Untargeted metabolomics and mendelian randomization analysis identify alpha-linolenic acid and linoleic acid as novel biomarkers of perioperative neurocognitive dysfunction.

Perioperative neurocognitive dysfunction (PND) occurs in elderly individuals undergoing anesthesia and surgery. To explore the potential molecular mechanisms, we performed right-sided cervical exploratory surgery under sevoflurane anesthesia in 18-month-old male Sprague-Dawley rats. Anxiety-depression-like behaviors and learning memory abilities were assessed using the Open Field Test (OFT) and Novel Object Recognition (NOR). Additionally, the hippocampus was collected one day after surgery for inflammatory factor detection, TUNEL staining, and metabolomics analysis. Mendelian randomization (MR) analyses were subsequently conducted to validate the causal relationships by using a series of GWAS datasets related to representative differential metabolites as exposures and cognitive impairment as endpoints. The results indicated that rats exposed to anesthesia and surgery exhibited poorer cognitive performance, significant elevations in hippocampal inflammatory factors such as IL-1ß and TNF-α, and extensive neuronal apoptosis. LC-MS/MS-based untargeted metabolomics identified 19 up-regulated and 32 down-regulated metabolites in the test group, with 6 differential metabolites involved in metabolic pathways enriched according to the KEGG database. ROC analysis revealed a correlation between α-linolenic acid (ALA) and linoleic acid (LA) and the development of PND. Further MR analysis confirmed that ALA was significantly associated with cognitive performance and the risk of depression, while LA was significantly associated with the risk of memory loss. Taken together, our results identified ALA and LA as potentially powerful biomarkers for PND.

Plant Omega-3 Fatty Acids May Lower Risk of Atrial Fibrillation in Individuals with a Low Intake of Marine Omega-3 Fatty Acids.

BACKGROUND: Omega-3 fatty acids derived from seafood acids may influence cardiac arrhythmogenesis, whereas the role of the major plant-derived omega-3 fatty acid, alpha-linolenic acid (ALA), on atrial fibrillation (AF) is largely unknown. OBJECTIVES: We aimed to investigate the association between ALA intake and risk of incident AF overall and in subjects with a low intake of marine omega-3 fatty acids. METHODS: We followed a total of 54,260 middle-aged men and women enrolled into the Danish Diet, Cancer, and Health cohort for development of AF using nationwide registries. Intake of ALA was assessed using a validated food frequency questionnaire and modeled as a restricted cubic spline. Statistical analyses were conducted using Cox proportional hazards regression. RESULTS: We identified a total of 4902 incident AF events during a median of 16.9 y of follow-up. In multivariable analyses, we observed indications of a statistically nonsignificant inverse association between ALA intake and risk of AF up to an ALA intake of 2.5 g/d, whereas no appreciable association was found for higher intakes of ALA. A statistically significant dose-dependent negative association was found between ALA intake and risk of AF in individuals consuming < 250 mg marine omega-3 fatty acids daily, whereas no association was found in those with a higher intake of marine omega-3 fatty acids. CONCLUSIONS: Intake of ALA was associated with a lower risk of AF in individuals consuming a low intake of marine omega-3 fatty acids. This finding is novel and warrants further investigation.

Flaxseed Oil Alleviates Trimethyltin-Induced Cell Injury and Inhibits the Pro-Inflammatory Activation of Astrocytes in the Hippocampus of Female Rats.

Exposure to the neurotoxin trimethyltin (TMT) selectively induces hippocampal neuronal injury and astrocyte activation accompanied with resultant neuroinflammation, which causes severe behavioral, cognitive, and memory impairment. A large body of evidence suggests that flaxseed oil (FSO), as one of the richest sources of essential omega-3 fatty acids, i.e., α-linolenic acids (ALA), displays neuroprotective properties. Here, we report the preventive effects of dietary FSO treatment in a rat model of TMT intoxication. The administration of FSO (1 mL/kg, orally) before and over the course of TMT intoxication (a single dose, 8 mg/kg, i.p.) reduced hippocampal cell death, prevented the activation of astrocytes, and inhibited their polarization toward a pro-inflammatory/neurotoxic phenotype. The underlying protective mechanism was delineated through the selective upregulation of BDNF and PI3K/Akt and the suppression of ERK activation in the hippocampus. Pretreatment with FSO reduced cell death and efficiently suppressed the expression of inflammatory molecules. These beneficial effects were accompanied by an increased intrahippocampal content of n-3 fatty acids. In vitro, ALA pretreatment prevented the TMT-induced polarization of cultured astrocytes towards the pro-inflammatory spectrum. Together, these findings support the beneficial neuroprotective properties of FSO/ALA against TMT-induced neurodegeneration and accompanied inflammation and hint at a promising preventive use of FSO in hippocampal degeneration and dysfunction.

