-6 to n-3 ratio despite the genetic predisposition, age, gender and disease severity. Moreover, a better understanding of the potential risks and benefits as well as the cellular and molecular mechanisms of the basic actions of these PUFAs is required to explore their role as adjuvants in cancer therapy. All these aspects will be reviewed in this chapter.

Impact of omega-3 fatty acids on hypertriglyceridemia, lipidomics, and gut microbiome in patients with type 2 diabetes.

BACKGROUND: Fish oil (FO), a mixture of omega-3 fatty acids mainly comprising docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), has been recommended for patients with type 2 diabetes (T2D) and hypertriglyceridemia. However, its effects on lipidomic profiles and gut microbiota and the factors influencing triglyceride (TG) reduction remain unclear. METHODS: We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 309 Chinese patients with T2D with hypertriglyceridemia (ClinicalTrials.gov: NCT03120299). Participants were randomly assigned (1:1) to receive either 4 g FO or corn oil for 12 weeks. The primary outcome was changes in serum TGs and the lipidomic profile, and the secondary outcome included changes in the gut microbiome and other metabolic variables. FINDINGS: The FO group had significantly better TG reduction (mean [95% confidence interval (CI)]: -1.51 [-2.01, -1.01] mmol/L) compared to the corn oil group (-0.66 [-1.15, -0.16] mmol/L, p = 0.02). FO significantly altered the serum lipid profile by reducing low-unsaturated TG species and increasing those containing DHA or EPA. FO had minor effects on gut microbiota, while baseline microbial features predicted the TG response to FO better than phenotypic or lipidomic features, potentially mediated by specific lipid metabolites. A total of 9 lipid metabolites significantly mediated the link between 4 baseline microbial variables and the TG response to FO supplementation. CONCLUSIONS: Our findings demonstrate differential impacts of omega-3 fatty acids on lipidomic and microbial profiles in T2D and highlight the importance of baseline gut microbiota characteristics in predicting the TG-lowering efficacy of FO. FUNDING: This study was funded by the National Nature Science Foundation.

The role of lipid emulsions containing omega-3 fatty acids for medical and surgical critical care patients.

In critical illness the regulation of inflammation and oxidative stress can improve patient outcomes, and thus omega-3 polyunsaturated fatty acids (PUFAs) have been used as part of parenteral nutrition (PN) owing to their potential anti-inflammatory effects. The international lipids in PN Summit, encompassed discussions and the production of consensus guidelines concerning PN intravenous lipid emulsion (ILE) use in critical care. The Lipid Summit participants agreed that the inclusion of fish oil in ILEs is associated with meaningful clinical benefits without signals of harm, based on a strong biological rationale and current clinical evidence. Decisions concerning ILE choice should be made based on current evidence, thus addressing clinical requirements for guidance, particularly as further definitive evidence seems unlikely to occur. In addition, a future of individualized ICU care is envisioned, yielding better clinical outcomes. This approach will require the greater use of intelligent study designs incorporating the use of biomarkers of omega-3 derivatives, inflammatory-resolving processes, and/or muscle protein breakdown.

Pre-pregnancy overweight or obesity moderates the association between prenatal maternal depressive symptoms and infant cord blood omega-3 levels.

BACKGROUND: Empirical evidence has demonstrated associations between pre-pregnancy obesity and perinatal maternal depressive symptoms. Omega-3 is an essential fatty acid derived from dietary sources that is critical for fetal brain development. Pre-pregnancy obesity is associated with higher omega-3 intake, but a weaker association between dietary intake and respective maternal and cord blood omega-3 levels. Further, lower intake of omega-3 during pregnancy has been linked to higher depressive symptoms. Yet, prior studies have not examined the interactive effects of pre-pregnancy overweight or obesity (OWOB) and prenatal maternal mental health symptoms on infant cord blood omega-3 levels. METHODS: Participants included 394 maternal-infant dyads from the NIH Environmental influences on Child Health Outcomes (ECHO) - Safe Passage Study in South Dakota. A pre-pregnancy body mass index (BMI) > 25 was used to dichotomize participants as OWOB (54%) vs. non-OWOB (46%). Prenatal maternal depressive symptoms were measured using the Edinburgh Postnatal Depression Scale (EPDS) and prenatal maternal anxiety symptoms were measured using the State-Trait Anxiety Inventory (STAI). We implemented linear regression models to examine the interaction term between pre-pregnancy BMI category and prenatal maternal mental health symptoms on cord blood omega-3 levels. Secondary analyses were stratified by pre-pregnancy BMI category. RESULTS: We observed a significant interaction between pre-pregnancy BMI category and prenatal maternal depressive symptoms with cord blood omega-3 (F(4,379) = 6.21, p < .0001, adj. R2 = 0.05). Stratified models revealed an association between prenatal maternal depressive symptoms with lower cord blood omega-3 levels only among individuals with pre-pregnancy OWOB (ß = -0.06, 95% CI = -0.11, -0.02; F (2,208) = 4.00, p < .05, adj R2 = 0.03). No associations were observed among non-OWOB participants. CONCLUSIONS: Findings suggest maternal-placental transfer of omega-3 may represent one pathway by which maternal metabolic and mental health impacts infant development.

