Biochemical and Molecular Insights into Variation in Sesame Seed Antioxidant Capability as Revealed by Metabolomics and Transcriptomics Analysis.

Sesame seeds are important resources for relieving oxidation stress-related diseases. Although a significant variation in seeds' antioxidant capability is observed, the underlying biochemical and molecular basis remains elusive. Thus, this study aimed to reveal major seed components and key molecular mechanisms that drive the variability of seeds' antioxidant activity (AOA) using a panel of 400 sesame accessions. The seeds' AOA, total flavonoid, and phenolic contents varied from 2.03 to 78.5%, 0.072 to 3.104 mg CAE/g, and 2.717 to 21.98 mg GAE/g, respectively. Analyses revealed that flavonoids and phenolic acids are the main contributors to seeds' AOA variation, irrespective of seed coat color. LC-MS-based polyphenol profiling of high (HA) and low (LA) antioxidant seeds uncovered 320 differentially accumulated phenolic compounds (DAPs), including 311 up-regulated in HA seeds. Tricin, persicoside, 5,7,4',5'-tetrahydro-3',6-dimethoxyflavone, 8-methoxyapigenin, and 6,7,8-tetrahydroxy-5-methoxyflavone were the top five up-regulated in HA. Comparative transcriptome analysis at three seed developmental stages identified 627~2357 DEGs and unveiled that differential regulation of flavonoid biosynthesis, phenylpropanoid biosynthesis, and stilbene biosynthesis were the key underlying mechanisms of seed antioxidant capacity variation. Major differentially regulated phenylpropanoid structural genes and transcription factors were identified. SINPZ0000571 (MYB), SINPZ0401118 (NAC), and SINPZ0500871 (C3H) were the most highly induced TFs in HA. Our findings may enhance quality breeding.

Soft gliadin nanoparticles at air/water interfaces: The transition from a particle-laden layer to a thick protein film.

HYPOTHESIS: Protein-based soft particles possess a unique interfacial deformation behavior, which is difficult to capture and characterize. This complicates the analysis of their interfacial properties. Here, we aim to establish how the particle deformation affects their interfacial structural and mechanical properties. EXPERIMENTS: Gliadin nanoparticles (GNPs) were selected as a model particle. We studied their adsorption behavior, the time-evolution of their morphology, and rheological behavior at the air/water interface by combining dilatational rheology and microstructure imaging. The rheology results were analyzed using Lissajous plots and quantified using the recently developed general stress decomposition (GSD) method. FINDING: Three distinct stages were revealed in the adsorption and rearrangement process. First, spherical GNPs (∼105 nm) adsorbed to the interface. Then, these gradually deformed along the interface direction to a flattened shape, and formed a firm viscoelastic 2D solid film. Finally, further stretching and merging of GNPs at the interface resulted in rearrangement of their internal structure to form a thick film with lower stiffness than the initial film. These results demonstrate that the structure of GNPs confined at the interface is controlled by their deformability, and the latter can be used to tune the properties of prolamin particle-based multiphase systems.

The soybean lecithin-cyclodextrin-vitamin E complex nanoparticles stabilized Pickering emulsions for the delivery of ß-carotene: Physicochemical properties and in vitro digestion.

In this work, soybean lecithin (LC) was used to modify ß-cyclodextrin (ß-CD) with hydrophobic fat chains to become amphiphilic (LC-CD), and vitamin E (VE) was encapsulated in former modified ß-CD complexes (LC-CD-VE), the new Pickering emulsions stabilized by LC-CD-VE and LC-CD complexes for the delivery of ß-carotene (BC) were created. The surface tension, contact angle, zeta potential, and particle size were used to assess the changes in complexes nanoparticles at various pH values. Furthermore, LC-CD-VE has more promise as Pickering emulsion stabilizer than LC-CD because of the smaller particle size (271.11 nm), proper contact angle (58.02°), and lower surface tension (42.49 mN/m). The interactions between ß-cyclodextrin, soybean lecithin, and vitamin E were confirmed using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), nuclear magnetic resonance (NMR), and thermogravimetric analysis (TGA). The durability of Pickering emulsions was examined at various volume fractions of the oil phase and concentrations of nanoparticles. Compared to the emulsion stabilized by LC-CD, the one stabilized by LC-CD-VE showed superior storage stability. Moreover, for the delivery of BC, Pickering emulsions stabilized by LC-CD and LC-CD-VE can outperform bulk oil and Tween 80 stabilized emulsions in terms of UV light stability, storage stability, and bioaccessibility. This work could offer fresh perspectives on stabilizer alternatives for Pickering emulsion delivery systems.

