Association of serum n-3 and n-6 docosapentaenoic acid with cognitive performance in elderly adults: National Health and Nutrition Examination Survey 2011-2014.

Limited information exists on the influence of docosapentaenoic acid (DPA) on cognitive function. We investigated the association between serum n-3 and n-6 DPAs and cognitive performance in an elderly population from the National Health and Nutrition Examination Survey, 2011-2014. Restricted cubic spline and logistic regression analyses were utilized. A total of 1366 older participants were included. Elevated proportions of DPA(n3) in total serum fatty acids were slightly associated with higher DSST scores (OR 0.61, 95% CI (0.38-0.97)), and higher proportions of DPA(n6) in total serum fatty acids were significantly associated with lower scores on different cognitive tests (CERAD (1.64, 1.02-2.65), AFT (2.31, 1.43- 3.75), DSST (3.21, 1.98-5.22) and global cognition (2.85, 1.74-4.66)). After multivariable adjustment, DPA(n3) exhibited no association with cognitive performance, whereas DPA(n6) remained correlated with AFT (1.98, 1.13-3.48), DSST (2.63, 1.43-4.82) and global cognition (2.15, 1.19-3.90). In stratified analyses, higher levels of DPA(n3) were associated with better performance in CERAD among participants aged≥70, in DSST among those without diabetes and in global cognition among people with lower incomes. Increased DPA(n6) levels were associated with worse performance in AFT and DSST among those aged 60-70 and in all cognitive tests among those with better incomes. In conclusions, elevated levels of serum DPA(n3) may be beneficial for cognitive performance among elderly adults, especially in those over 70 years, with lower incomes and without diabetes. Serum n-6 DPA might be negatively associated with cognitive function, and this association is more pronounced among those who aged 60-70 with higher incomes.

The negative association between the docosapentaenoic acid intake and the incidence of AMD based on NHANES 2005-2008.

Introduction: Age-related macular degeneration (AMD) is an ophthalmic disease that causes visual impairment and is one of the leading causes of blindness in the elderly. Fatty acids are essential nutrients required by the body and play a cornerstone role in the life activities of the body. Many studies have reported that fatty acids are involved in the development of AMD. To confirm this association, we conducted the present study. Methods: We analyzed the association between all fatty acid intake and AMD using National Health and Nutrition Examination Survey (NHANES) data from 2005-2008. Quantile regression was performed to assess the effect of fatty acids on AMD at different intake levels. Results: After adjusting for covariates, only saturated fatty acids showed no significant difference between AMD patients and non-AMD patients (23.64 g vs. 26.03 g, p = 0.052). Total fat (70.88 g vs. 78.86 g, p = 0.024), monounsaturated fatty acids (25.87 g vs. 28.95 g, p = 0.019), polyunsaturated fatty acids (15.10 g vs. 17.07 g, p = 0.017) showed significant differences between the two groups. When AMD was considered as an outcome, the association between AMD and docosaentaenoic acid (DPA) was negative in the multivariate logic model (model 1: OR = <0.001, 95% CI = <0.001 ~ 0.734; model 2: OR = <0.001, 95% CI = <0.001 ~ 0.002; model 3: OR = <0.001, 95% CI = <0.001 ~ 0.002). In the quantile regression, DPA was shown to be negatively associated with the presence of AMD only in the fourth quartile in model 2 and model 3 (model 2: OR = <0.001, 95% CI = <0.001 ~ 0.927; model 3: OR = <0.001, 95% CI = <0.001 ~ 0.775). Discussion: Therefore, based on above results, we concluded that DPA intake could prevent the development of AMD.

Unsaturated fatty acids, omega-3 index and hospitalization in MISC.

