Efficient Expression and Application of a Modified Rhizomucor miehei Lipase for Simultaneous Production of Biodiesel and Eicosapentaenoic Acid Ethyl Ester from Nannochloropsis Oil.

Few reports exist on one-step enzymatic methods for the simultaneous production of biodiesel and eicosapentaenoic acid ethyl ester (EPA-EE), a high-value pharmaceutical compound. This study aimed to efficiently express Rhizomucor miehei lipase (pRML) in Pichia pastoris X-33 via propeptide mutation and high-copy strain screening. The mutated enzyme was then used to simultaneously catalyze the production of both biodiesel and EPA-EE. The P46N mutation in the propeptide (P46N-pRML) significantly boosted its production, with the four-copy strain increasing enzyme yield by 3.7-fold, reaching 3425 U/mL. Meanwhile, its optimal temperature increased to 45-50 °C, pH expanded to 7.0-8.0, specific activity doubled, Km reduced to one-third, and kcat/Km increased 7-fold. Notably, P46N-pRML efficiently converts Nannochloropsis gaditana oil's eicosapentaenoic acid (EPA). Under optimal conditions, it achieves up to 93% biodiesel and 92% EPA-EE yields in 9 h. Our study introduces a novel, efficient one-step green method to produce both biodiesel and EPA-EE using this advanced enzyme.

15-epi-lipoxin A5 promotes neutrophil exit from exudates for clearance by splenic macrophages.

Specialized proresolving mediators (SPMs) promote local macrophage efferocytosis but excess leukocytes early in inflammation require additional leukocyte clearance mechanism for resolution. Here, neutrophil clearance mechanisms from localized acute inflammation were investigated in mouse dorsal air pouches. 15-HEPE (15-hydroxy-5Z,8Z,11Z,13E,17Z-eicosapentaenoic acid) levels were increased in the exudates. Activated human neutrophils converted 15-HEPE to lipoxin A5 (5S,6R,15S-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), 15-epi-lipoxin A5 (5S,6R,15R-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), and resolvin E4 (RvE4; 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid). Exogenous 15-epi-lipoxin A5, 15-epi-lipoxin A4 and a structural lipoxin mimetic significantly decreased exudate neutrophils and increased local tissue macrophage efferocytosis, with comparison to naproxen. 15-epi-lipoxin A5 also cleared exudate neutrophils faster than the apparent local capacity for stimulated macrophage efferocytosis, so the fate of exudate neutrophils was tracked with CD45.1 variant neutrophils. 15-epi-lipoxin A5 augmented the exit of adoptively transferred neutrophils from the pouch exudate to the spleen, and significantly increased splenic SIRPa+ and MARCO+ macrophage efferocytosis. Together, these findings demonstrate new systemic resolution mechanisms for 15-epi-lipoxin A5 and RvE4 in localized tissue inflammation, which distally engage the spleen to activate macrophage efferocytosis for the clearance of tissue exudate neutrophils.

Inclusion of oil from transgenic Camelina sativa in feed effectively supplies EPA and DHA to Atlantic salmon (Salmo salar) grown to market size in seawater pens.

Atlantic salmon were fed either a diet reflecting current commercial feeds with added oil supplied by a blend of fish oil and rapeseed oil (COM), or a diet formulated with oil from transgenic Camelina sativa containing 20% EPA + DHA (TCO). Salmon were grown from smolt to market size (>3 kg) in sea pens under semi-commercial conditions. There were no differences in growth, feed efficiency or survival between fish fed the TCO or COM diets at the end of the trial. Levels of EPA + DHA in flesh of salmon fed TCO were significantly higher than in fish fed COM. A 140 g fillet from TCO-fed salmon delivered 2.3 g of EPA + DHA, 67% of the weekly requirement level recommended by many health agencies, and 1.5-fold more than the 1.5 g of EPA + DHA for COM-fed fish. Oil from transgenic Camelina supported growth and improved the nutritional quality of farmed salmon in terms of increased "omega-3" supply for human consumers.

The sphingosine-1-phosphate receptor 1 mediates the atheroprotective effect of eicosapentaenoic acid.