Comparative Analysis of Grape Seed Oil, Linseed Oil, and a Blend: In Vivo Effects of Supplementation.

Grape seeds are rich in bioactive substances, including polyphenols, terpenoids, and phytosterols. Linseed (Linum usitatissimum L.) boasts a high concentration of polyunsaturated fatty acids (PUFAs), lignans, phytoestrogens, and soluble fibers, all contributing to its therapeutic potential. In this study, we pioneered the formulation of an oil blend (GL) combining grape seed oil (G) and golden linseed oil (GL) in equal volumes (1:1 (v/v)) and we evaluated in terms of the nutritional, physical, and chemical properties and their influence in an in vivo experimental model. We analyzed the oils by performing physical-chemical analyses, examining the oxidative stability using Rancimat; conducting thermal analyses via thermogravimetry/derivative thermogravimetry (TG/DTG) and differential scanning calorimetry (DSC), performing optical UV-vis absorption analyses; examining the fluorescence emission-excitation matrix, total carotenoids, and color, and conducting metabolic assessments in an in vivo experimental trial. The fatty acid profile presented a higher fraction of linoleic acid (C18:2) in G and GL and alpha-linolenic acid (C18:3) in L. The acidity and peroxide indices were within the recommended ranges. The TG/DTG, DSC, and Rancimat analyses revealed similar behaviors, and the optical analyses revealed color variations caused by carotenoid contents in L and GL. In the in vivo trial, G (G2: 2000 mg/kg/day) promoted lower total consumption, and the blend (GL: 2000 mg/kg/day) group exhibited less weight gain per gram of consumed food. The group with G supplementation (G2: 2000 mg/kg/day) and GL had the highest levels of HDL-c. The group with L supplementation (L2: 2000 mg/kg/day) had the lowest total cholesterol level. The L2, G1 (1000 mg/kg/day), and G2 groups exhibited the lowest MCP-1 and TNF-α values. Additionally, the lowest adipocyte areas occurred in G and GL. Our results suggest that this combination is of high quality for consumption and can influence lipid profiles, markers of inflammation, and antioxidant status.

Dietary α-linolenic acid supplementation enhances resistance to Salmonella Typhimurium challenge in chickens by altering the intestinal mucosal barrier integrity and cecal microbes.

Salmonella is an important foodborne pathogen. Given the ban on the use of antibiotics during the egg-laying period in China, finding safe and effective alternatives to antibiotics to reduce Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) infections in chickens is essential for the prevention and control of this pathogen and the protection of human health. Numerous studies have shown that unsaturated fatty acids have a positive effect on intestinal inflammation and resistance to infection by intestinal pathogens. Here we investigated the protective effect of α-linolenic acid (ALA) against S. Typhimurium infection in chickens and further explored its mechanism of action. We added different proportions of ALA to the feed and observed the effect of ALA on S. Typhimurium colonization using metagenomic sequencing technology and physiological index measurements. The role of gut flora on S. Typhimurium colonization was subsequently verified by fecal microbiota transplantation (FMT). We found that ALA protects chickens from S. Typhimurium infection by reducing intestinal inflammation through remodeling the gut microbiota, up-regulating the expression of ileocecal barrier-related genes, and maintaining the integrity of the intestinal epithelium. Our data suggest that supplementation of feed with ALA may be an effective strategy to alleviate S. Typhimurium infection in chickens.

Integrated multi-omics analysis reveals liver metabolic reprogramming by fish iridovirus and antiviral function of alpha-linolenic acid.