The growing interest in Omega-3 fatty acids as diagnostic markers or new therapeutic approaches also for COVID-19 disease, led us to investigate the presence of potential correlations between Omega-3 fatty acids' levels in whole blood and days of hospitalization or admission to the paediatric intensive care unit (PICU) in 51 children with MIS-C diagnosis following SARS-CoV-2 infection. A statistically significant negative correlation was observed between days of hospitalization and docosapentaenoic acid (22:5n-3,DPA), docosahexaenoic acid (DHA) and total Omega-3 FA levels. Dividing the study group into quartiles according to Omega-3-Index (O3I), no statistically significant difference was observed with respect to the PICU admission rate. In contrast, the number of days of hospitalization in Q4 (O3I ≥ 2.51 %) was different from the number observed in groups Q1-3 (O3I < 2.51 %), with subjects showing higher O3I needing shorter hospitalizations than the subjects with lower O3I. According to previous study investigating O3I in adults affected by Sars-cov-2 we explored the levels of this nutrients in children with MIS-C. Our exploratory study shows that high DPA, DHA and O3I levels could be effective in reducing the length of hospitalization.

Circulating Omega-3 Polyunsaturated Fatty Acids Levels in Coronary Heart Disease: Pooled Analysis of 36 Observational Studies.

Long-chain n-3 polyunsaturated fatty acid (PUFA) supplementation has shown potential benefits in the prevention of coronary heart disease (CHD); however, the impact of omega-3 fatty acid levels on CHD risk remains a subject of debate. Here, we aimed to investigate the association between n-3 PUFA levels and the risk of CHD, with particular reference to the subtypes of n-3 PUFA. METHODS: Prospective studies and retrospective case-control studies analyzing n-3 PUFA levels in CHD, published up to 30 July 2022, were selected. A random effects meta-analysis was used for pooled assessment, with relative risks (RRs) expressed as 95% confidence intervals (CIs) and standardized mean differences expressed as weight mean differences (WMDs). Subgroup and meta-regression analyses were conducted to assess the impact of n-3 PUFA exposure interval on the CHD subtype variables of the study. RESULTS: We included 20 prospective studies (cohort and nested case-control) and 16 retrospective case-control studies, in which n-3 PUFAs were measured. Higher levels of n-3 PUFAs (ALA, EPA, DPA, DHA, EPA + DHA, total n-3 PUFAs) were associated with a reduced risk of CHD, with RRs (95% CI) of 0.89 (0.81, 0.98), 0.83 (0.72, 0.96); 0.80 (0.67,0.95), 0.75 (0.64, 0.87), 0.83 (0.73, 0.95), and 0.80 (0.70, 0.93), respectively, p < 0.05. CHD patients had significantly lower n-3 PUFA levels compared to healthy controls (p < 0.05). In the subgroup analysis, a significant inverse trend was found for both fatal CHD and non-fatal CHD with n-3 PUFA (EPA + DHA) levels. Also, the link between n-3 PUFA levels in erythrocytes with total CHD was generally stronger than other lipid pools. CONCLUSIONS: n-3 PUFAs are significantly related to CHD risk, and these findings support the beneficial effects of n-3 PUFAs on CHD.

Biology and Total Synthesis of n-3 Docosapentaenoic Acid-Derived Specialized Pro-Resolving Mediators.

Research over the last 25 years related to structural elucidations and biological investigations of the specialized pro-resolving mediators has spurred great interest in targeting these endogenous products in total synthesis. These lipid mediators govern the resolution of inflammation as potent and stereoselective agonists toward individual G-protein-coupled receptors, resulting in potent anti-inflammatory activities demonstrated in many human disease models. Specialized pro-resolving mediators are oxygenated polyunsaturated products formed in stereoselective and distinct biosynthetic pathways initiated by various lipoxygenase and cyclooxygenase enzymes. In this review, the reported stereoselective total synthesis and biological activities of the specialized pro-resolving mediators biosynthesized from the polyunsaturated fatty acid n-3 docosapentaenoic acid are presented.

Omega-3 Long-Chain Polyunsaturated Fatty Acids in Nonseafood and Estimated Intake in the USA: Quantitative Analysis by Covalent Adduct Chemical Ionization Mass Spectrometry.

