-
Acta Pharmaceutica Sinica. B Nov 2021Detailed knowledge on tissue-specific metabolic reprogramming in diabetic nephropathy (DN) is vital for more accurate understanding the molecular pathological signature...
Detailed knowledge on tissue-specific metabolic reprogramming in diabetic nephropathy (DN) is vital for more accurate understanding the molecular pathological signature and developing novel therapeutic strategies. In the present study, a spatial-resolved metabolomics approach based on air flow-assisted desorption electrospray ionization (AFADESI) and matrix-assisted laser desorption ionization (MALDI) integrated mass spectrometry imaging (MSI) was proposed to investigate tissue-specific metabolic alterations in the kidneys of high-fat diet-fed and streptozotocin (STZ)-treated DN rats and the therapeutic effect of astragaloside IV, a potential anti-diabetic drug, against DN. As a result, a wide range of functional metabolites including sugars, amino acids, nucleotides and their derivatives, fatty acids, phospholipids, sphingolipids, glycerides, carnitine and its derivatives, vitamins, peptides, and metal ions associated with DN were identified and their unique distribution patterns in the rat kidney were visualized with high chemical specificity and high spatial resolution. These region-specific metabolic disturbances were ameliorated by repeated oral administration of astragaloside IV (100 mg/kg) for 12 weeks. This study provided more comprehensive and detailed information about the tissue-specific metabolic reprogramming and molecular pathological signature in the kidney of diabetic rats. These findings highlighted the promising potential of AFADESI and MALDI integrated MSI based metabolomics approach for application in metabolic kidney diseases.
PubMed: 34900545
DOI: 10.1016/j.apsb.2021.05.013 -
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 -
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 -
Pharmacological Research Jun 2017PCSK9 (proprotein convertase subtilisin kexin type 9) is a liver secretory enzyme that regulates plasma low-density lipoprotein (LDL) cholesterol (LDL-C) levels through... (Review)
Review
PCSK9 (proprotein convertase subtilisin kexin type 9) is a liver secretory enzyme that regulates plasma low-density lipoprotein (LDL) cholesterol (LDL-C) levels through modulation of LDL receptor (LDLR) density on the surface of hepatocytes. Inhibition of PCSK9 using monoclonal antibodies can efficiently lower plasma LDL-C, non-high-density lipoprotein cholesterol and lipoprotein (a). PCSK9 inhibition is also an effective adjunct to statin therapy; however, the cost-effectiveness of currently available PCSK9 inhibitors is under question. Nutraceuticals offer a safe and cost-effective option for PCSK9 inhibition. Several nutraceuticals have been reported to modulate PCSK9 levels and exert LDL-lowering activity. Mechanistically, those nutraceuticals that inhibit PCSK9 through a SREBP (sterol-responsive element binding protein)-independent pathway can be more effective in lowering plasma LDL-C levels compared with those inhibiting PCSK9 through the SREBP pathway. The present review aims to collect available data on the nutraceuticals with PCSK9-inhibitory effect and the underlying mechanisms.
Topics: Animals; Anticholesteremic Agents; Cholesterol, LDL; Dietary Supplements; Enzyme Inhibitors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; PCSK9 Inhibitors; Proprotein Convertase 9; Signal Transduction; Transcriptional Activation
PubMed: 28363723
DOI: 10.1016/j.phrs.2017.03.023 -
Current Opinion in Clinical Nutrition... Mar 2016Docosapentaenoic acid (DPA) is a long-chain n-3 polyunsaturated fatty acid that is intermediary between eicosapentaenoic acid and docosahexaenoic acid in the n-3... (Review)
Review
PURPOSE OF REVIEW
Docosapentaenoic acid (DPA) is a long-chain n-3 polyunsaturated fatty acid that is intermediary between eicosapentaenoic acid and docosahexaenoic acid in the n-3 synthesis pathway. DPA is part of our normal diet through fish and lean red meat. In recent years, DPA has received increasing attention as an important bioactive fatty acid in light of its potential beneficial health effects, which include anti-inflammatory actions, antiplatelet aggregation, and improved plasma lipid prolife. This review provides a short summary of the most recent research on DPA.
RECENT FINDINGS
In this review, we report on the latest association data as well as data generated from in-vitro and in-vivo studies on DPA and cardiovascular health, mental health, inflammation, and cancer. We also report on the newly identified DPA metabolites and their effects on exacerbation of inflammation in animal models.
SUMMARY
Although there is a growing body of evidence supporting DPA's role as an important bioactive fatty acid, there is a need for more 'cause and effect studies', clinical trials and studies which can reveal whether DPA plays separate roles to those identified for eicosapentaenoic acid and docosahexaenoic acid.
Topics: Animals; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Unsaturated; Humans; Inflammation; Lipid Metabolism; Mental Health; Neoplasms
PubMed: 26808265
DOI: 10.1097/MCO.0000000000000252 -
Nutrients Oct 2018Cardiovascular disease (CVD) is a major cause of mortality. The effects of several unsaturated fatty acids on cardiometabolic health, such as eicosapentaenoic acid (EPA)... (Review)
Review
Cardiovascular disease (CVD) is a major cause of mortality. The effects of several unsaturated fatty acids on cardiometabolic health, such as eicosapentaenoic acid (EPA) docosahexaenoic acid (DHA), α linolenic acid (ALA), linoleic acid (LA), and oleic acid (OA) have received much attention in past years. In addition, results from recent studies revealed that several other uncommon fatty acids (fatty acids present at a low content or else not contained in usual foods), such as furan fatty acids, -3 docosapentaenoic acid (DPA), and conjugated fatty acids, also have favorable effects on cardiometabolic health. In the present report, we searched the literature in PubMed, Embase, and the Cochrane Library to review the research progress on anti-CVD effect of these uncommon fatty acids. DPA has a favorable effect on cardiometabolic health in a different way to other long-chain -3 polyunsaturated fatty acids (LC -3 PUFAs), such as EPA and DHA. Furan fatty acids and conjugated linolenic acid (CLNA) may be potential bioactive fatty acids beneficial for cardiometabolic health, but evidence from intervention studies in humans is still limited, and well-designed clinical trials are required. The favorable effects of conjugated linoleic acid (CLA) on cardiometabolic health observed in animal or in vitro cannot be replicated in humans. However, most intervention studies in humans concerning CLA have only evaluated its effect on cardiometabolic risk factors but not its direct effect on risk of CVD, and randomized controlled trials (RCTs) will be required to clarify this point. However, several difficulties and limitations exist for conducting RCTs to evaluate the effect of these fatty acids on cardiometabolic health, especially the high costs for purifying the fatty acids from natural sources. This review provides a basis for better nutritional prevention and therapy of CVD.
Topics: Cardiovascular Diseases; Diet; Fatty Acids; Humans
PubMed: 30347833
DOI: 10.3390/nu10101559