Iridovirus poses a substantial threat to global aquaculture due to its high mortality rate; however, the molecular mechanisms underpinning its pathogenesis are not well elucidated. Here, a multi-omics approach was applied to groupers infected with Singapore grouper iridovirus (SGIV), focusing on the roles of key metabolites. Results showed that SGIV induced obvious histopathological damage and changes in metabolic enzymes within the liver. Furthermore, SGIV significantly reduced the contents of lipid droplets, triglycerides, cholesterol, and lipoproteins. Metabolomic analysis indicated that the altered metabolites were enriched in 19 pathways, with a notable down-regulation of lipid metabolites such as glycerophosphates and alpha-linolenic acid (ALA), consistent with disturbed lipid homeostasis in the liver. Integration of transcriptomic and metabolomic data revealed that the top enriched pathways were related to cell growth and death and nucleotide, carbohydrate, amino acid, and lipid metabolism, supporting the conclusion that SGIV infection induced liver metabolic reprogramming. Further integrative transcriptomic and proteomic analysis indicated that SGIV infection activated crucial molecular events in a phagosome-immune depression-metabolism dysregulation-necrosis signaling cascade. Of note, integrative multi-omics analysis demonstrated the consumption of ALA and linoleic acid (LA) metabolites, and the accumulation of L-glutamic acid (GA), accompanied by alterations in immune, inflammation, and cell death-related genes. Further experimental data showed that ALA, but not GA, suppressed SGIV replication by activating antioxidant and anti-inflammatory responses in the host. Collectively, these findings provide a comprehensive resource for understanding host response dynamics during fish iridovirus infection and highlight the antiviral potential of ALA in the prevention and treatment of iridoviral diseases.

Cardiovascular risk and inflammation in a population with autoimmune diseases: a narrative review.

Juvenile Systemic Connective Tissue Diseases (JSCTD) are a heterogeneous group of chronic autoimmune diseases, associated with dyslipidemia and increased cardiovascular risk are related. Studies from the last 10 years, from 2013 to 2022, on lipid profiles in JSCTD were collected. Different studies on lipid profiles in children affected by JSCTD were selected, because the aim is to analyze the cardiovascular risk and the possibility of atherosclerosis in these patients in whom, sometimes, corticosteroid therapies and immunosuppressants increase the state of dyslipidemia. Several studies have shown that autoimmune diseases with an inflammatory substrate also share abnormalities in lipid profile and increased cardiovascular risk. Specifically, associations have been found between Juvenile Systemic Connective Tissue Diseases and elevated triglycerides, TC-C (Total Cholesterol), LDL-C (Low-Density Lipoprotein), low HDL-C (High-Density Lipoprotein), and increased risk of developing diseases such as myocardial infarction, peripheral vascular disease, pulmonary and arterial hypertension, and atrial fibrillation. Supplementation with alpha-linolenic acid (ALA) on the other hand has also been analyzed with positive results in reducing inflammatory parameters, such as IL-6 (Interleukin-6), CRP (C-reactive protein), and fasting glucose, in subjects with dyslipidemia. These observations suggest that supplementation with ALA, an omega-3 precursor, may positively modulate both the inflammatory status and dyslipidemic conditions in patients with autoimmune disorders.

Alpha-Linolenic Acid Ameliorates Cognitive Impairment and Liver Damage Caused by Obesity.

Background: Obesity is a growing global problem that causes various complications such as diabetes, cognitive dysfunction, cardiovascular diseases, and hepatobiliary disease. Alpha-linolenic acid (ALA) has been reported to exhibit multiple pharmaceutical effects. This study aimed to explore the effects of ALA on obesity-induced adipose tissue accumulation, cognitive impairment, inflammation, and colonic mucosal barrier integrity. Methods: Mice were fed with high-fat diet (HFD) and were treated with ALA (60 or 100 mg/kg). Body weight, adipose tissue, serum glucose and lipid levels, glucose resistance, and insulin resistance were measured. Cognitive ability was analyzed using the behavior tests. PTP1B and IRS/p-AKT/p-GSK3ß/p-Tau signaling were examined to evaluate inflammation and synaptogenesis. Colon mucosal barrier integrity was examined by Alcian blue staining and expression of the tight junction proteins. The production of pro-inflammatory cytokines and liver damages were evaluated. 3T3-L1 cells were used for in vitro experiments. Cell viability, migration and invasion were detected. The levels of ROS, iron, and ferrous ions were measured to assess ferroptosis. Metabolomic analysis of adipose tissues was performed. Results: ALA treatment prevented HFD-induced adipose tissue accumulation, improved glucose and lipid homeostasis and metabolism. Administration of ALA repressed the HFD-induced increase in insulin levels and insulin resistance index. Serum and colon levels of pro-inflammatory cytokines were decreased after ALA treatment. ALA elevated mitochondrial content in brown adipose tissues. ALA ameliorated obesity-induced cognitive impairment and hippocampal inflammation, enhanced colon mucosa integrity. ALA treatment ameliorated HFD-induced liver damage and lipid accumulation and inhibited differentiation of preadipocyte 3T3-L1 cells into mature adipocytes and induces ferroptosis. Metabolomic analysis suggested that ALA may target the glycerolipid metabolism pathway to ameliorate obesity. Knockdown of AGPAT2 abolished the protective effects of ALA. Conclusion: ALA treatment suppressed adipose accumulation in adipocytes, improved cognitive ability and colon integrity, and alleviated liver damage by modulating the 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2).