Fatty Acid Release and Gastrointestinal Oxidation Status: Different Methods of Processing Flaxseed.

Flaxseed has been recognized as a superfood worldwide due to its abundance of diverse functional phytochemicals and nutrients. Various studies have shown that flaxseed consumption is beneficial to human health, though methods of processing flaxseed may significantly affect the absorption and metabolism of its bioactive components. Hence, flaxseed was subjected to various processing methods including microwaving treatment, microwave-coupled dry milling, microwave-coupled wet milling, and high-pressure homogenization. In vitro digestion experiments were conducted to assess the impact of these processing techniques on the potential gastrointestinal fate of flaxseed oil. Even though more lipids were released by the flaxseed at the beginning of digestion after it was microwaved and dry-milled, the full digestion of flaxseed oil was still restricted in the intestine. In contrast, oil droplets were more evenly distributed in wet-milled flaxseed milk, and there was a greater release of fatty acids during simulated digestion (7.33 ± 0.21 µmol/mL). Interestingly, wet-milled flaxseed milk showed higher oxidative stability compared with flaxseed powder during digestion despite the larger specific surface area of its oil droplets. This study might provide insight into the choice of flaxseed processing technology for better nutrient delivery efficiency.

Recent advances in understanding the interfacial activity of antioxidants in association colloids in bulk oil.

The chemical stability of edible oils rich in polyunsaturated fatty acids (PUFAs) is a major challenge within the food and supplement industries, as lipid oxidation reduces oil quality and safety. Despite appearing homogeneous to the human eye, bulk oils are actually multiphase heterogeneous systems at the nanoscale level. Association colloids, such as reverse micelles, are spontaneously formed within bulk oils due to the self-assembly of amphiphilic molecules that are present, like phospholipids, free fatty acids, and/or surfactants. In bulk oil, lipid oxidation often occurs at the oil-water interface of these association colloids because this is where different reactants accumulate, such as PUFAs, hydroperoxides, transition metals, and antioxidants. Consequently, the efficiency of antioxidants in bulk oils is governed by their chemical reactivity, but also by their ability to be located close to the site of oxidation. This review describes the impact of minor constituents in bulk oils on the nature of the association colloids formed. And then the formation of mixed reverse micelles (LOOH, (co)surfactants, or antioxidations) during the peroxidation of bulk oils, as well as changes in their composition and structure over time are also discussed. The critical importance of selecting appropriate antioxidants and surfactants for the changes of interface and colloid, as well as the inhibition of lipid oxidation is emphasized. The knowledge presented in this review article may facilitate the design of bulk oil products with improved resistance to oxidation, thereby reducing food waste and improving food quality and safety.

Identification of the key aroma compounds in flaxseed milk using stir bar sorptive extraction, aroma recombination, and omission tests.

Flaxseed milk is a plant-based dairy alternative that is rich in nutrients. Due to the low concentration of odor compounds in flaxseed milk, it cannot be completely extracted. This poses significant challenges for analysis. Therefore, this study developed a method suitable for extracting volatile compounds from flaxseed milk and compared it with three other extraction methods. It was found that Stir Bar Sorptive Extraction had the best extraction performance, identifying 39 odorants. Flavor dilution factors ranged from 1 to 512, with higher values observed for esters. 13 key odor compounds were identified (odor activity value > 1) using the external standard method for quantification; these included four aldehydes, three pyrazines, two alcohols, two esters, and two other compounds. Pyrazine compounds exhibited the highest concentrations. Aroma recombination and omission experiments showed that nine key odorants contributed significantly to the flavor profile of flaxseed milk, imparting aroma of cucumber, green, mushroom, fruity, sweet, and coconut.

Hollow Hierarchical Porous and Antihydrolytic Spherical Zeolitic Imidazolate Frameworks for Enzyme Encapsulation and Biocatalysis.