Omega-3 long-chain polyunsaturated fatty acids (LCPUFA) play critical roles in human development and health. Their intake is often effectively estimated solely based on seafood consumption, though the high intake of terrestrial animal-based foods with minor amounts of LCPUFA may be significant. Covalent adduct chemical ionization (CACI) tandem mass spectrometry is one approach for de novo structural and quantitative analysis of minor unsaturated fatty acids (FA), for which standards are unavailable. Here, CACI-MS and MS/MS are used to identify and quantify minor omega-3 LCPUFA of terrestrial animal foods based on the application of measured response factors (RFs) to various FA. American mean intakes of pork, beef, chicken, and eggs contribute 20, 27, 45, and 71 mg/day of docosahexaenoic acid (DHA), respectively. The estimated intake of omega-3 DHA, eicosapentaenoic acid, and docosapentaenoic acid from nonseafood sources is significant, at 164, 103, and 330 mg/day, greater than most existing estimates of omega-3 LCPUFA intake.

Correlation of meniscus tear type with synovial inflammation and the therapeutic potential of docosapentaenoic acid.

BACKGROUND: Synovitis, characterized by inflammation of the synovial membrane, is commonly induced by meniscus tears. However, significant differences in inflammatory responses and the key inflammatory mediators of synovium induced by different types of meniscal tears remain unclear. METHODS: Magnetic resonance imaging (MRI) was employed to identify the type of meniscus tear, and the quantification of synovial inflammation was assessed through H&E staining assay. Transcription and expression levels of IL-1ß and IL-6 were evaluated using bioinformatics, ELISA, RT-qPCR, and IHC of CD68 staining assays. The therapeutic potential of Docosapentaenoic Acid (DPA) was determined through network pharmacology, ELISA, and RT-qPCR assays. The safety of DPA was assessed using colony formation and EdU staining assays. RESULTS: The results indicate that both IL-1ß and IL-6 play pivotal roles in synovitis pathogenesis, with distinct expression levels across various subtypes. Among tested meniscus tears, oblique tear and bucket handle tear induced the most severe inflammation, followed by radial tear and longitudinal tear, while horizontal tear resulted in the least inflammation. Furthermore, in synovial inflammation induced by specific meniscus tears, the anterior medial tissues exhibited significantly higher local inflammation than the anterior lateral and suprapatellar regions, highlighting the clinical relevance and practical guidance of anterior medial tissues' inflammatory levels. Additionally, we identified the essential omega-3 fatty acid DPA as a potential therapeutic agent for synovitis, demonstrating efficacy in blocking the transcription and expression of IL-1ß and IL-6 with minimal side effects. CONCLUSION: These findings provide valuable insights into the nuanced nature of synovial inflammation induced by various meniscal tear classifications and contribute to the development of new adjunctive therapeutic agents in the management of synovitis.

Correlation between omega-3 intake and the incidence of diabetic retinopathy based on NHANES from 2005 to 2008.

AIMS: To identify correlations between omega-3 intake and incidence of diabetic retinopathy (DR). METHODS: This was a cross-sectional study using data from participants over age 40 in the National Health and Nutrition Examination Survey (NHANES) 2005-2008. Metrics included participants' intake of omega-3 fatty acids, specifically three types of representative polyunsaturated fatty acids, DR prevalence, and demographic characteristics. Multiple logistic regression models were used to assess the relationship between omega-3 intake and DR. RESULTS: Of the 1243 participants included in this study, omega-3 intake was lower in patients with DR relative to those without DR. Of the three polyunsaturated fatty acids within the omega-3 fatty acid family that we focused on, participants without DR consumed more docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) than those with DR. In contrast, there was no significant difference in the intake of eicosapentaenoic acid (EPA). Higher omega-3 intake was associated with a decreased risk of DR. In a crude model, the odds ratio (OR) was 0.548 (95% CI 0.315, 0.951; p = 0.033). In the fully adjusted model of omega-3 (model II), the adjusted OR was 0.525 (95% CI 0.306, 0.901; p = 0.021). DPA and DHA were also associated with a decreased risk of DR. In the full adjustment model (model II) of DPA and DHA, the adjusted ORs were 0.0002 (95% CI 0.000, 0.166; p = 0.014) and 0.293 (95% CI 0.105, 0.819; p = 0.020). Subgroup analysis showed that the protective effect of omega-3 against DR was more significant in younger patients (p value = 0.015). CONCLUSIONS: In this cross-sectional study of the U.S. general population, we found that increased intake of omega-3 and its components, specifically DPA and DHA were negatively associated with DR incidence. This suggests that omega-3 may be a potential protective factor for DR and may help to prevent or delay the onset and progression of DR.