Omega-3 and -6 Fatty Acids Alter the Membrane Lipid Composition and Vesicle Size to Regulate Exocytosis and Storage of Catecholamines.

The two essential fatty acids, alpha-linolenic acid and linoleic acid, and the higher unsaturated fatty acids synthesized from them are critical for the development and maintenance of normal brain functions. Deficiencies of these fatty acids have been shown to cause damage to the neuronal development, cognition, and locomotor function. We combined electrochemistry and imaging techniques to examine the effects of the two essential fatty acids on catecholamine release dynamics and the vesicle content as well as on the cell membrane phospholipid composition to understand how they impact exocytosis and by extension neurotransmission at the single-cell level. Incubation of either of the two fatty acids reduces the size of secretory vesicles and enables the incorporation of more double bonds into the cell membrane structure, resulting in higher membrane flexibility. This subsequently affects proteins regulating the dynamics of the exocytotic fusion pore and thereby affects exocytosis. Our data suggest a possible pathway whereby the two essential fatty acids affect the membrane structure to impact exocytosis and provide a potential treatment for diseases and impairments related to catecholamine signaling.

Serum phospholipid fatty acids are associated with bone mass in healthy 4-years-old children.

BACKGROUND: Fatty acids are involved in bone development but knowledge in children is limited. The aim of this study was to investigate bone mass and mineral density in healthy preschool children in relation to fatty acids. MATERIAL AND METHODS: In 111 healthy 4-yrs-old children (20 % overweight) bone was analysed by dual X-ray absorptiometry and serum phospholipid fatty acid by gas chromatography. Fat intake was calculated from 7 days self-reported dietary records and food frequency questionnaire. RESULTS: Total bone mass content (BMC) and mineral density (BMD) differed by sex in normal weight, but not in overweight children showing generally higher bone mass density than children with normal weight. Linoleic acid intake was strongly correlated to BMC and femoral BMD in normal weight children. Serum concentration of docosahexaenoic acid correlated positively to BMD in all children (p = 0.01), but linoleic and arachidonic acids, and monounsaturated fatty acids showed diverging associations with bone in normal weight and overweight children. CONCLUSION: Serum phospholipid DHA was associated with bone density. Other fatty acids associations to bone sites differed in overweight children, analogue to the pattern in healthy 8-yrs-old.The finding need to be confirmed longitudinally and in a larger group of overweight individuals.

Exogenous alpha-linolenic acid and Vibrio parahaemolyticus induce EPA and DHA levels mediated by delta-6 desaturase to enhance shrimp immunity.

Globally, penaeid shrimp are the most farmed and traded aquatic organisms, although they are easily susceptible to microbial pathogens. Moreover, there is a desire to increase the nutritional value of shrimp, especially the levels of n-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which also possess immunomodulatory and anti-inflammatory properties. Some aquatic animals can synthesize EPA and DHA from dietary plant-sourced alpha-linolenic acid (ALA), but penaeid shrimps' ability to synthesize these n-3 PUFAs is unknown. Here, molecular biology techniques, including gas chromatography-mass spectrometry, qPCR, ELISA, etc., were used to demonstrate that exogenous ALA or Vibrio parahaemolyticus could modulate EPA and DHA levels and immune genes in Penaeus vannamei by inducing key enzymes involved in n-3 PUFAs biosynthesis, such as delta desaturases and elongation of very long-chain fatty acid (ELOVLs). Most importantly, knockdown or inhibition of ∆6 desaturase significantly decreased EPA and DHA levels and immune gene expression even with exogenous ALA treatment, consequently affecting shrimp antibacterial immunity and survival. This study provides new insight into the potential of P. vannamei to synthesize n-3 PUFAs from exogenous ALA or upon bacteria challenge, which could be leveraged to increase their nutritional content and antimicrobial immunity.

