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Marine Drugs Oct 2021Microglia M1 phenotype causes HPA axis hyperactivity, neurotransmitter dysfunction, and production of proinflammatory mediators and oxidants, which may contribute to the...
ω-3 DPA Protected Neurons from Neuroinflammation by Balancing Microglia M1/M2 Polarizations through Inhibiting NF-κB/MAPK p38 Signaling and Activating Neuron-BDNF-PI3K/AKT Pathways.
Microglia M1 phenotype causes HPA axis hyperactivity, neurotransmitter dysfunction, and production of proinflammatory mediators and oxidants, which may contribute to the etiology of depression and neurodegenerative diseases. Eicosapentaenoic acid (EPA) may counteract neuroinflammation by increasing n-3 docosapentaenoic acid (DPA). However, the cellular and molecular mechanisms of DPA, as well as whether it can exert antineuroinflammatory and neuroprotective effects, are unknown. The present study first evaluated DPA's antineuroinflammatory effects in lipopolysaccharide (LPS)-activated BV2 microglia. The results showed that 50 μM DPA significantly decreased BV2 cell viability after 100 ng/mL LPS stimulation, which was associated with significant downregulation of microglia M1 phenotype markers and proinflammatory cytokines but upregulation of M2 markers and anti-inflammatory cytokine. Then, DPA inhibited the activation of mitogen-activated protein kinase (MAPK) p38 and nuclear factor-κB (NF-κB) p65 pathways, which results were similar to the effects of NF-κB inhibitor, a positive control. Second, BV2 cell supernatant was cultured with differentiated SH-SY5Y neurons. The results showed that the supernatant from LPS-activated BV2 cells significantly decreased SH-SY5Y cell viability and brain-derived neurotrophic factor (BDNF), TrkB, p-AKT, and PI3K expression, which were significantly reversed by DPA pretreatment. Furthermore, DPA neuroprotection was abrogated by BDNF-SiRNA. Therefore, n-3 DPA may protect neurons from neuroinflammation-induced damage by balancing microglia M1 and M2 polarizations, inhibiting microglia-NF-κB and MAPK p38 while activating neuron-BDNF/TrkB-PI3K/AKT pathways.
Topics: Animals; Aquatic Organisms; Brain-Derived Neurotrophic Factor; Fatty Acids, Unsaturated; Humans; Microalgae; Microglia; Neuroinflammatory Diseases; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; p38 Mitogen-Activated Protein Kinases
PubMed: 34822458
DOI: 10.3390/md19110587 -
EBioMedicine Dec 2021Metabolic syndrome (MetS) is a cluster of multiple cardiometabolic risk factors that increase the risk of type 2 diabetes and cardiovascular diseases. Identifying novel...
BACKGROUND
Metabolic syndrome (MetS) is a cluster of multiple cardiometabolic risk factors that increase the risk of type 2 diabetes and cardiovascular diseases. Identifying novel biomarkers of MetS and their genetic associations could provide insights into the mechanisms of cardiometabolic diseases.
METHODS
Potential MetS-associated metabolites were screened and internally validated by untargeted metabolomics analyses among 693 patients with MetS and 705 controls. External validation was conducted using two well-established targeted metabolomic methods among 149 patients with MetS and 253 controls. The genetic associations of metabolites were determined by linear regression using our previous genome-wide SNP data. Causal relationships were assessed using a one-sample Mendelian Randomization (MR) approach.
FINDINGS
Nine metabolites were ultimately found to be associated with MetS or its components. Five metabolites, including LysoPC(14:0), LysoPC(15:0), propionyl carnitine, phenylalanine, and docosapentaenoic acid (DPA) were selected to construct a metabolite risk score (MRS), which was found to have a dose-response relationship with MetS and metabolic abnormalities. Moreover, MRS displayed a good ability to differentiate MetS and metabolic abnormalities. Three SNPs (rs11635491, rs7067822, and rs1952458) were associated with LysoPC(15:0). Two SNPs, rs1952458 and rs11635491 were found to be marginally correlated with several MetS components. MR analyses showed that a higher LysoPC(15:0) level was causally associated with the risk of overweight/obesity, dyslipidaemia, high uric acid, high insulin and high HOMA-IR.
INTERPRETATION
We identified five metabolite biomarkers of MetS and three SNPs associated with LysoPC(15:0). MR analyses revealed that abnormal LysoPC metabolism may be causally linked the metabolic risk.
FUNDING
This work was supported by grants from the National Key Research and Development Program of China (2017YFC0907004).