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have been associated with potential cardiovascular benefits, partly attributed to their bioactive metabolites. However, the underlying mechanisms responsible for these advantages are not fully understood. We previously reported that metabolites of the cytochrome P450 pathway derived from eicosapentaenoic acid (EPA) mediated the atheroprotective effect of ω-3 PUFAs. Here, we show that 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and its receptor, sphingosine-1-phosphate receptor 1 (S1PR1), in endothelial cells (ECs) can inhibit oscillatory shear stress- or tumor necrosis factor-α-induced endothelial activation in cultured human ECs. Notably, the atheroprotective effect of 17,18-EEQ and purified EPA is circumvented in male mice with endothelial S1PR1 deficiency. Mechanistically, the anti-inflammatory effect of 17,18-EEQ relies on calcium release-mediated endothelial nitric oxide synthase (eNOS) activation, which is abolished upon inhibition of S1PR1 or Gq signaling. Furthermore, 17,18-EEQ allosterically regulates the conformation of S1PR1 through a polar interaction with Lys34Nter. Finally, we show that Vascepa, a prescription drug containing highly purified and stable EPA ethyl ester, exerts its cardiovascular protective effect through the 17,18-EEQ-S1PR1 pathway in male and female mice. Collectively, our findings indicate that the anti-inflammatory effect of 17,18-EEQ involves the activation of the S1PR1-Gq-Ca2+-eNOS axis in ECs, offering a potential therapeutic target against atherosclerosis.

Similar Distribution between EPA-containing Phosphatidylcholine and Mesenchymal Stem Marker Positive Cells in the Aortic Wall of Abdominal Aortic Aneurysm Model Rat Fed a Low-EPA Content Diet.

Abdominal aortic aneurysm (AAA) is a vascular disease characterized by progressive dilation of the abdominal aorta. Previous studies have suggested that dietary components are closely associated with AAA. Among those dietary components, eicosapentaenoic acid (EPA) is considered to have suppressive effects on AAA. In the AAA wall of AAA model animals bred under EPA-rich condition, the distribution of EPA-containing phosphatidylcholine (EPA-PC) has been reported to be similar to that of the markers of mesenchymal stem cells (MSCs) and M2 macrophages. These data suggest that the suppressive effects of EPA on AAA are related to preferential distribution of specific cells in the aortic wall. However, the distribution of EPA-PC in the AAA wall of AAA model animals fed a diet containing small amounts of EPA, which has not been reported to inhibit AAA, has not yet been explored. In the present study, we visualized the distribution of EPA-PCs in the AAA wall of AAA model animals fed a diet containing small amounts of EPA (1.5% EPA in the fatty acid composition) to elucidate the vasoprotective effects of EPA. Positive areas for markers of MSCs were significantly higher in the region where EPA-PC was abundant compared to the regions where EPA-PC was weakly detected, but not for markers of M2 macrophages, matrix metalloproteinase (MMP)-2, and MMP-9. The distribution of MSC markers was similar to that of EPA-PC but not that of M2 macrophages and MMPs. These data suggest preferential incorporation of EPA into MSCs under the conditions used in this study. The incorporation of EPA into certain cells may differ according to dietary conditions, which affect the development of AAA.

Biochemical characterization of acyl-CoA:diacylglycerol acyltransferase2 from the diatom Phaeodactylum tricornutum and its potential effect on LC-PUFAs biosynthesis in planta.