Enrichment of a fruit-based smoothie beverage with omega-3 fatty acids from microencapsulated chia seed oil.

BACKGROUND: Omega-3 fatty acids are known for their various health benefits. Chia is the richest vegetable source of omega-3 fatty acids. However, its oil is highly susceptible to oxidative deterioration and should be protected for incorporation into food matrices. This work aimed to study the incorporation of different chia oil microcapsules in a powdered beverage, analyzing the effect on the physicochemical characteristics and stability during storage. RESULTS: Different types of microcapsules were obtained: monolayer microcapsules using sodium caseinate and lactose as wall material, and multilayer microcapsules produced through electrostatic deposition using lecithins, chitosan, and chia mucilage as the first, second, and third layers, respectively. The results demonstrated an efficient enrichment of smoothies, with omega-3 fatty acid values ranging from 24.09% to 42.73%, while the original food matrix powder lacked this component. These powder beverages exhibited low moisture content (≤ 2.91%) and low water activity (≤ 0.39). The aerated, packed density and compressibility assays indicated that adding microcapsules made the powders less dense and compressible. The color of the original powdered beverage was not modified. The dispersibility reflected an acceptable instantaneity, reaching the maximum obscuration after 30 s of stirring. The solubility of all the enriched products was higher than 70%, whereas the pH was ~6.8. The contact angle between the powder and liquid indicated an excellent ability to be reconstituted in water. The analysis of the glass transition temperature showed that the storage temperature (25 °C) was adequate. The peroxide value of all the products was low throughout the storage (≤ 1.63 meq peroxide kg-1 of oil at 90 days at 25 ± 2 °C), thus maintaining the quality of the microencapsulated chia oil. CONCLUSIONS: The results suggest that incorporating the monolayer and multilayer chia oil microcapsules that were studied could be a viable strategy for enriching smoothies with the omega-3 fatty acids present in chia seed oil. © 2023 Society of Chemical Industry.

Research progress in the neuroprotective effect of α-linolenic acid on amyotrophic lateral sclerosis / 中华神经科杂志

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease caused by the loss of motor neurons in the brain and spinal cord. Amyotrophic lateral sclerosis is currently incurable and treatment drugs are limited and can only delay the condition. The latest research shows that α-linolenic acid can prolong the survival period of patients with amyotrophic lateral sclerosis. This article reviews the neuroprotective effects of α-linolenic acid on amyotrophic lateral sclerosis through different mechanisms of action, aiming at providing some references for the treatment of amyotrophic lateral sclerosis.

Gut microbiota-related metabolite alpha-linolenic acid mitigates intestinal inflammation induced by oral infection with Toxoplasma gondii.

BACKGROUND: Oral infection with cysts is the main transmission route of Toxoplasma gondii (T. gondii), which leads to lethal intestinal inflammation. It has been widely recognized that T. gondii infection alters the composition and metabolism of the gut microbiota, thereby affecting the progression of toxoplasmosis. However, the potential mechanisms remain unclear. In our previous study, there was a decrease in the severity of toxoplasmosis after T. gondii α-amylase (α-AMY) was knocked out. Here, we established mouse models of ME49 and Δα-amy cyst infection and then took advantage of 16S rRNA gene sequencing and metabolomics analysis to identify specific gut microbiota-related metabolites that mitigate T. gondii-induced intestinal inflammation and analyzed the underlying mechanism. RESULTS: There were significant differences in the intestinal inflammation between ME49 cyst- and Δα-amy cyst-infected mice, and transferring feces from mice infected with Δα-amy cysts into antibiotic-treated mice mitigated colitis caused by T. gondii infection. 16S rRNA gene sequencing showed that the relative abundances of gut bacteria, such as Lactobacillus and Bacteroides, Bifidobacterium, [Prevotella], Paraprevotella and Macellibacteroides, were enriched in mice challenged with Δα-amy cysts. Spearman correlation analysis between gut microbiota and metabolites indicated that some fatty acids, including azelaic acid, suberic acid, alpha-linolenic acid (ALA), and citramalic acid, were highly positively correlated with the identified bacterial genera. Both oral administration of ALA and fecal microbiota transplantation (FMT) decreased the expression of pro-inflammatory cytokines and restrained the MyD88/NF-κB pathway, which mitigated colitis and ultimately improved host survival. Furthermore, transferring feces from mice treated with ALA reshaped the colonization of beneficial bacteria, such as Enterobacteriaceae, Proteobacteria, Shigella, Lactobacillus, and Enterococcus. CONCLUSIONS: The present findings demonstrate that the host gut microbiota is closely associated with the severity of T. gondii infection. We provide the first evidence that ALA can alleviate T. gondii-induced colitis by improving the dysregulation of the host gut microbiota and suppressing the production of pro-inflammatory cytokines via the MyD88/NF-κB pathway. Our study provides new insight into the medical application of ALA for the treatment of lethal intestinal inflammation caused by Toxoplasma infection. Video Abstract.