The creation of a new metal-organic framework (MOF) with a hollow hierarchical porous structure has gained significant attention in the realm of enzyme immobilization. The present work employed a novel, facile, and effective combinatorial technique to synthesize modified MOF (N-PVP/HZIF-8) with a hierarchically porous core-shell structure, allowing for the preservation of the structural integrity of the encapsulated enzyme molecules. Scanning electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, confocal laser scanning microscopy, and other characterization tools were used to fully explore the changes of morphological structure and surface properties in different stages of the preparation of immobilization enzyme CRL-N-PVP/HZIF-8, thus showing the superiority of N-PVP/HZIF-8 as an enzyme immobilization platform and the logic of the immobilization process on the carrier. Additionally, the maximum enzyme loading was 216.3 mg mL-1, the relative activity of CRL-N-PVP/HZIF-8 increased by 15 times compared with the CRL@ZIF-8 immobilized in situ, and exhibited quite good thermal, chemical, and operational stability. With a maximal conversion of 88.8%, CRL-N-PVP/HZIF-8 demonstrated good catalytic performance in the biosynthesis of phytosterol esters as a proof of concept. It is anticipated that this work will offer fresh concepts from several perspectives for the creation of MOF-based immobilized enzymes for biotechnological uses.

Regulation of interfacial mechanics of soy protein via co-extraction with flaxseed protein for efficient fabrication of foams and emulsions.

Enrichment of plant proteins with functionality is of great importance for expanding their application in food formulations. This study proposed an innovation to co-enrich soy protein and flaxseed protein to act as efficient interfacial stabilizers for generating foams and emulsions. The structure, interfacial properties, and functionalities of the soy protein-flaxseed protein natural nanoparticles (SFNPs) obtained by alkali extraction-isoelectric precipitation (AE) and salt extraction-dialysis (SE) methods were investigated. Overall, the foamability of AE-SFNPs (194.67 %) was 1.45-fold that of SE-SFNPs, due to their more flexible structure, smaller particle size, and suitable surface wettability, promoting diffusion and adsorption at the air-water interface. AE-SFNPs showed higher emulsion stability (140.89 min), probably because the adsorbed AE-SFNPs with smaller size displayed soft particle-like properties and stronger interfacial flexibility, and therefore could densely and evenly arrange at the interface, facilitating the formation of a stiff and solid-like interfacial layer, beneficial for more stable emulsion formation. The findings may innovatively expand the applications of SFNPs as food ingredients.

Redesign of air/oil-water interface via physical fields coupled with pH shifting to improve the emulsification, foaming, and digestion properties of plant proteins.

The application of plant proteins in food systems is largely hindered by their poor foaming or emulsifying properties and low digestibility compared with animal proteins, especially due to the aggregate state with tightly folded structure, slowly adsorbing at the interfaces, generating films with lower mechanical properties, and exposing less cutting sites. Physical fields and pH shifting have certain synergistic effects to efficiently tune the structure and redesign the interfacial layer of plant proteins, further enhancing their foaming or emulsifying properties. The improvement mechanisms mainly include: i) Aggregated plant proteins are depolymerized to form small protein particles and flexible structure is more easily exposed by combination treatment; ii) Particles with appropriate surface properties are quickly adsorbed to the interfacial layer, and then unfolded and rearranged to generate a tightly packed stiff interfacial layer to enhance bubble and emulsion stability; and iii) The unfolding and rearrangement of protein structure at the interface may result in the exposure of more cutting sites of digestive enzymes. This review summarizes the latest research progress on the structural changes, interfacial behaviors, and digestion properties of plant proteins under combined treatment, and elucidates the future development of these modification technologies for plant proteins in the food industry.

Effect of Different Temperatures on the Storage Stability of Flaxseed Milk.

In this study, the physical and oxidative stability of flaxseed milk without food additives at different temperatures (25 °C and 37 °C) was assessed. Over in 206 days in storage, the particle size, Turbiscan stability index (TSI), centrifugal sedimentation rate, and primary and secondary oxidation products of flaxseed milk increased, viscosity decreased, and the absolute value of the potential first decreased and then increased. These phenomena indicated a gradual decrease in the physical stability of flaxseed milk, accompanied by drastic oxidative changes. The antioxidant capacity of flaxseed milk was related to the location of the physical distribution of flaxseed lignin, which was more effective in the aqueous phase compared to the non-aqueous phase. Interestingly, after 171 days in storage at 37 °C, the particle size of flaxseed milk was approximately doubled (6.98 µm → 15.27 µm) and the absolute value of the potential reached its lowest point (-13.49 mV), when the content of primary oxidation products reached its maximum (8.29 mmol/kg oil). The results showed that temperature had a significant effect on the stability of flaxseed milk and that stability decreased with increasing temperature and shortened shelf life. This work provides a theoretical basis for elucidating the stabilization-destabilization mechanism of flaxseed milk.

A curcumin oral delivery system based on sodium caseinate and carboxymethylpachymaran nanocomposites.