BACKGROUND: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), belonging to ω-3 long-chain polyunsaturated fatty acids (ω3-LC-PUFAs), are essential components of human diet. They are mainly supplemented by marine fish consumption, although their native producers are oleaginous microalgae. Currently, increasing demand for fish oils is insufficient to meet the entire global needs, which puts pressure on searching for the alternative solutions. One possibility may be metabolic engineering of plants with an introduced enzymatic pathway producing ω3-LC-PUFAs. RESULT: In this study we focused on the acyl-CoA:diacylglycerol acyltransferase2b (PtDGAT2b) from the diatom Phaeodactylum tricornutum, an enzyme responsible for triacylglycerol (TAG) biosynthesis via acyl-CoA-dependent pathway. Gene encoding PtDGAT2b, incorporated into TAG-deficient yeast strain H1246, was used to confirm its activity and conduct biochemical characterization. PtDGAT2b exhibited a broad acyl-CoA preference with both di-16:0-DAG and di-18:1-DAG, whereas di-18:1-DAG was favored. The highest preference for acyl donors was observed for 16:1-, 10:0- and 12:0-CoA. PtDGAT2b also very efficiently utilized CoA-conjugated ω-3 LC-PUFAs (stearidonic acid, eicosatetraenoic acid and EPA). Additionally, verification of the potential role of PtDGAT2b in planta, through its transient expression in tobacco leaves, indicated increased TAG production with its relative amount increasing to 8%. Its co-expression with the gene combinations aimed at EPA biosynthesis led to, beside elevated TAG accumulation, efficient accumulation of EPA which constituted even 25.1% of synthesized non-native fatty acids (9.2% of all fatty acids in TAG pool). CONCLUSIONS: This set of experiments provides a comprehensive biochemical characterization of DGAT enzyme from marine microalgae. Additionally, this study elucidates that PtDGAT2b can be used successfully in metabolic engineering of plants designed to obtain a boosted TAG level, enriched not only in ω-3 LC-PUFAs but also in medium-chain and ω-7 fatty acids.

Differential Remodeling of the Oxylipin Pool After FLASH Versus Conventional Dose-Rate Irradiation In Vitro and In Vivo.

PURPOSE: The products of lipid peroxidation have been implicated in human diseases and aging. This prompted us to investigate the response to conventional (CONV) versus FLASH irradiation of oxylipins, a family of bioactive lipid metabolites derived from omega-3 or omega-6 polyunsaturated fatty acids through oxygen-dependent non-enzymatic as well as dioxygenase-mediated free radical reactions. METHODS AND MATERIALS: Ultrahigh performance liquid chromatography coupled to tandem mass spectrometry was used to quantify the expression of 37 oxylipins derived from eicosatetraenoic, eicosapentaenoic and docosahexaenoic acid in mouse lung and in normal or cancer cells exposed to either radiation modality under precise monitoring of the temperature and oxygenation. Among the 37 isomers assayed, 14-16 were present in high enough amount to enable quantitative analysis. The endpoints were the expression of oxylipins as a function of the dose of radiation, normoxia versus hypoxia, temperature and post-irradiation time. RESULTS: In normal, normoxic cells at 37°C radiation elicited destruction and neosynthesis of oxylipins acting antagonistically on a background subject to rapid remodeling by oxygenases. Neosynthesis was observed in the CONV mode only, in such a way that the level of oxylipins at 5 minutes after FLASH irradiation was 20-50% lower than in non-irradiated and CONV-irradiated cells. Hypoxia mitigated the differential CONV versus FLASH response in some oxylipins. These patterns were not reproduced in tumor cells. Depression of specific oxylipins following FLASH irradiation was observed in mouse lung at 5 min following irradiation, with near complete recovery in 24 hours and further remodeling at one week and two months post-irradiation. CONCLUSIONS: Down-regulation of oxylipins was a hallmark of FLASH irradiation specific of normal cells. Temperature effects suggest that this process occurs via diffusion-controlled, bimolecular recombination of a primary radical species upstream from peroxyl radical formation and evoke a major role of the membrane composition and fluidity in response to the FLASH modality.

n-3 PUFAs Show Promise as Adjuvants in Chemotherapy, Enhancing their Efficacy while Safeguarding Hematopoiesis and Promoting Bone Generation.