Decoding the therapeutic landscape of alpha-linolenic acid: a network pharmacology and bioinformatics investigation against cancer-related epigenetic modifiers.

Omega-3 (n - 3) and omega-6 (n - 6) polyunsaturated fatty acids (PUFAs) are vital for human health, but an imbalance between these types is associated with chronic diseases, including cancer. Alpha-linolenic acid (ALA), a n - 3 PUFA, shows promise as an anticancer agent in both laboratory and animal studies. However, the precise molecular mechanisms underlying ALA's actions against cancer-related epigenetic modifiers (CaEpM) remain unclear. To understand this, we employed network pharmacology (NP) and molecular docking techniques. Our study identified 51 potential ALA targets and GO and KEGG pathway analysis revealed possible molecular targets and signaling pathways of ALA against CaEpM. From PPI analysis, EZH2, KAT2B, SIRT1, KAT2A, KDM6B, EHMT2, WDR5, SETD7, SIRT2, and HDAC3 emerged as the top 10 potential targets. Additionally, GeneMANIA functional association (GMFA) network analysis of these top 10 targets was performed to enhance NP insights and explore ALA's multi-target approach. After an exhaustive analysis of the core FGN subnetwork, it became evident that 9 out of the 15 targets-namely EZH2, SUZ12, EED, PARP1, HDAC3, DNMT1, NCOR2, KAT2B, and TRRAP-manifested evidently strong and abundant interconnections among each other. Molecular docking of both top 10 targets and core FGN targets confirmed strong binding affinity between ALA and SIRT2, WDR5, KDM6B, EHMT2, HDAC3, EZH2, PARP1, and KAT2B, underscoring their roles in ALA's anti-CaEpM mechanism. Our findings suggest that ALA may target key signaling pathways related to transcriptional regulation, microRNA involvement, stem cell pluripotency and cellular senescence in cancer epigenetics. These findings illuminate ALA's potential as a multi-target agent against CaEpM.Communicated by Ramaswamy H. Sarma.

Influence of unsaturated fatty acids on the antitumor activity of polymeric conjugates grafted with cabazitaxel against prostate cancer.

Cabazitaxel (CTX) is a medication used for treating metastatic prostate cancer. However, its effectiveness is majorly limited by its poor water solubility and lack of tumor targeting. In this study, three unsaturated fatty acids, GLA, ALA and DHA, were separately connected with CTX and then covalently attached to bifunctionalized dextran through a linker to produce three dual drug conjugates named dextran-GLA-CTX, dextran-ALA-CTX and dextran-DHA-CTX. The three conjugates displayed enhanced solubility of CTX in water and improved antitumor effects compared to the conventional CTX formulation. The results also confirmed that dextran-GLA-CTX exhibited the strongest antitumor activity, while dextran-DHA-CTX displayed less efficacy, as evaluated through xenografted nude mice bearing PC-3 and DU145 prostate cancer cells. Additionally, dextran-GLA-CTX showed greater inhibition of tumor growth than dextran-CTX. Moreover, the dextran-GLA-CTX conjugate was found to prolong the half-life of CTX in plasma and selectively accumulate in tumors. This study revealed that unsaturated fatty acids can enhance the antitumor activity of dextran-based conjugates grafted with CTX.