The food industry has paid lots of attentions to curcumin because of its potential bioactive qualities. However, its use is severely constrained by its low bioavailability, stability and water solubility. Herein, we created sodium caseinate and carboxymethylpachymaran (CMP) nanoparticles (SMCNPs) that were loaded with curcumin. The composite nanoparticles were spherical, as characterized by SEM and TEM, the fluorescence spectroscopy, FTIR and XRD research revealed that hydrogen bonding, hydrophobic interaction and electrostatic interaction were the main drivers behind the creation of the nanoparticles. The SMCNPs exhibited lower particle size, greater dispersion and higher encapsulation rate when the mass ratio of sodium caseinate to CMP was 3:5 (particle size of 166.8 nm, PDI of 0.15, and encapsulation efficiency of 88.07 %). The composite nanoparticles had good antioxidant activity, physical stability and sustained release effect on intestinal tract during the in vitro simulation experiments, successfully preventing the early release of curcumin into gastric fluid. Finally, cytotoxicity studies told that the prepared composite nanoparticles have good biocompatibility and can inhibit the growth of tumor cells (HT-29). In conclusion, using CMP and sodium caseinate as carriers in this study may open up a fresh, environmentally friendly, and long-lasting way to construct a bioactive material delivery system.

Combination modes impact on the stability of ß-carotene-loaded emulsion constructed by soy protein isolate, ß-glucan and myricetin ternary complex.

A ß-carotene rich emulsion with improved physical and chemical stability was obtained in this study, using different types of protein-polysaccharide-polyphenol ternary complexes as novel emulsifiers. The ternary complexes were prepared by covalent or non-covalent binding of soy protein isolate (SPI), ß-glucan (DG) and myricetin (MC), which were evidenced to be stable. It was indicated that the emulsion stabilized by covalent complex of SPI, DG and MC, exhibited higher zeta-potential and smaller particle size than those stabilized by non-covalent complex. Furthermore, the covalent complexes prepared from different addition sequences showed different efficiencies in stabilizing the emulsion, in which SPI-DG-MC and SPI-MC-DG-stabilized emulsions possess better stability, emulsifying activity and storage resistance under adverse environmental treatment, with CI values of 62.7% and 64.3% after 25 days, respectively. According to oxidative stability and rheology analysis of the emulsions, it was found that the SPI-MC-DG complex prepared at the ratio of 4:2:1 was more stable with relatively less lipid oxidation products and a tighter stacking structure, and the final LH value was 39.98 mmol/L and the MDA value was 6.34 mmol/L. These findings implied that the ternary complex has the potential to deliver fat-soluble active ingredient by means of emulsion, but which depends on the mode and sequence of the molecular interactions.

The physicochemical stability and in vivo gastrointestinal digestion of flaxseed milk: Implication of microwave on flaxseed.

The current study was to investigate how microwave on flaxseed affected the physicochemical stability and gastrointestinal digestion of oil bodies (OBs) in flaxseed milk. Flaxseed was subjected to moisture adjustment (30-35 wt%, 24 h), and microwave exposure (0-5 min, 700  W). Microwave treatment slightly weakened the physical stability of flaxseed milk indicated by Turbiscan Stability Index, but there were no visual phase separation during 21 days of storage at 4 °C. Upon microwave treatment, OBs experienced the layer-by-layer encapsulation into loose interface embedding by storage protein-gum polysaccharide complex from bulk phase, resulting in lower viscoelasticity of flaxseed milk. The OBs underwent earlier interface collapse and lipolysis during gastrointestinal digestion, followed by synergistic micellar absorption, faster chylomicrons transport within enterocytes of rats fed flaxseed milk. The accumulation of α-linolenic acid and synergistic conversion into docosapentaenoic and docosahexanoic acids in jejunum tissue were achieved accompanied by the interface remodeling of OBs in flaxseed milk.

Co-Extraction of Flaxseed Protein and Polysaccharide with a High Emulsifying and Foaming Property: Enrichment through the Sequence Extraction Approach.