Cancer ranks as the second leading cause of mortality in high-income countries, underscoring the critical need for effective therapeutic strategies. One prominent approach, chemotherapy, is widely employed for treating solid tumors. However, the significant adverse effects associated with chemotherapy, notably myeloablation and osteonecrosis, impart considerable challenges by compromising immune function and diminishing patients' quality of life. Furthermore, the emergence of chemotherapy resistance poses a formidable hurdle in achieving successful cancer treatment outcomes. In this context, the focus is on exploring alternative approaches to enhance the efficacy of cancer treatment and mitigate its adverse consequences. Among these approaches, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), two n-3 polyunsaturated fatty acids (PUFAs), have garnered substantial interest. These PUFAs exhibit the potential to influence membrane lipid composition and modulate critical gene expressions associated with cancer, such as Bcl-2, PI3K, NF-κB, and phosphorylated Akt, thereby potentially reducing cancer risk. Moreover, emerging evidence highlights their ability to augment chemotherapy efficacy, particularly in drug-resistant cancer cells. Importantly, both preclinical and clinical investigations have provided compelling evidence supporting the protective effects of n-3 PUFAs on healthy cells. Leveraging these findings, there has been growing attention on the exploration of n-3 PUFAs as adjuvants to chemotherapy. This strategic approach holds promise in mitigating the adverse effects linked to chemotherapy, notably myeloablation and osteonecrosis, while simultaneously enhancing its effectiveness in combating cancer. This comprehensive review delves into the multifaceted attributes of n-3 PUFAs, encompassing their cytotoxic properties, potential as chemopreventive agents, and their prospective role in ameliorating the adverse effects commonly associated with chemotherapy, with a particular emphasis on myeloablation and osteonecrosis. By elucidating the intricate interplay between n-3 PUFAs and cancer treatment paradigms, this review contributes to the expanding body of knowledge aimed at refining cancer therapeutic strategies and enhancing patient outcomes.

Fish oil-derived n-3 polyunsaturated fatty acids downregulate aquaporin 9 protein expression of liver and white adipose tissues in diabetic KK mice and 3T3-L1 adipocytes.

Aquaporin 9 (AQP9) is an integral membrane protein that facilitates glycerol transport in hepatocytes and adipocytes. Glycerol is necessary as a substrate for gluconeogenesis in the physiological fasted state, suggesting that inhibiting AQP9 function may be beneficial for treating type 2 diabetes associated with fasting hyperglycemia. The n-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are rich in fish oil and lower the risk of metabolic syndrome; however, the effects of EPA and DHA on AQP9 expression in obese and type 2 diabetes are unclear. The KK mouse is an animal model of obesity and type 2 diabetes because of the polymorphisms on leptin receptor gene, which results in a part of cause for obese and diabetic conditions. In this study, we determined the effect of fish oil-derived n-3 PUFA on AQP9 protein expression in the liver and white adipose tissue (WAT) of KK mice and mouse 3T3-L1 adipocytes. The expression of AQP9 protein in the liver, epididymal WAT, and inguinal WAT were markedly decreased following fish oil administration. We also demonstrated that n-3 PUFAs, such as DHA, and to a lesser extent EPA, downregulated AQP9 protein expression in 3T3-L1 adipocytes. Our results suggest that fish oil-derived n-3 PUFAs may regulate the protein expressions of AQP9 in glycerol metabolism-related organs in KK mice and 3T3-L1 adipocytes.

Enzymatic hydrolysis allows an integral valorization of Nannochloropsis oceanica resulting in the production of bioactive peptide extracts and an eicosapentaenoic acid enriched fraction.

Nannochloropsis oceanica is a microalga with relevant protein content, making it a potential source of bioactive peptides. Furthermore, it is also rich in fatty acids, with a special focus on eicosapentaenoic acid (EPA), an omega-3 fatty acid mainly obtained from marine animal sources, with high importance for human health. N. oceanica has a rigid cell wall constraining protein extraction, thus hydrolyzing it may help increase its components' extractability. Therefore, a Box-Behnken experimental design was carried out to optimize the hydrolysis. The hydrolysate A showed 67% ± 0.7% of protein, antioxidant activity of 1166 ± 63.7 µmol TE g-1 of protein and an ACE inhibition with an IC50 of 379 µg protein mL-1 . The hydrolysate B showed 60% ± 1.8% of protein, antioxidant activity of 775 ± 13.0 µmol TE g-1 of protein and an ACE inhibition with an IC50 of 239 µg protein mL-1 . The by-product showed higher yields of total fatty acids when compared to "raw" microalgae, being 5.22% and 1%, respectively. The sustainable developed methodology led to the production of one fraction rich in bioactive peptides and another with interesting EPA content, both with value-added properties with potential to be commercialized as ingredients for different industrial applications, such as functional food, supplements, or cosmetic formulations.