Accumulation of docosapentaenoic acid (n-3 DPA) in a novel isolate of the marine ichthyosporean Sphaeroforma arctica.

OBJECTIVE: Currently, there is lack of a consistent and highly enriched source for docosapentaenoic acid (n-3 DPA, C22:5), and this work report the isolation of microorganism that naturally produces n-3 DPA. RESULTS: In this work, we screened microorganisms in our culture collections with the goal to isolate a strain with high levels of n-3 DPA. We isolated a strain of Sphaeroforma arctica that produces up to 11% n-3 DPA in total fatty acid and has a high n-3 DPA to DHA/EPA ratio. The cell growth of the isolated strain was characterized using microscopy imaging and flow cytometer technologies to confirm the coenocytic pattern of cell divisions previously described in S. arctica. Our novel isolate of S. arctica grew more robustly and produced significantly more n-3 DPA compared to previously isolated and described strains indicating the uniqueness of the discovered strain. CONCLUSION: Overall, this work reports a first isolate n-3 DPA producing microorganism and establishes the foundation for future strain improvement and elucidation of the physiological function of this LC-PUFA for human nutrition and health.

Epigenome-wide association study of dietary fatty acid intake.

BACKGROUND: Dietary intake of n-3 polyunsaturated fatty acids (PUFA) may have a protective effect on the development of cardiovascular diseases, diabetes, depression and cancer, while a high intake of n-6 PUFA was often reported to be associated with inflammation-related traits. The effect of PUFAs on health outcomes might be mediated by DNA methylation (DNAm). The aim of our study is to identify the impact of PUFA intake on DNAm in the Cooperative Health Research in the Region of Augsburg (KORA) FF4 cohort and the Leiden Longevity Study (LLS). RESULTS: DNA methylation levels were measured in whole blood from the population-based KORA FF4 study (N = 1354) and LLS (N = 448), using the Illumina MethylationEPIC BeadChip and Illumina HumanMethylation450 array, respectively. We assessed associations between DNAm and intake of eight and four PUFAs in KORA and LLS, respectively. Where possible, results were meta-analyzed. Below the Bonferroni correction threshold (p < 7.17 × 10-8), we identified two differentially methylated positions (DMPs) associated with PUFA intake in the KORA study. The DMP cg19937480, annotated to gene PRDX1, was positively associated with docosahexaenoic acid (DHA) in model 1 (beta: 2.00 × 10-5, 95%CI: 1.28 × 10-5-2.73 × 10-5, P value: 6.98 × 10-8), while cg05041783, annotated to gene MARK2, was positively associated with docosapentaenoic acid (DPA) in our fully adjusted model (beta: 9.80 × 10-5, 95%CI: 6.25 × 10-5-1.33 × 10-4, P value: 6.75 × 10-8). In the meta-analysis, we identified the CpG site (cg15951061), annotated to gene CDCA7L below Bonferroni correction (1.23 × 10-7) associated with eicosapentaenoic acid (EPA) intake in model 1 (beta: 2.00 × 10-5, 95% CI: 1.27 × 10-5-2.73 × 10-5, P value = 5.99 × 10-8) and we confirmed the association of cg19937480 with DHA in both models 1 and 2 (beta: 2.07 × 10-5, 95% CI: 1.31 × 10-5-2.83 × 10-5, P value = 1.00 × 10-7 and beta: 2.19 × 10-5, 95% CI: 1.41 × 10-5-2.97 × 10-5, P value = 5.91 × 10-8 respectively). CONCLUSIONS: Our study identified three CpG sites associated with PUFA intake. The mechanisms of these sites remain largely unexplored, highlighting the novelty of our findings. Further research is essential to understand the links between CpG site methylation and PUFA outcomes.