The polyunsaturated fatty acid docosahexaenoic affects mitochondrial function in prostate cancer cells.

BACKGROUND: Prostate cancer (PCa) shows a rewired metabolism featuring increased fatty acid uptake and synthesis via de novo lipogenesis, both sharply related to mitochondrial physiology. The docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid (PUFA) that exerts its antitumoral properties via different mechanisms, but its specific action on mitochondria in PCa is not clear. Therefore, we investigated whether the DHA modulates mitochondrial function in PCa cell lines. METHODS: Here, we evaluated mitochondrial function of non-malignant PNT1A and the castration-resistant (CRPC) prostate 22Rv1 and PC3 cell lines in response to DHA incubation. For this purpose, we used Seahorse extracellular flux assay to assess mitochondria function, [14C]-glucose to evaluate its oxidation as well as its contribution to fatty acid synthesis, 1H-NMR for metabolite profile determination, MitoSOX for superoxide anion production, JC-1 for mitochondrial membrane polarization, mass spectrometry for determination of phosphatidylglycerol levels and composition, staining with MitoTracker dye to assess mitochondrial morphology under super-resolution in addition to Transmission Electron Microscopy, In-Cell ELISA for COX-I and SDH-A protein expression and flow cytometry (Annexin V and 7-AAD) for cell death estimation. RESULTS: In all cell lines DHA decreased basal respiratory activity, ATP production, and the spare capacity in mitochondria. Also, the omega-3 induced mitochondrial hyperpolarization, ROS overproduction and changes in membrane phosphatidylglycerol composition. In PNT1A, DHA led to mitochondrial fragmentation and it increased glycolysis while in cancer cells it stimulated glucose oxidation, but decreased de novo lipogenesis specifically in 22Rv1, indicating a metabolic shift. In all cell lines, DHA modulated several metabolites related to energy metabolism and it was incorporated in phosphatidylglycerol, a precursor of cardiolipin, increasing the unsaturation index in the mitochondrial membrane. Accordingly, DHA triggered cell death mainly in PNT1A and 22Rv1. CONCLUSION: In conclusion, mitochondrial metabolism is significantly affected by the PUFA supplementation to the point that cells are not able to proliferate or survive under DHA-enriched condition. Moreover, combination of DHA supplementation with inhibition of metabolism-related pathways, such as de novo lipogenesis, may be synergistic in castration-resistant prostate cancer.

Effects of Age and Diet on Triglyceride Metabolism in Mice.

Background: Both age and diet can contribute to alterations in triglyceride metabolism and subsequent metabolic disease. In humans, plasma triglyceride levels increase with age. Diets high in saturated fats can increase triglyceride levels while diets high in omega-3 fatty acids decrease triglyceride levels. Here we asked how age and long-term diet effected triglyceride metabolism in mice. Methods: We fed male and female mice a low-fat diet, a western diet, or a diet high in polyunsaturated and omega-3 (n-3) fatty acids for up to 2 years. We measured survival, body composition, plasma triglyceride levels, chylomicron clearance, and oral fat, glucose, and insulin tolerance. Results: Triglyceride levels in mice did not increase with age, regardless of diet. Oral fat tolerance increased with age, while chylomicron clearance remained unchanged. Mice fed western diet had decreased survival. Interestingly, mice fed the n-3 diet gained more lean mass, and had lower insulin levels than mice fed either low-fat or western diet. Moreover, triglyceride uptake into the hearts of mice fed the n-3 diet was strikingly higher than in other groups. Conclusions: In mice, age-induced changes in triglyceride metabolism did not match those in humans. Our data suggested that mice, like humans, had decreased fat absorption with age, but plasma triglyceride clearance did not decrease with age in mice, resulting in lower plasma triglyceride levels and improved oral fat tolerance with age. A chronic diet high in n-3 fatty acids increased insulin sensitivity and uptake of triglycerides specifically into the heart but how these observations are connected is unclear.