Omega-3 Polyunsaturated Fatty Acid Eicosapentaenoic Acid or Docosahexaenoic Acid Improved Ageing-Associated Cognitive Decline by Regulating Glial Polarization.

Neuroinflammation induced by microglial and astrocyte polarizations may contribute to neurodegeneration and cognitive impairment. Omega (n)-3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory and neuroprotective effects, but conflicting results were reported after different n-3 PUFA treatments. This study examined both the change in glial polarizations in ageing rats and the differential effects of two omega-3 PUFAs. The results showed that both PUFAs improved spatial memory in ageing rats, with docosahexaenoic acid (DHA) being more effective than eicosapentaenoic acid (EPA). The imbalance between microglial M1/M2 polarizations, such as up-regulating ionized calcium binding adaptor molecule 1 (IBA1) and down-regulating CD206 and arginase-1 (ARG-1) was reversed in the hippocampus by both n-3 PUFAs, while the DHA effect on CD206 was stronger. Astrocyte A1 polarization presented increasing S100B and C3 but decreasing A2 parameter S100A10 in the ageing brain, which were restored by both PUFAs, while DHA was more effective on S100A10 than EPA. Consistent with microglial M1 activation, the concentration of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6 were significantly increased, which were attenuated by DHA, while EPA only suppressed IL-6. In correlation with astrocyte changes, brain-derived neurotrophic factor precursor was increased in ageing rats, which was more powerfully down-regulated by DHA than EPA. In summary, enhanced microglial M1 and astrocytic A1 polarizations may contribute to increased brain pro-inflammatory cytokines, while DHA was more powerful than EPA to alleviate ageing-associated neuroimmunological changes, thereby better-improving memory impairment.

Individual resolvin E family members work distinctly and in a coordinated manner in the resolution of inflammation.

Three main E-type resolvins (RvEs): RvE1, RvE2, and RvE3, have roles in the resolution of inflammation as anti-inflammatory activities. To investigate the roles of each RvE in the resolution of inflammation, timing of interleukin (IL)- 10 release and IL-10 receptor expressions, and phagocytosis evoked by each RvE in differentiated human monocytes, macrophage-like U937 cells were examined. Here, we show that RvEs enhance the expression of IL-10, and IL-10 receptor-mediated signaling pathways and IL-10-mediated-signaling-independent resolution of inflammatory effects by activating the phagocytotic function. Thus, RvE2 mainly evoked an IL-10-mediated anti-inflammatory function, whereas RvE3 principally activated phagocytotic activity of macrophages, which may be involved in tissue repair. On the other hand, RvE1 showed both functions, although not prominent but rather acting as a relief mediator that takes over the RvE2 function and passes over to the RvE3 function. Therefore, each RvE may act as an important role/stage-specific mediator in a coordinated manner with other RvEs in the processes of the resolution of inflammation.

Different Dietary Ratios of Camelina Oil to Sandeel Oil Influence the Capacity to Synthesise and Deposit EPA and DHA in Zucker Fa/Fa Rats.

Plant-based food provides more ALA (α-linolenic acid) and less EPA (eicosapentaenoic acid) and DHA (docosahexanoic acid) than marine food. Earlier studies indicate that cetoleic acid (22:1n-11) stimulates the n-3 pathway from ALA to EPA and DHA. The present study aimed to investigate the dietary effects of camelina oil (CA) high in ALA and sandeel oil (SA) high in cetoleic acid on the conversion of ALA to EPA and DHA. Male Zucker fa/fa rats were fed a diet of soybean oil (Ctrl) or diets of CA, SA, or a combination of CA and SA. Significantly higher levels of DPA (docosapentaenoic acid) and DHA in blood cells from the CA group compared to the Ctrl indicate an active conversion of ALA to DPA and DHA. Increasing the uptake and deposition of EPA and DHA meant that a trend towards a decrease in the liver gene expression of Elovl5, Fads1, and Fads2 along with an increase in the dietary content of SA was observed. However, 25% of the SA could be exchanged with CA without having a significant effect on EPA, DPA, or DHA in blood cells, indicating that bioactive components in SA, such as cetoleic acid, might counteract the inhibiting effect of the high dietary content of DHA on the n-3 biosynthetic pathway.