Association between serum polyunsaturated fatty acids and bone mineral density in US adults: NHANES 2011-2014.

Objective: The purpose of this study was to investigate the association between serum polyunsaturated fatty acids (PUFAs) and bone mineral density (BMD). Methods: We performed a cross-sectional study based on data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. The weighted multiple linear regression model was utilized to determine the association between serum PUFAs and BMD. Further smoothed curve fitting and threshold effect analysis were conducted. Finally, we performed a subgroup analysis. Results: In total, 1979 participants aged 20-59 years were enrolled. After adjusting for all covariates, we found that serum docosapentaenoic acid (DPA) was positively associated with head BMD (ß = 0.0015, 95% Cl: 0.0004, 0.0026, P = 0.008296) and lumbar spine BMD (ß = 0.0005, 95% Cl: 0.0000, 0.0010, P = 0.036093), and serum eicosadienoic acid (EDA) was negatively associated with thoracic spine BMD (ß = -0.0008, 95% Cl: -0.0016, -0.0000, P = 0.045355). Smoothed curve fitting revealed a nonlinear positive association between serum DPA and lumbar spine BMD. Threshold effect analysis indicated that the threshold of serum DPA was 81.4 µmol/L. Subgroup analysis revealed a positive correlation between serum DPA and head BMD in the subgroup aged 50-59 years (ß = 0.0025, 95% Cl: 0.0002, 0.0049, P = 0.035249) and females (ß = 0.0026, 95% Cl: 0.0008, 0.0044, P = 0.005005). There was a positive relationship between serum DPA and lumbar spine BMD in females (ß = 0.0008, 95% Cl: 0.0001, 0.0015, P = 0.017900) and a negative association between serum EDA and thoracic spine BMD in the subgroup aged 30-39 years (ß = -0.0016, 95% Cl: -0.0031, -0.0001, P = 0.041331), males (ß = -0.0012, 95% Cl: -0.0023, -0.0001, P = 0.039364) and other races (ß = -0.0021, 95% Cl: -0.0037, -0.0006, P = 0.008059). Conclusion: This study demonstrated a linear positive relationship between serum DPA and head BMD, a nonlinear positive association between serum DPA and lumbar spine BMD, and a linear negative correlation between serum EDA and thoracic spine BMD in US adults.

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.

Omega-3 Fatty Acid Biomarkers and Incident Atrial Fibrillation.

BACKGROUND: The relationship between omega-3 fatty acids and atrial fibrillation (AF) remains controversial. OBJECTIVES: This study aimed to determine the prospective associations of blood or adipose tissue levels of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with incident AF. METHODS: We used participant-level data from a global consortium of 17 prospective cohort studies, each with baseline data on blood or adipose tissue omega-3 fatty acid levels and AF outcomes. Each participating study conducted a de novo analyses using a prespecified analytical plan with harmonized definitions for exposures, outcome, covariates, and subgroups. Associations were pooled using inverse-variance weighted meta-analysis. RESULTS: Among 54,799 participants from 17 cohorts, 7,720 incident cases of AF were ascertained after a median 13.3 years of follow-up. In multivariable analysis, EPA levels were not associated with incident AF, HR per interquintile range (ie, the difference between the 90th and 10th percentiles) was 1.00 (95% CI: 0.95-1.05). HRs for higher levels of DPA, DHA, and EPA+DHA, were 0.89 (95% CI: 0.83-0.95), 0.90 (95% CI: 0.85-0.96), and 0.93 (95% CI: 0.87-0.99), respectively. CONCLUSIONS: In vivo levels of omega-3 fatty acids including EPA, DPA, DHA, and EPA+DHA were not associated with increased risk of incident AF. Our data suggest the safety of habitual dietary intakes of omega-3 fatty acids with respect to AF risk. Coupled with the known benefits of these fatty acids in the prevention of adverse coronary events, our study suggests that current dietary guidelines recommending fish/omega-3 fatty acid consumption can be maintained.