Long-chain polyunsaturated fatty acids and brain functions - literature review.

Long-chain ω-3 PUFAs such as DHA and EPA are often present in high amounts in algae and fish. DHA in particular is crucial for the proper development and functioning of the brain because it is the main structural component of ω-3 PUFA in the brain. This makes it an indispensable element of the phospholipids of the nervous membrane. The purpose of this article is to present the benefits of Omega-3 acids in the functioning of the nervous system. The text discusses a literature review focusing on the impact of omega-3 fatty acids. Polyunsaturated fatty acids (PUFAs) are essential for overall health and have been extensively studied for their contributions to human well-being and disease management. Recent research indicates their effectiveness in preventing and treating various diseases. Omega-3 PUFAs have been identified as therapeutic agents, particularly in combating inflammatory conditions like cardiovascular and neurodegenerative diseases. The aim of this article is to present the benefits of omega-3 fatty acids supplementation. Publications outlining properties of polyunsaturated fatty acids on the brain and articles presenting the effects of polyunsaturated fatty acids were reviewed using the Pubmed platform. The review included the keywords "Omega-3 fatty acids" "DHA" "EPA" "PUFA.

The Role of Nutritional Factors in Transitioning between Early, Mid and Late Stages of Age-Related Macular Degeneration: prospective longitudinal analysis.

BACKGROUND: Transitions between different stages of age-related macular degeneration (AMD) are not completely captured by traditional survival models with an endpoint of advanced AMD. OBJECTIVE: This study aimed to explore the transitions from early and intermediate AMD to higher non-advanced and advanced stages and determine the contributions of nutritional factors to these outcomes. METHODS: Eyes with early or intermediate AMD at baseline, classified according to the Age-Related Eye Disease Study severity score, were included in this prospective longitudinal analysis. Foods and the biologically active nutrients associated with AMD [green leafy vegetables, fish, lutein/zeaxanthin (LZ), and ω-3 fatty acids] were determined by a baseline food frequency questionnaire. Progression was defined as eyes transitioning to higher severity groups including non-advanced and advanced stages over 5 years, confirmed at 2 consecutive visits. Cox proportional hazards models for foods and nutrients were analyzed adjusting for demographics, lifestyle, baseline macular status, family history of AMD, caloric intake and genetic risk. RESULTS: Among 2697 eyes, 616 (23%) progressed to higher severity groups. In the food group model, higher intake of green leafy vegetables reduced incidence of transitions [hazard ratio (HR) (≥ 2.7 servings/week vs. none) = 0.75 (95% confidence interval 0.59 - 0.96), P = 0.02]. Higher fish intake was also protective [HR (≥ two 4-ounce servings/week vs. < 2) = 0.79 (0.65 - 0.95), P = 0.01]. In the nutrient model, LZ intake was protective [HR (≥ 2 mg/day vs. < 2) = 0.76 (0.60 - 0.96), P = 0.02]. Higher intake of ω-3 fatty acids also tended to be beneficial [HR (≥ 0.7 g/week vs. < 0.7) = 0.85 (0.71 - 1.01), P = 0.06]. CONCLUSIONS: Increased consumption of green leafy vegetables, LZ, and fish nutritionally rich in ω-3 fatty acids during the initial stages of AMD may reduce rates of progression to higher severity of this debilitating disease. CLINICAL TRIAL: NCT00594672.

Lipid-Lowering Medications for Managing Dyslipidemia: A Narrative Review.

Dyslipidemia refers to the change in the normal levels of one or more lipid components in the bloodstream, which include triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C). Dyslipidemia represents a substantial source of danger for cardiovascular disease (CVD). Effectively managing dyslipidemia involves a thorough strategy that includes changing one's lifestyle and using medications that are specifically designed to target the complex processes involved in lipid metabolism. Lipid-lowering treatments play a crucial role in this approach, providing a wide range of medications that are developed to specifically target different components of dyslipidemia. Statins are the main drug among these medications. Other drugs that are used with statin or as monotherapy include fibrates, omega-3 fatty acids (OM3FAs), ezetimibe, bile acid sequestrants, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and bempedoic acid. Using the PubMed database, we reviewed the literature about dyslipidemia, drugs used for treating dyslipidemia, their efficacy parameters, and common adverse events. We also reviewed the international guidelines for treating dyslipidemia and discussed the future of lipid-lowering medications. More trials and experiments are still required to verify the effectiveness of many lipid-lowering drugs and to know their common adverse events to be able to manage them properly.