Eicosapentaenoic Acid-Enriched Phospholipids Alleviate Skeletal Muscle Atrophy in Lewis Lung Carcinoma Mouse Model.

SCOPE: Skeletal muscle atrophy is a critical feature of cancer-associated cachexia (CAC) and it is responsible for poor quality of life and high mortality in cancer patients. The previous study demonstrates that eicosapentaenoic acid-enriched phospholipids (EPA-PL) prevent body weight loss in a mouse model of CAC. However, the role of EPA-PL on cancer-induced skeletal muscle atrophy remains unclear. METHODS AND RESULTS: In the present study, a Lewis lung carcinoma (LLC) mouse model is established, then the effect and underlying mechanism of EPA-PL on skeletal muscle atrophy in LLC-bearing mice are investigated. The results reveal that EPA-PL treatment significantly attenuates skeletal muscle atrophy in LLC-bearing mice, as evidenced by suppressing the reductions of skeletal muscle mass, myofiber cross-sectional area, and grip strength. Besides, the study finds that EPA-PL alleviated cancer-induced skeletal muscle atrophy via balancing muscle protein degradation and synthesis, inhibiting type I oxidative muscle fibers atrophy, and promoting mitochondrial function. Furthermore, the results also indicate that EPA-PL may counteract skeletal muscle atrophy in LLC mouse model via a sirtuin 1-dependent mechanism. CONCLUSION: These findings provide evidence that EPA-PL may be beneficial as a nutritional supplement for prevention and treatment of cancer-induced skeletal muscle atrophy.

The Potential of DHA as Cancer Therapy Strategies: A Narrative Review of In Vitro Cytotoxicity Trials.

Docosahexaenoic acid (DHA), also known as omega-3 (n-3) polyunsaturated fatty acid (PUFA), is a natural compound that has demonstrated pharmacological activity against several malignant neoplasms. Available cancer treatments cause side effects, affect healthy cells, reduce the quality of life of patients and may cause resistance to antineoplastics. For these reasons, the search for new therapies is continuous. This narrative review aimed to compile information on in vitro experiments that study the cytotoxic effect of DHA or molecules derived from DHA in tumor and nontumor cells. This was performed to highlight the potential of DHA as a strategy for cancer therapy and to gather information, which will help researchers plan experimental designs and develop research to discover effective therapies against cancer. In addition, studies were presented that demonstrate the dose of DHA that can treat patients with cancer. Thus, a search was conducted for articles on the SCOPUS and Web of Science platforms, published until 2022, that analyzed the action of DHA against breast, lung, colorectal, prostate, stomach and liver cancers. Cytotoxic effects were observed in tumor and nontumor cell lines, and these results varied with the type of cell line studied, drug concentration, incubation time and treatment combination, i.e., with DHA alone, combined with other drugs and with molecules derived from DHA. In patients with cancer, in all analyzed studies, DHA intake was associated with eicosapentaenoic acid (EPA) and/or proteins to aid chemotherapy, and with this procedure, tumor reduction, chemotherapy tolerance and muscle mass gain were obtained. This work contributes to the community by demonstrating the possible applicability of DHA in the pharmaceutical area of oncological therapies.

Equal bioavailability of omega-3 PUFA from Calanus oil, fish oil and krill oil: A 12-week randomized parallel study.