A new focus with respect to the extraction of plant protein is that ingredient enrichment should target functionality instead of pursuing purity. Herein, the sequence aqueous extraction method was used to co-enrich five protein-polysaccharide natural fractions from flaxseed meal, and their composition, structure, and functional properties were investigated. The total recovery rate of flaxseed protein obtained by the sequence extraction approach was more than 80%, which was far higher than the existing reports. The defatted flaxseed meal was soaked by deionized water to obtain fraction 1 (supernatant), and the residue was further treated to get fraction 2 (supernatant) and 3 (precipitate) through weak alkali solubilization. Part of the fraction 2 was taken out, followed by adjusting its pH to 4.2. After centrifuging, the albumin-rich supernatant and precipitate with protein content of 73.05% were gained and labeled as fraction 4 and fraction 5. The solubility of fraction 2 and 4 exceeded 90%, and the foaming ability and stability of fraction 5 were 12.76 times and 9.89 times higher than commercial flaxseed protein, respectively. The emulsifying properties of fractions 1, 2, and 5 were all greater than that of commercial sodium caseinate, implying that these fractions could be utilized as high-efficiency emulsifiers. Cryo-SEM results showed that polysaccharides in fractions were beneficial to the formation of network structure and induced the formation of tighter and smoother interfacial layers, which could prevent emulsion flocculation, disproportionation, and coalescence. This study provides a reference to promote the high-value utilization of flaxseed meals.

Improvement of Oxidative Stability of Fish Oil-in-Water Emulsions through Partitioning of Sesamol at the Interface.

The susceptibility of polyunsaturated fatty acids to oxidation severely limits their application in functional emulsified foods. In this study, the effect of sesamol concentration on the physicochemical properties of WPI-stabilized fish oil emulsions was investigated, focusing on the relationship between sesamol-WPI interactions and interfacial behavior. The results relating to particle size, zeta-potential, microstructure, and appearance showed that 0.09% (w/v) sesamol promoted the formation of small oil droplets and inhibited oil droplet aggregation. Furthermore, the addition of sesamol significantly reduced the formation of hydrogen peroxide, generation of secondary reaction products during storage, and degree of protein oxidation in the emulsions. Molecular docking and isothermal titration calorimetry showed that the interaction between sesamol and ß-LG was mainly mediated by hydrogen bonds and hydrophobic interactions. Our results show that sesamol binds to interfacial proteins mainly through hydrogen bonding, and increasing the interfacial sesamol content reduces the interfacial tension and improves the physical and oxidative stability of the emulsion.

Formation and application of edible oleogels prepared by dispersing soy fiber particles in oil phase.

Oleogels containing less saturated and trans-fats were considered as an ideal option to replace the solid fats in foods. In this research, oleogel was fabricated by dispersing soy fiber particles (SFP) in soy oil, and further it was used in bread preparation. Effect of the particle size, particle content and the second fluid content on the formation of oleogels were evaluated, based on the appearance and rheological properties. Results showed that the suspension of SFP in soy oil (24%, w/w) could be transformed into gel-like state, upon the addition of the second fluid. The SFP based networks were dominated by the capillary force which was originated from the second fluid. The rheological properties and yield stress of the oleogels could be modulated by particle size and particle content of SFP in oil phase, as well as the second fluid content in the system. When the oleogels were applicated in bread preparation, a layered structure could be formed in the bread, indicating the possibility of replacing the solid fats in bakery products by our oleogels. Our results offered a feasibility approach for oil structuring with natural raw materials, and developed a new approach to replace the solid fats in foods.

Hollow Mesoporous Carbon-Based Enzyme Nanoreactor for the Confined and Interfacial Biocatalytic Synthesis of Phytosterol Esters.

Rationally designing carriers to obtain efficient and stable immobilized enzymes for the production of food raw materials is always a challenge. In this work, hollow cube carbon (HMC) as a carrier of Candida rugosa lipase (CRL) was prepared to construct a Pickering interfacial biocatalysis system, which was applied to biphasic biocatalysis. For comparison, the nonporous carbon (HC) and porous MoS2 (HMoS2) were also designed. On these grounds, p-NPP and linolenic acid were selected as the representative substrates for hydrolysis and esterification reactions. Under the optimal conditions, the protein loading amount, specific activity, and expressed activity of CRL immobilized on HMC (HMC@CRL) were 167.2 mg g-1, 5.41 U mg-1, and 32.34 U/mg protein, respectively. In the "oil-water" biphase, the relative hydrolytic activity of HMC@CRL was higher than that of HC@CRL, HMoS2@CRL, and CRL by 50, 68, and 80%, respectively, as well as itself in one phase. Compared to other reports (1.13%), HMC@CRL demonstrated a satisfactory hydrolysis rate (3.02%) and was the fastest among all other biocatalysts in the biphase. Moreover, compared with the free CRL in one-phase system, the Pickering interfacial biphasic biocatalyst, HMC@CRL, exhibited a higher esterification rate (85%, 2.7-fold enhancement). Therefore, the HMC@CRL nanoreactors had more optimal performance in the field of biomanufacturing and food industry.