Corrigendum: Circulating polyunsaturated fatty acids and COVID-19: a prospective cohort study and Mendelian randomization analysis.

[This corrects the article DOI: 10.3389/fmed.2022.923746.].

Relationship Between Cardiovascular Events and Serum Lipid and Plasma Fatty Acid Profile in Maintenance Hemodialysis Patients With Diabetic Mellitus.

BACKGROUND/AIM: Cardiovascular disease (CVD) is a frequent complication in hemodialysis (HD) patients, especially when the underlying disease is diabetes mellitus (DM). In this study, we investigated cardiovascular events and lipid and fatty acid profile in maintenance HD patients with diabetic kidney disease (DKD). PATIENTS AND METHODS: The subjects were 123 patients undergoing HD at Oyokyo Kidney Research Institute Hirosaki Hospital, who were considered to have DKD as the underlying cause of dialysis induction. Among these patients, the lipid and fatty acid profile were examined in two groups, CVD group (n=53) and non-CVD group (n=70), according to the presence or absence of a history of cardiovascular events (coronary artery disease, stroke, arteriosclerosis obliterans, valvular disease, and aortic disease). For serum lipid profile, the levels of total-cholesterol (T-C), triglycerides (TG), high density lipoprotein-cholesterol (HDL-C), and low density lipoprotein-cholesterol (LDL-C) were measured, and for fatty acid balance, 24 fractions of fatty acid composition in plasma total lipids were measured. These markers were compared between the CVD and non-CVD groups. RESULTS: The levels of T-C and TG were significantly lower in the CVD group compared with the non-CVD group (147.7±36.9 mg/dl vs. 159.2±35.6 mg/dl, p<0.05, 120.2±65.7 mg/dl vs. 143.8±124.4 mg/dl, p<0.05). In the plasma fatty acid composition, alpha-linolenic acid (ALA) and docosapentaenoic acid (DPA) were significantly lower in the CVD group compared with the non-CVD group (0.74±0.26 wt% vs. 0.84±0.31 wt%, p<0.05; 0.61±0.21 wt% vs. 0.70±0.30 wt%, p<0.05). CONCLUSION: Abnormal fatty acid balance, especially low levels of ALA and DPA, rather than serum lipids, are more likely the factors associated with cardiovascular events in maintenance HD patients with underlying DKD.

7S,15R-Dihydroxy-16S,17S-epoxy-docosapentaenoic Acid Overcomes Chemoresistance of 5-Fluorouracil by Suppressing the Infiltration of Tumor-Associated Macrophages and Inhibiting the Activation of Cancer Stem Cells in a Colorectal Cancer Xenograft Model.