The bioavailability of long-chain omega-3 polyunsaturated fatty acids (n3 PUFA) can be affected by the form in which they are bound. An alternative source of n3 PUFA is Calanus finmarchicus oil (CO), which, unlike fish oil (FO) and krill oil (KO), contains fatty acids primarily bound as wax esters. Recent studies have shown that n3 PUFA from CO are bioavailable to humans, but CO has not been compared to other marine oils such as FO or KO. Therefore, the aim of this study was to investigate the influence of 12 weeks supplementation with CO, FO and KO on the long-term n3 PUFA status in healthy volunteers. The Omega-3 Index (O3I), defined as red blood cell EPA + DHA content as a percentage of total identified fatty acids, was used as a measure to assess n3 PUFA status. Sixty-two participants (mean ± standard deviation [SD] age: 29.7 ± 8.43 years) completed the randomized parallel group study (CO group: n = 21, 4 capsules/day, EPA + DHA dose: 242 mg/day; FO group: n = 22, 1 capsule/day, EPA + DHA dose: 248 mg/day; KO group: n = 19, 2 capsules/day, EPA + DHA dose: 286 mg/day). At baseline, the three groups showed comparable (mean ± SD) O3I values (CO: 5.13 ± 1.12%, FO: 4.90 ± 0.57%, KO: 4.87 ± 0.77%). The post-interventional (mean ± SD) O3I increase was comparable between the three groups (CO: 1.09 ± 0.55%; FO: 1.0 ± 0.53%; KO: 1.15 ± 0.65%, all p < 0.001). The study confirms that CO can increase the n3 PUFA status comparable to FO and KO and is therefore an alternative marine source of bioavailable n3 PUFA, especially with regard to sustainability.

Increased Expression of Hepatic Stearoyl-CoA Desaturase (SCD)-1 and Depletion of Eicosapentaenoic Acid (EPA) Content following Cytotoxic Cancer Therapy Are Reversed by Dietary Fish Oil.

Cancer treatment evokes impediments to liver metabolism that culminate in fatty liver. This study determined hepatic fatty acid composition and expression of genes and mediators involved in lipid metabolism following chemotherapy treatment. Female rats bearing the Ward colon tumor were administered Irinotecan (CPT-11) +5-fluorouracil (5-FU) and maintained on a control diet or a diet containing eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) (2.3 g/100 g fish oil). Healthy animals provided with a control diet served as a reference group. Livers were collected one week after chemotherapy. Triacylglycerol (TG), phospholipid (PL), ten lipid metabolism genes, leptin, and IL-4 were measured. Chemotherapy increased TG content and reduced EPA content in the liver. Expression of SCD1 was upregulated by chemotherapy, while dietary fish oil downregulated its expression. Dietary fish oil down-regulated expression of the fatty acid synthesis gene FASN, while restoring the long chain fatty acid converting genes FADS2 and ELOVL2, and genes involved in mitochondrial ß-oxidation (CPT1α) and lipid transport (MTTP1), to values similar to reference animals. Neither leptin nor IL-4 were affected by chemotherapy or diet. Depletion of EPA is associated with pathways evoking enhanced TG accumulation in the liver. Restoring EPA through diet may pose a dietary strategy to attenuate chemotherapy-associated impediments in liver fatty acid metabolism.

Endometrial microbial alterations disrupt endometrial immune homeostasis by overactivation of Eicosapentaenoic acid biosynthesis leading to altered endometrial receptivity.

Embryo implantation is a key step in human reproduction, and the endometrium plays a key role in this process. Changes in the receptive state of the endometrium are one of the main reasons for embryo implantation failure. However, the mechanism underlying the altered endometrial receptivity remains unclear. In this study, we recruited 140 women undergoing assisted reproductive technology and divided them into a shifting group and a normal group based on their embryo implantation window results. Endometrial transcriptome data suggested that changes in the remodeling process of decidual spiral arterioles and changes in the immune environment might be important mechanisms of implantation window shift. The functional enrichment analysis results also suggested that the changes in microbiota had an important role in the changes in endometrial status. The endometrial functionally active microbial profiles were obtained based on previously validated metatranscriptomic analysis pipelines. Combining host gene expression information, immune cell abundance information and functionally active microbial abundance and activity information, we found that Treponema succinifaciens, Fusobacterium sp. oral taxon 203 and other potentially harmful species may over-activate Eicosapentaenoic acid (EPA) biosynthesis Thus, the balance of the immune environment of the endometrium is disrupted, resulting in the shift of the implantation window and the failure of embryo implantation.

Intranasal Administration of Resolvin E1 Produces Antidepressant-Like Effects via BDNF/VEGF-mTORC1 Signaling in the Medial Prefrontal Cortex.