Topics: Case-Control Studies; Early Diagnosis; Female; Genome-Wide Association Study; Humans; Linear Models; Lysophosphatidylcholines; Male; Mendelian Randomization Analysis; Metabolic Syndrome; Metabolomics; Middle Aged; Polymorphism, Single Nucleotide
PubMed: 34801968
DOI: 10.1016/j.ebiom.2021.103707 -
Nutrients Feb 2023Increasingly, studies have discovered that different fatty acids (Fas) are linked to colorectal cancer (CRC) risk. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Increasingly, studies have discovered that different fatty acids (Fas) are linked to colorectal cancer (CRC) risk.
METHODS
We systematically searched Embase and Medline databases to identify eligible studies that examined the associations of different types of Fas with CRC risk. The effect estimates and their 95% confidence intervals (Cis) were pooled using a random-effects model. Subgroup and sensitivity analyses were performed to examine the robustness of the study findings.
RESULTS
This study evaluated the associations of 28 dietary and 18 blood Fas with CRC risk by summarizing the most updated evidence from 54 observational and four Mendelian Randomization (MR) studies. The present findings suggested that high dietary intake of eicosapentaenoic acid (EPA), docosahexanoic acid (DHA), and docosapentaenoic acid (DPA) are related to low risk of CRC, while the -6/-3 PUFA ratio and trans-FA are related to high risk of CRC. The summary of all cohort studies found that a high intake of SFA and DHA was a protective factor for CRC, and a high intake of the -6/-3 PUFA ratio was a risk factor for CRC. In the subgroup analysis of cancer subsites, we found that the dietary intake of linoleic acid (LA) and trans-FA are risk factors, while DPA is a protective factor for colon cancer. High dietary DHA intake was associated with a lower risk of rectal cancer, while the dietary -6/-3 PUFA ratio was associated with a higher risk of rectal cancer. Meta-analysis of blood FA levels showed a significant reverse association between blood pentadecanoic acid and CRC risk, whilst other blood Fas showed no significant association with CRC risk. All included MR studies showed that high plasma arachidonic acid (AA) is associated with increased CRC risk.
CONCLUSIONS
Current evidence on the dietary intake and blood levels of Fas in relation to CRC risk is less consistent. Future studies are needed to investigate how the metabolism of Fas contributes to CRC development.
Topics: Humans; Fatty Acids; Fatty Acids, Omega-3; Eating; Risk Factors; Colorectal Neoplasms; Rectal Neoplasms; Observational Studies as Topic
PubMed: 36771436
DOI: 10.3390/nu15030730 -
BMJ (Clinical Research Ed.) Jan 2023To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD).
DESIGN
Pooled analysis.
DATA SOURCES
A consortium of 19 studies from 12 countries identified up to May 2020.
STUDY SELECTION
Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate.
DATA EXTRACTION AND SYNTHESIS
Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis.
MAIN OUTCOME MEASURES
Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m. In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m and <75% of baseline rate.
RESULTS
25 570 participants were included in the primary outcome analysis and 4944 (19.3%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95% confidence interval 0.86 to 0.98; P=0.009, I=9.9%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I=0.0%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I=5.8%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (≥60 <60 years), estimated glomerular filtration rate (60-89 ≥90 mL/min/1.73 m), hypertension, diabetes, and coronary heart disease at baseline.
CONCLUSIONS
Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD.
Topics: Humans; Middle Aged; alpha-Linolenic Acid; Prospective Studies; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Renal Insufficiency, Chronic; Risk Factors
PubMed: 36653033
DOI: 10.1136/bmj-2022-072909 -
Journal of Affective Disorders Jun 2023Observational studies have suggested that polyunsaturated fatty acids (PUFAs) decrease the risk of anorexia nervosa (AN). In the present study, we examined this... (Meta-Analysis)
Meta-Analysis
PURPOSE
Observational studies have suggested that polyunsaturated fatty acids (PUFAs) decrease the risk of anorexia nervosa (AN). In the present study, we examined this hypothesis using a Mendelian randomization analysis.
METHODS
We used summary statistics for single-nucleotide polymorphisms associated with plasma levels of n-6 (linoleic acid and arachidonic acid) and n-3 PUFAs (alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) and the corresponding data for AN from a genome-wide association meta-analysis of 72,517 individuals (16,992 diagnosed AN cases and 55,525 controls).
RESULTS
None of the genetically predicted PUFAs were significantly associated with the risk of AN; odds ratios (95 % confidence interval) per 1 standard deviation increase in PUFA levels were 1.03 (0.98, 1.08) for linoleic acid, 0.99 (0.96, 1.03) for arachidonic acid, 1.03 (0.94, 1.12) for alpha-linolenic acid, 0.98 (0.90, 1.08) for eicosapentaenoic acid, 0.96 (0.91, 1.02) for docosapentaenoic acid, and 1.01 (0.90, 1.36) for docosahexaenoic acid.
LIMITATION
Only two types of fatty acids (LA and DPA) can be used for pleiotropy tests using the MR-Egger intercept test.
CONCLUSION
This study does not support the hypothesis that PUFAs decrease the risk of AN.