Although the tumor bulk is initially reduced by 5-fluorouracil (5-FU), chemoresistance developed due to prolonged chemotherapy in colorectal cancer (CRC). The enrichment of cancer stem cells (CSCs) and the infiltration of tumor-associated macrophages (TAMs) contribute to chemoresistance and poor outcomes. A docosahexaenoic acid derivative developed by our group, 7S,15R-dihydroxy-16S,17S-epoxy-docosapentaenoic acid (diHEP-DPA), exerts antitumor effects against TAMs infiltration and CSCs enrichment in our previous study. The current study aimed to investigate whether diHEP-DPA was able to overcome chemoresistance to 5-FU in CRCs, together with the potential synergistic mechanisms in a CT26-BALB/c mouse model. Our results suggested that although 5-FU inhibited tumor growth, 5-FU enriched CSCs via the WNT/ß-catenin signaling pathway, resulting in chemoresistance in CRCs. However, we revealed that 5-FU promoted the infiltration of TAMs via the NF-kB signaling pathway and improved epithelial-mesenchymal transition (EMT) via the signal transducer and activator of the transcription 3 (STAT3) signaling pathway; these traits were believed to contribute to CSC activation. Furthermore, supplementation with diHEP-DPA could overcome drug resistance by decreasing the CSCs, suppressing the infiltration of TAMs, and inhibiting EMT progression. Additionally, the combinatorial treatment of diHEP-DPA and 5-FU effectively enhanced phagocytosis by blocking the CD47/signal regulatory protein alpha (SIRPα) axis. These findings present that diHEP-DPA is a potential therapeutic supplement to improve drug outcomes and suppress chemoresistance associated with the current 5-FU-based therapies for colorectal cancer.

Docosapentaenoic Acid (DPA, 22:5n-3) Alleviates Ulcerative Colitis via Modification of Gut Microbiota and Their Metabolism.

N-3 polyunsaturated fatty acids (n-3PUFA) are regarded as viable alternatives to aid the treatment of ulcerative colitis (UC). Most research focuses on eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA); little information is available about the effect of docosapentaenoic acid (DPA) on the gut microbiota and their metabolism in UC mice. In this study, the changes in gut microbiota and their metabolism in UC mice were studied through the 16S rRNA sequencing method and untargeted metabolomics. Moreover, the differential bacterial genus and differential metabolites in responding to DPA supplementation were screened through permutation test after orthogonal partial least squares discriminant analysis (OPLS-DA). The results indicated that DPA supplementation increased the diversity and altered the composition of the gut microbiota in UC mice; Akkermansia, Alistipes, Butyricicoccus, and Lactobacillus were selected as the differential bacterial genus. Supplementation of DPA also altered the fecal metabolite profile in the UC mice. Moreover, butyrate, N-carbamylglutamate (NCG), and histamine were screened as the differential metabolites. In conclusion, the regulation effect of DPA on the gut microbiota and their metabolism might be involved in the intervention mechanism of DPA in UC. More research needs to be carried out to elucidate the mechanism systematically.

Association between polyunsaturated fatty acid intake and infertility among American women aged 20-44 years.

Background: Infertility is a nationwide public health priority in the U.S. However, few studies have investigated the effects of dietary intake of polyunsaturated fatty acids (PUFAs) on female infertility. This study explored the association between PUFA intake and risk of infertility. Methods: A total of 1,785 women aged 20-44 years from three National Health and Nutrition Examination Survey cycles (2013-2018) were included in this cross-sectional study. The intake of PUFAs was obtained from a 24-h dietary interview on two separate days with a 3-10-day interval, and nutrient residue models were used. Fertility status was assessed by positive response to two relative questions via a questionnaire. Logistic regression models were used and some covariates were adjusted. Results: Among all the participants, 340 (19.05%) women suffered from infertility. The intake of docosahexaenoic acid (DHA) (OR = 0.998, 95% CI 0.998, 0.009) was slightly related to the risk of infertility. In contrast, women with higher α-linolenic acid (ALA) (OR = 1.416, 95% CI 1.138, 1.763) and linoleic acid (LA) intake (OR = 1.020, 95% CI 1.002, 1.038) presented with a relatively higher risk of primary infertility. Furthermore, in 20-34-year-old women, higher omega-6/omega-3 was significant associated with the risk of infertility (OR = 1.002, 95%CI 1.000, 1.005). Conclusions: Our results suggest that PUFA intake is only slightly associated with infertility. The higher the DHA intake, the lower the risk of infertility regardless of age. In women with primary infertility, ALA and LA has negative effect.

Circulating Polyunsaturated Fatty Acids and COVID-19: A Prospective Cohort Study and Mendelian Randomization Analysis.