Intracerebroventricular infusion of resolvin E1 (RvE1), a bioactive metabolite derived from eicosapentaenoic acid, exerts antidepressant-like effects in a mouse model of lipopolysaccharide (LPS)-induced depression; these effects are blocked by systemic injection of rapamycin, a mechanistic target of rapamycin complex 1 (mTORC1) inhibitor. Additionally, local infusion of RvE1 into the medial prefrontal cortex (mPFC) or dorsal hippocampal dentate gyrus (DG) produces antidepressant-like effects. To evaluate the potential of RvE1 for clinical use, the present study examined whether treatment with RvE1 via intranasal (i.n.) route, a non-invasive route for effective drug delivery to the brain, produces antidepressant-like effects in LPS-challenged mice using tail suspension and forced swim tests. Intranasal administration of RvE1 significantly attenuated LPS-induced immobility, and these antidepressant-like effects were completely blocked by an AMPA receptor antagonist or L-type voltage-dependent Ca2+ channel blocker. The antidepressant-like effects of both i.n. and intra-mPFC administrations of RvE1 were blocked by intra-mPFC infusion of a neutralizing antibody (nAb) for brain-derived neurotrophic factor (BDNF) or vascular endothelial growth factor (VEGF). Intra-mPFC infusion of rapamycin completely blocked the antidepressant-like effects of both i.n. and intra-mPFC administrations of RvE1 as well as those of intra-mPFC infusion of BDNF and VEGF. Moreover, i.n. RvE1 produced antidepressant-like effects via mTORC1 activation in the mPFC of a mouse model of repeated prednisolone-induced depression. Intra-dorsal DG infusion of BDNF and VEGF nAbs, but not rapamycin, blocked the antidepressant-like effects of i.n. RvE1. These findings suggest that i.n. administration of RvE1 produces antidepressant-like effects through activity-dependent BDNF/VEGF release in the mPFC and dorsal DG, and mTORC1 activation in the mPFC, but not in the dorsal DG. Thus, RvE1 can be a promising candidate for a novel rapid-acting antidepressant.

Icosapent ethyl alleviates acetic acid-induced ulcerative colitis via modulation of SIRT1 signaling pathway in rats.

Ulcerative colitis (UC) is a global inflammatory bowel disease. This study aimed to assess the effects of icosapent ethyl on acetic acid-induced colitis in rats as well as the underlying mechanisms involved. 36 male Wister rats were equally divided into six groups: control, UC, mesalamine 100 mg/kg, icosapent 150mg/kg, icosapent 300 mg/kg, and EX527-icosapent 300 mg/kg groups. Except for control group, UC was induced by acetic acid instillation into colon. Drugs were administered once daily for one week then under thiopental anaesthesia, colons were excised. Colitis macroscopic and microscopic scores were assessed. A part of colon was homogenized for detection of malondialdehyde (MDA), inerleukin1 (IL-1ß), tumor necrosis factor (TNF-α), superoxide dismutase (SOD), phosphorylated Akt (pAkt) and caspase 3 levels. Silent information regulator 1 (SIRT1), heme oxygenase 1 (HO-1), and nuclear factor erythroid 2 (Nrf2) mRNA expressions were detected. Mallory-stained colonic sections were examined for collagen fibres detection. Immunohistochemistry of NF-κB and p53 expressionsin colonic sections were assessed. Acetic acid induced colitis with increments in MDA, IL-1ß, TNF-α, and caspase 3 levels while decreased SOD, pAkt, SIRT1, HO-1, and Nrf2 with increased collagen fibres as well as NF-κB and p53. Icosapent decreased macro& microscopic colitis scores, MDA, IL-1ß, TNF-α, and caspase 3 levels while increased SOD, pAkt, SIRT1, HO-1, and Nrf2 with decreased collagen fibres as well as NF-κB and p53. The effects of icosapent 300 mg/kg were similar to mesalamine. Icosapent effects were antagonized by EX527. Icosapent alleviated acetic acid-induced colitis via its anti-inflammatory, antioxidant, and anti-apoptotic effects mediated in part by SIRT1 pathway activation.