Topics: Humans; Eicosapentaenoic Acid; Docosahexaenoic Acids; alpha-Linolenic Acid; Genome-Wide Association Study; Mendelian Randomization Analysis; Anorexia Nervosa; Fatty Acids, Unsaturated; Fatty Acids, Omega-3; Linoleic Acid; Arachidonic Acid
PubMed: 36907461
DOI: 10.1016/j.jad.2023.03.016 -
Biochemical Pharmacology Dec 2022Several lipoxygenase enzymes and cyclooxygenase-2 stereoselectively convert the polyunsaturated fatty acids arachidonic acid, eicosapentaenoic acid, docosahexaenoic... (Review)
Review
Several lipoxygenase enzymes and cyclooxygenase-2 stereoselectively convert the polyunsaturated fatty acids arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and n-3 docosapentaenoic acid into numerous oxygenated products. Biosynthetic pathway studies have shown, during the resolution phase of acute inflammation, that distinct families of endogenous products are formed. These products were named specialized pro-resolving mediators, given their specialized functions in the inflammation-resolution circuit, enhancing the return of inflamed and injured tissue to homeostasis. The lipoxins, resolvins, protectins and maresins, together with the sulfido-conjugates of the resolvins, protectins and maresins, constitute the four individual families of these local mediators. When administrated in vivo in a wide range of human disease models, the specialized pro-resolving mediators display potent bioactions. The detailed and individual biosynthetic steps constituting the biochemical pathways, the metabolism, recent reports on structure-function studies and pharmacodynamic data of the protectins, are presented herein. Emphasis is on the structure-function results on the recent members of the sulfido conjugated protectins and further metabolism of protectin D1. Moreover, the members of the individual families of specialized pro-resolving mediators and their biosynthetic precursor are presented. Today 43 specialized pro-resolving mediators possessing pro-resolution and anti-inflammatory bioactions are reported and confirmed, constituting a basis for resolution pharmacology. This emerging biomedical field provides a new approach for drug discovery, that is also discussed.
Topics: Humans; CD59 Antigens; Docosahexaenoic Acids; Inflammation; Eicosapentaenoic Acid; Inflammation Mediators; Anti-Inflammatory Agents
PubMed: 36341938
DOI: 10.1016/j.bcp.2022.115330 -
Frontiers in Nutrition 2023Previous studies have suggested a potential association between nutrients and cerebral small vessel disease (CSVD), but this association has not been fully addressed.
BACKGROUND
Previous studies have suggested a potential association between nutrients and cerebral small vessel disease (CSVD), but this association has not been fully addressed.
OBJECT
We intended to clarify the causal associations between four categories of essential nutrients (amino acids, polyunsaturated fatty acids, minerals and vitamins) and two acute manifestations of CSVD (intracerebral hemorrhage and small vessel stroke) using two-sample Mendelian randomization (MR) analysis.
METHOD
We obtained European-based large-scale genome-wide association studies (GWASs) related to CSVD (6,255 cases and 233,058 controls) and nutrient concentrations. Causality evaluation mainly included the results of the inverse variance-weighted (IVW) method. The simple median method, the weighted median method and the MR-Egger method were adopted for sensitivity analyses.
RESULTS
For ICH or SVS, increased levels of phenylalanine (OR = 1.188, < 0.001) and dihomo-gamma-linolenic acid (DGLA) (OR = 1.153, = 0.001) showed risk effects, while docosapentaenoic acid (DPA) (OR = 0.501, < 0.001), zinc (OR = 0.919, < 0.001), and arachidonic acid (OR = 0.966, = 0.007) showed protective effects. For lobar hemorrhage or SVS, AA (OR = 0.978, < 0.001), zinc (OR = 0.918, < 0.001), and retinol (OR = 0.753, < 0.001) showed risk effects; DPA (OR = 0.682, = 0.022), gamma-linolenic acid (OR = 0.120, = 0.033) and 25(OH)D (OR = 0.874, = 0.040) showed protective effects. For nonlobar hemorrhage or SVS, DGLA (OR = 1.088, < 0.001) and phenylalanine (OR = 1.175, = 0.001) showed risk effects.
CONCLUSION
Our study analyzed the effect of nutrients on CSVD risk from a genetic perspective, with implications for CSVD prevention through nutrient supplementation.