High-performance electrochemiluminescence sensors based on ultra-stable perovskite quantum dots@ZIF-8 composites for aflatoxin B1 monitoring in corn samples.

Aflatoxin B1 (AFB1) that is prone to contaminate corns brings a serious threat to human health. Therefore, it is of great significance to construct novel detection methods for AFB1 tracing. Here, methylamine perovskite quantum dots (MP QDs) encapsulated by ZIF-8 metal-organic frameworks (MP QDs@ZIF-8) were prepared and then ultra-stable electrochemiluminescence (ECL) sensors were developed. By the confinement of cavities structure, multiple MP QDs were crystallized and embedded inside ZIF-8 to form MP QDs@ZIF-8, achieving stable and robust ECL responds in aqueous environment. Further combined with AFB1-imprinted polymer, the constructed ECL sensor showed good selectivity and ultra-sensitivity (the detection limit was 3.5 fg/mL, S/N = 3) with a wide linear range from 11.55 fg/mL to 20 ng/mL for AFB1 quantification. Satisfactory recoveries in corn samples indicated the reliable practicability of the proposed sensor for AFB1 assay. This work provided a novel pathway in designing high-performance ECL sensing platform for food safety.

Composition, processing, and quality control of whole flaxseed products used to fortify foods.

Whole flaxseed (flour) as a good source of omega-3 fatty acid and phytochemicals with excellent nutritional and functional attributes has been used to enrich foods for health promotion and disease prevention. However, several limitations and contemporary challenges still impact the development of whole flaxseed (flour)-enriched products on the global market, such as naturally occurring antinutritional factors and entrapment of nutrients within food matrix. Whole flaxseed (flour) with different existing forms could variably alter the techno-functional performance of food matrix, and ultimately affect the edible qualities of fortified food products. The potential interaction mechanism between the subject and object components in fortified products has not been elucidated yet. Hence, in this paper, the physical structure and component changes of flaxseed (flour) by pretreatments coupled with their potential influences on the edible qualities of multiple fortified food products were summarized and analyzed. In addition, several typical food products, including baked, noodle, and dairy products were preferentially selected to investigate the potential influencing mechanisms of flaxseed (flour) on different substrate components. In particular, the altered balance between water absorption of flaxseed protein/gum polysaccharides and the interruption of gluten network, lipid lubrication, lipid-amylose complexes, syneresis, and so forth, were thoroughly elucidated. The overall impact of incorporating whole flaxseed (flour) on the quality and nutritional attributes of fortified food products, coupled with the possible solutions against negative influences are aimed. This paper could provide useful information for expanding the application of whole flaxseed (flour) based on the optimal edible and nutritional properties of fortified food products.

Docosahexaenoic acid enhances hippocampal insulin sensitivity to promote cognitive function of aged rats on a high-fat diet.

INTRODUCTION: Diminished brain insulin sensitivity is associated with reduced cognitive function. Docosahexaenoic acid (DHA) is known to maintain normal brain function. OBJECTIVES: This study aimed to determine whether DHA impacts hippocampal insulin sensitivity and cognitive function in aged rats fed a high-fat diet (HFD). METHODS: Eight-month-old female Sprague-Dawley rats were randomly divided into three groups (n = 50 each). Rats in the aged group, HFD group, and DHA treatment group received standard diet (10 kcal% fat), HFD (45 kcal% fat), and DHA-enriched HFD (45 kcal% fat, 1% DHA, W/W) for 10 months, respectively. Four-month-old female rats (n = 40) that received a standard diet served as young controls. Neuroinflammation, oxidative stress, amyloid formation, and tau phosphorylation in the hippocampus, as well as systemic glucose homeostasis and cognitive function, were tested. RESULTS: DHA treatment relieved a block in the insulin signaling pathway and consequently protected aged rats against HFD-induced hippocampal insulin resistance. The beneficial effects were explained by a DHA-induced decrease in systemic glucose homeostasis dysregulation, hippocampal neuroinflammation and oxidative stress. In addition, DHA treatment broke the reciprocal cycle of hippocampal insulin resistance, Aß burden, and tau hyperphosphorylation. Importantly, treatment of model rats with DHA significantly increased their cognitive capacity, as evidenced by their increased hippocampal-dependent learning and memory, restored neuron morphology, enhanced cholinergic activity, and activated cyclic AMP-response element-binding protein. CONCLUSION: DHA improves cognitive function by enhancing hippocampal insulin sensitivity.