Overcoming biological barriers BBB/BBTB by designing PUFA functionalised lipid-based nanocarriers for glioblastoma targeted therapy.

A major obstacle for chemotherapeutics in Glioblastoma (GB) is to reach the tumour cells due to the presence of the blood-brain barrier (BBB) and chemoresistance of anticancer drugs. The present study reports two polyunsaturated fatty acids, gamma-linolenic acid (GLA) and alpha-linolenic acid (ALA) appended nanostructured lipid carriers (NLCs) of a CNS negative chemotherapeutic drug docetaxel (DTX) for targeted delivery to GB. The ligand appended DTX-NLCs demonstrated particle size < 160 nm, PDI < 0.29 and a negative surface charge. The successful linkage of GLA (41 %) and ALA (30 %) ligand conjugation to DTX- NLCs was confirmed by diminished surface amino groups on the NLCs, lower surface charge and FTIR profiling. Fluorophore labelled GLA-DTX-NLCs and ALA-DTX-NLCs permeated the in-vitro 3D BBB model with Papp values of 1.8 × 10-3 and 1.9 × 10-3 cm/s respectively. Following permeation, both formulations showed enhanced uptake by GB immortalised cells while ALA-DTX-NLCs showed higher uptake in patient-derived GB cells as evidenced in an in-vitro 3D blood brain tumour barrier (BBTB) model. Both surface functionalised formulations showed higher internalisation in GB cells as compared to bare DTX-NLCs. ALA-DTX-NLCs and GLA-DTX-NLCs showed 13.9-fold and 6.8-fold higher DTX activity respectively at 24 h as indicated by IC50 values when tested in patient-derived GB cells. ALA-DTX-NLCs displayed better efficacy than GLA-DTX-NLCs when tested against 3D tumour spheroids and patient-derived cells. These novel formulations will contribute widely to overcoming biological barriers for treating glioblastoma.

Predicted essential fatty acid intakes for a group of dairy cows also apply at individual animal level.

The ruminant requirements for essential fatty acids (EFAs), particularly linoleic acid (LA) and alpha-linolenic acid (ALA), have not been fully determined, although evidence suggests that an adequate supply of polyunsaturated fatty acids (FAs) could improve immunity and reproduction in transition cows. In previous studies, we predicted EFA intake for a group of cows based on animal characteristics and milk EFA secretions. However, to support precision livestock feeding, we need to match the nutrient requirements and intakes of each cow as closely as possible. Our group-level predictions may not be accurate enough to estimate the EFA intake of an individual cow, due to inter-individual variations in EFA digestion and metabolism related to differences in feed intake, intake patterns, and the composition and functioning of the rumen microbiota. To address this issue, here we set out to establish specific equations that predict EFA intake for an individual cow based on the difference (i.e. the residuals) between observed EFA intake and the predicted EFA intake based on our group-level equations. We studied a database of individual dairy cows (26 experiments; 503 datapoints from three research teams) and we predicted the residuals from (1) dietary and animal-related factors (i.e. full predictions) and (2) animal-related factors only (i.e. field predictions), which are considered more field-amenable. The variance of predicted LA and log ALA intake was explained to 68% by observed LA intake and 66% by observed log ALA intake, respectively. The residuals of LA intake were predicted by dietary ALA content, total FA intake, BW, milk yield and fat content in full predictions, and by BW, feeding level, milk yield and fat content, and sum of milk C4:0 to C14:0 FA in field predictions. The log residuals of ALA intake were predicted by dietary NDF and total FA contents, NDF intake, BW, milk protein, LA and ALA contents, and fat yield in full predictions, and by BW, DM intake, milk LA and ALA contents, and fat yield in field predictions. The field predictions showed a moderate loss of accuracy compared to full predictions based on RMSE of prediction (from 38 to 54 g/d for LA and from 0.090 to 0.12 log (g/d) for ALA). This work is the first to predict the EFA intake of an individual cow based on previously established group-level predictions of EFA intake adjusted for dietary and animal-related factors.