PubMed: 37426181
DOI: 10.3389/fnut.2023.1172587 -
Advances in Experimental Medicine and... 2020Our own studies and those of others have shown that defects in essential fatty acid (EFA) metabolism occurs in age-related disorders such as obesity, type 2 diabetes... (Review)
Review
Our own studies and those of others have shown that defects in essential fatty acid (EFA) metabolism occurs in age-related disorders such as obesity, type 2 diabetes mellitus, hypertension, atherosclerosis, coronary heart disease, immune dysfunction and cancer. It has been noted that in all these disorders there could occur a defect in the activities of desaturases, cyclo-oxygenase (COX), and lipoxygenase (LOX) enzymes leading to a decrease in the formation of their long-chain products gamma-linolenic acid (GLA), arachidonic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA). This leads to an increase in the production of pro-inflammatory prostaglandin E2 (PGE2), thromboxanes (TXs), and leukotrienes (LTs) and a decrease in anti-inflammatory lipoxin A4, resolvins, protectins and maresins. All these bioactive molecules are termed as bioactive lipids (BALs). This imbalance in the metabolites of EFAs leads to low-grade systemic inflammation and at times acute inflammatory events at specific local sites that trigger the development of various age-related disorders such as obesity, type 2 diabetes mellitus, hypertension, coronary heart disease, atherosclerosis, and immune dysfunction as seen in rheumatoid arthritis, lupus, nephritis and other localized inflammatory conditions. This evidence implies that methods designed to restore BALs to normal can prevent age-related disorders and enhance longevity and health.
Topics: Aging; Disease; Docosahexaenoic Acids; Fatty Acids, Essential; Fatty Acids, Unsaturated; Humans; Inflammation
PubMed: 32304030
DOI: 10.1007/978-3-030-42667-5_3 -
Molecules (Basel, Switzerland) Jun 2024Research over the last 25 years related to structural elucidations and biological investigations of the specialized pro-resolving mediators has spurred great interest in... (Review)
Review
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.
Topics: Humans; Fatty Acids, Unsaturated; Animals; Prostaglandin-Endoperoxide Synthases; Anti-Inflammatory Agents; Inflammation
PubMed: 38930898
DOI: 10.3390/molecules29122833 -
International Archives of Allergy and... 2023Eczema is a common allergic skin condition among children and adolescents, and polyunsaturated fatty acids (PUFAs) are a kind of fatty acid which were reported to be...
INTRODUCTION
Eczema is a common allergic skin condition among children and adolescents, and polyunsaturated fatty acids (PUFAs) are a kind of fatty acid which were reported to be associated with reduced risk of eczema. Previous studies explored different types of PUFAs with various age groups of children and adolescents, and the influence of confounding factors such as medicine use was not considered. In the present study, we aimed to identify the associations between PUFAs and the risk of eczema in children and adolescents. These findings of our study might help better understand the associations between PUFAs and eczema.
METHODS
This cross-sectional study collected the data of 2,560 children and adolescents aged 6-19 years from National Health and Nutrition Examination Surveys (NHANES) between 2005 and 2006. Total PUFA, omega-3 (n-3), including octadecatrienoic acid/18:3, octadecatrienoic acid/18:4, eicosapentaenoic acid/20:5, docosapentaenoic acid/22:5, and docosahexaenoic acid/22:6, omega-6 (n-6), including octadecatrienoic acid/18:2 and eicosatetraenoic acid/20:4, total n-3 intake, total n-6 intake, and n-3/n-6 were main variables in this study. Univariate logistic regression was applied for identifying potential confounders for eczema. Univariate and multivariate logistic regression analysis were conducted to explore the associations between PUFAs and eczema. Subgroup analysis was performed on subjects with different ages, and patients complicated with other allergic diseases, allergy, and medicine use or not.
RESULTS
In total, there were 252 (9.8%) subjects who had eczema. After adjusting for confounding factors including age, race, poverty to income ratio (PIR), medicine use, hay fever, sinus infection, body mass index (BMI), serum total immunoglobulin E (IgE) antibody, and IgE, we observed that eicosatetraenoic acid/20:4 (OR = 0.17, 95% CI: 0.04-0.68) and total n-3 (OR = 0.88, 95% CI: 0.77-0.99) were linked with decreased risk of eczema in children and adolescents. Eicosatetraenoic acid/20:4 was correlated with decreased risk of eczema in participants without hay fever (OR = 0.82, 95% CI: 0.70-0.97) and medicine use (OR = 0.80, 95% CI: 0.68-0.94) or with allergy (OR = 0.75, 95% CI: 0.59-0.94). Total n-3 intake was associated with a reduced risk of eczema with the adjusted OR of 0.84, 95% CI: 0.72-0.98) in participants without hay fever. In those without sinus infection, octadecatrienoic acid/18:4 was linked with decreased risk of eczema (OR = 0.83, 95% CI: 0.69-0.99).
CONCLUSION
N-3 and eicosatetraenoic acid/20:4 might be associated with the risk of eczema in children and adolescents.
Topics: Humans; Child; Adolescent; Rhinitis, Allergic, Seasonal; Nutrition Surveys; Cross-Sectional Studies; Eczema; Hypersensitivity; Fatty Acids, Omega-3; Immunoglobulin E; Arachidonic Acids
PubMed: 36996769
DOI: 10.1159/000529435