Higher circulating polyunsaturated fatty acids (PUFAs), especially omega-3 fatty acids, have been linked to a better prognosis in patients of coronavirus disease 2019 (COVID-19). However, the effects and causality of pre-infection PUFA levels remain unclear. This study aimed to investigate the observational and causal associations of circulating PUFAs with COVID-19 susceptibility and severity. We first performed a prospective cohort study in UK Biobank, with 20,626 controls who were tested negative and 4,101 COVID-19 patients, including 970 hospitalized ones. Plasma PUFAs at baseline (blood samples collected from 2007 to 2010) were measured by nuclear magnetic resonance, including total PUFAs, omega-3 PUFAs, omega-6 PUFAs, docosahexaenoic acid (DHA), linoleic acid (LA), and the omega-6/omega-3 ratio. Moreover, going beyond UK Biobank, we leveraged summary statistics from existing genome-wide association studies to perform bidirectional two-sample Mendelian randomization (MR) analyses to examine the causal associations of eight individual PUFAs, measured in either plasma or red blood cells, with COVID-19 susceptibility and severity. In the observational association analysis of each PUFA measure separately, total, omega-3, and omega-6 PUFAs, DHA, and LA were associated with a lower risk of severe COVID-19. Omega-3 PUFAs and DHA were also associated with a lower risk of testing positive for COVID-19. The omega-6/omega-3 ratio was positively associated with risks of both susceptibility and severity. When omega-6, omega-3, and their ratio are jointly analyzed, only omega-3 PUFAs remained significantly and inversely associated with both susceptibility and severity. The forward MR analysis indicated that docosapentaenoic acid (DPA-n3) and arachidonic acid (AA) might be causally associated with a lower risk of severe COVID-19, with OR (95% CI) per one SD increase in the plasma level as 0.89 (0.81, 0.99) and 0.96 (0.94, 0.99), respectively. The reverse MR analysis did not support any causal effect of COVID-19 on PUFAs. Our observational analysis supported that higher circulating omega-3 PUFAs, especially DHA, may lower the susceptibility to and alleviate the severity of COVID-19. Our MR analysis further supported causal associations of DPA-n3 and AA with a lower risk of severe COVID-19.

Protective effect of 17S­epoxy­docosapentaenoic acid against dextran sulfate sodium induced ulcerative colitis in BALB/c mice.

Ulcerative colitis (UC) is difficult to eradicate as it leads to chronic inflammation in the digestive tract due to immune system malfunction. The present study demonstrated the protective effect of 7S,15R­dihydroxy­16S,17S­epoxy­docosapentaenoic acid (diHEP­DPA), which had been previously synthesized, on a dextran sulfate sodium (DSS)­induced BALB/c mouse model of UC. UC was induced with 4% DSS drinking water for 7 days. Initially, the anti­inflammatory effect of diHEP­DPA was confirmed by demonstrating that lipopolysaccharide­stimulated THP1 cells treated with diHEP­DPA decreased IL­6, TNF­α and nitrite levels by fluorescence­activated cell sorting (FACS) and Griess reagent kit. The results indicated that the administration of diHEP­DPA at 20 µg/kg significantly reduced the severity of colitis, as determined by hematoxylin and eosin staining. The levels of TNF­α, IL­6 and IL­1ß in the colon tissue and serum were significantly reduced in the diHEP­DPA + DSS­treated group compared with in the control group, as determined by FACS and ELISA kit. It was also observed that diHEP­DPA decreased myeloperoxidase (MPO) and nitrite levels in the colon tissues of diHEP­DPA + DSS­treated mice, as indicated using commercial MPO and nitric oxide kits. The diHEP­DPA+DSS­treated mice also exhibited decreased expression levels of phosporylated (p)­inhibitor κB protein, p­p65 and inducible nitric oxide synthase in the colon tissue by inhibiting inflammation, which were measured by reverse transcription­quantitative PCR and weatern blot analysis. Overall, the present study demonstrated the protective effect of diHEP­DPA against a severe colitis condition in vivo.