Effect of Alpha-Linolenic Acid Supplementation on Cardiovascular Disease Risk Profile in Individuals with Obesity or Overweight: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Overweight and obesity are highly prevalent worldwide and are associated with cardiovascular disease (CVD) risk factors, including systematic inflammation, dyslipidemia, and hypertension. Alpha-linolenic acid (ALA) is a plant-based essential polyunsaturated fatty acid associated with reduced CVD risks. This systematic review and meta-analysis aimed to investigate the effects of supplementation with ALA compared with the placebo on CVD risk factors in people with obesity or overweight (International Prospective Register of Systematic Reviews Registration No. CRD42023429563). This review included studies with adults using oral supplementation or food or combined interventions containing vegetable sources of ALA. All studies were randomly assigned trials with parallel or crossover designs. The Cochrane Collaboration tool was used for assessing the risk of bias (Version 1). PubMed, Web of Science, Embase, and Cochrane library databases were searched from inception to April 2023. Nineteen eligible randomized controlled trials, including 1183 participants, were included in the meta-analysis. Compared with placebo, dietary ALA supplementation significantly reduced C-reactive protein concentration (standardized mean difference [SMD] = -0.38 mg/L; 95% confidence interval [CI]: -0.72, -0.04), tumor necrosis factor-α concentration (SMD = -0.45 pg/mL; 95% CI: -0.73, -0.17), triglyceride in serum (SMD = -4.41 mg/dL; 95% CI: -5.99, -2.82), and systolic blood pressure (SMD = -0.37 mm Hg; 95% CI: -0.66, -0.08); but led to a significant increase in low-density lipoprotein cholesterol concentrations (SMD = 1.32 mg/dL; 95% CI: 0.05, 2.59). ALA supplementation had no significant effect on interleukin-6, diastolic blood pressure, total cholesterol, or high-density lipoprotein cholesterol (all P ≥ 0.05). Subgroup analysis revealed that ALA supplementation at a dose of ≥3 g/d from flaxseed and flaxseed oil had a more prominent effect on improving CVD risk profiles, particularly where the intervention duration was ≥12 wk and where the baseline CVD profile was poor.

Association between dietary intake of omega-3 polyunsaturated fatty acids and all-cause and cardiovascular mortality among hypertensive adults: Results from NHANES 1999-2018.

BACKGROUND: Hypertensive adults are at a higher risk of cardiovascular morbidity and mortality. Dietary omega-3 polyunsaturated fatty acids (N3-PUFA) intake has been associated with cardiovascular benefits. However, few studies have specifically investigated whether dietary intake of N3-PUFA is associated with lower risk of all-cause and cardiovascular mortality among hypertensive adults in the U.S. METHODS: This prospective cohort study included 26,914 hypertensive individuals 18 years or older who participated in 10 NHANES cycles from 1999 to 2018. Dietary levels of N3-PUFA were obtained from the 24-hour dietary recalls. The dietary data were linked to mortality records from the National Death Index through December 31, 2019. The associations between dietary N3-PUFA levels and mortality were evaluated by constructing the Multivariable Cox Proportional Hazards models. RESULTS: We observed an increasing trend of dietary N3-PUFA intake levels over the years, mainly driven by alpha-linolenic acid (ALA). Lower all-cause mortality risk was observed among hypertensive adults with higher consumption of total N3-PUFA [adjusted hazards ratio, 95% confidence interval: 0.91 (0.86, 0.97)], plant-based ALA [0.88 (0.83, 0.93)], fish oil-based eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) [0.91 (0.83, 0.99)], EPA [0.93 (0.88, 0.98)], docosapentaenoic acid (DPA) [0.73 (0.58, 0.91)], or DHA [0.95 (0.90, 0.99)]. Hypertensive adults were at lower risk of cardiovascular mortality if their diet contained higher levels of total N3-PUFA [0.68 (0.53, 0.88)], ALA [0.89 (0.80, 0.99)], EPA [0.87 (0.79, 0.97)] or DPA [0.86 (0.78, 0.95)]. Weighted quantile sum analysis showed that ALA, EPA, and DPA were the main contributors of the N3-PUFA benefits against mortality among hypertensive adults. CONCLUSIONS: Dietary intake of N3-PUFA, particularly ALA, EPA, and DPA, was associated with lower risk of all-cause and cardiovascular mortality among U.S. hypertensive adults. These findings suggest that increasing dietary intake of N3-PUFA may serve as a potential strategy to lower hypertension-associated mortality risk.