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Nature Communications Dec 2023Aging is a major risk factor for metabolic disorders. Polyunsaturated fatty acid-derived bioactive lipids play critical roles as signaling molecules in metabolic...
Aging is a major risk factor for metabolic disorders. Polyunsaturated fatty acid-derived bioactive lipids play critical roles as signaling molecules in metabolic processes. Nonetheless, their effects on age-related liver steatosis remain unknown. Here we show that senescent liver cells induce liver steatosis in a paracrine manner. Linoleic acid-derived 9-hydroxy-octadecadienoic acid (9-HODE) and 13-HODE increase in middle-aged (12-month-old) and aged (20-month-old) male mouse livers and conditioned medium from senescent hepatocytes and macrophages. Arachidonate 15-lipoxygenase, an enzyme for 13-HODE and 9-HODE production, is upregulated in senescent cells. A 9-HODE and 13-HODE mixture induces liver steatosis and activates SREBP1. Furthermore, catalase (CAT) is a direct target of 13-HODE, and its activity is decreased by 13-HODE. CAT overexpression reduces 13-HODE-induced liver steatosis and protects male mice against age-related liver steatosis. Therefore, 13-HODE produced by senescent hepatocytes and macrophages activates SREBP1 by directly inhibiting CAT activity and promotes liver steatosis.
Topics: Male; Mice; Animals; Catalase; Linoleic Acids; Linoleic Acid; Fatty Liver; Liver
PubMed: 38071367
DOI: 10.1038/s41467-023-44026-z -
In Vivo (Athens, Greece) 2023Breast cancer stem cells (BCSCs) are involved in the development of breast cancer and contribute to therapeutic resistance. This study aimed to investigate the...
BACKGROUND/AIM
Breast cancer stem cells (BCSCs) are involved in the development of breast cancer and contribute to therapeutic resistance. This study aimed to investigate the anticancer stem cell (CSC) mechanism of 13-Oxo-9Z,11E-octadecadienoic acid (13-Oxo-ODE) as a potent CSC inhibitor in breast cancer.
MATERIALS AND METHODS
The effects of 13-Oxo-ODE on BCSCs were evaluated using a mammosphere formation assay, CD44/CD24 analysis, aldehyde dehydrogenase (ALDH) assay, apoptosis assay, quantitative real-time PCR, and western blotting.
RESULTS
We found that 13-Oxo-ODE suppressed cell proliferation, CSC formation, and mammosphere proliferation and increased apoptosis of BCSCs. Additionally, 13-Oxo-ODE reduced the subpopulation of CD44/CD24 cells and ALDH expression. Furthermore, 13-Oxo-ODE decreased c-myc gene expression. These results suggest that 13-Oxo-ODE has potential as a natural inhibitor targeting BCSCs through the degradation of c-Myc.
CONCLUSION
In summary, 13-Oxo-ODE induced CSC death possibly through reduced c-Myc expression, making it a promising natural inhibitor of BCSCs.
Topics: Humans; Female; Breast Neoplasms; Cell Proliferation; Neoplastic Stem Cells; Cell Line, Tumor
PubMed: 37103085
DOI: 10.21873/invivo.13183 -
[Effects of octadecadienoic acid on proliferation and apoptosis of glioma cells and its mechanisms].Zhongguo Ying Yong Sheng Li Xue Za Zhi... Sep 2022To study the effects of octadecadienoic acid (ODA) on the proliferation and apoptosis of glioma cells and its mechanisms.
OBJECTIVE
To study the effects of octadecadienoic acid (ODA) on the proliferation and apoptosis of glioma cells and its mechanisms.
METHODS
Cultured human glioma cells (cell density 2×10 cells/L) were divided into solvent control group (DMSO, 30 μl/L), 5-FU group (10 mg/L) and octadecadienic acid groups (0.3, 0.6 and 1.2 mg/L groups). The toxicity of ODA on glioma cells was detected by trypan blue and thiazolium blue (MTT). The expression levels of P53, PI3K, P21, PKB/Akt and Caspase-9 in glioma cells were determined by enzyme-linked immunosorbent assay (ELISA).
RESULTS
① Cell count under optical microscope showed that the inhibition rate of cell proliferation in ODA low, medium and high dose groups and 5-FU group was significantly higher than that in the solvent control group (<0.01), but there was no statistical significance compared with the 5-FU group (>0.05). ② MTT assay showed that the inhibition rate of cell proliferation was increased significantly in ODA low, medium and high dose groups and 5-FU groups (<0.01), compared with the solvent control group. Compared with 5-FU group, the inhibition rate of cell proliferation was increased significantly only in ODA high dose group (<0.01). ③ The number of G/G phase cells in ODA low, medium and high dose groups and 5-FU group were increased significantly (<0.05, <0.01), the number of G/M phase cells were decreased significantly (<0.01), and the apoptosis rate was increased significantly (<0.01),compared with the solvent control group. Compared with the 5-FU group, the number of cells in G/M phase was decreased significantly (<0.01) and the apoptosis rate was increased significantly (<0.01) in ODA high dose group. ④ ELISA test results showed that the protein expression levels of P53, PI3K and PKB/Akt in ODA low , medium and high dose groups and 5-FU group were significantly lower than those in solvent control group (all <0.01), but the protein expression levels in ODA high dose group were significantly lower than those in 5-FU group (<0.01). The protein expression levels of P21 and caspase-9 in ODA low , medium and high dose groups and 5-FU group were significantly higher than those in solvent control group (<0.05, <0.01), but the protein expression levels in ODA high dose group were significantly higher than those in 5-Fu group (<0.01).
CONCLUSION
ODA can significantly inhibit the proliferation and promote apoptosis of glioma cells. The mechanisms are related to up-regulating the levels of P21 and caspase-9 to promote apoptosis, down-regulating the levels of P53, PI3K and PKB/Akt to inhibit the cell division cycle, and reducing the activity of PI3K-Akt signal transduction pathway.
Topics: Humans; Proto-Oncogene Proteins c-akt; Caspase 9; Tumor Suppressor Protein p53; Phosphatidylinositol 3-Kinases; Glioma; Apoptosis; Cell Proliferation; Cell Line, Tumor; Fluorouracil
PubMed: 37088747
DOI: 10.12047/j.cjap.6271.2022.081 -
The Journal of Biological Chemistry Nov 2022Gut microbiota regulate physiological functions in various hosts, such as energy metabolism and immunity. Lactic acid bacteria, including Lactobacillus plantarum, have a...
Gut microbiota regulate physiological functions in various hosts, such as energy metabolism and immunity. Lactic acid bacteria, including Lactobacillus plantarum, have a specific polyunsaturated fatty acid saturation metabolism that generates multiple fatty acid species, such as hydroxy fatty acids, oxo fatty acids, conjugated fatty acids, and trans-fatty acids. How these bacterial metabolites impact host physiology is not fully understood. Here, we investigated the ligand activity of lactic acid bacteria-produced fatty acids in relation to nuclear hormone receptors expressed in the small intestine. Our reporter assays revealed two bacterial metabolites of γ-linolenic acid (GLA), 13-hydroxy-cis-6,cis-9-octadecadienoic acid (γHYD), and 13-oxo-cis-6,cis-9-octadecadienoic acid (γKetoD) activated peroxisome proliferator-activated receptor delta (PPARδ) more potently than GLA. We demonstrate that both γHYD and γKetoD bound directly to the ligand-binding domain of human PPARδ. A docking simulation indicated that four polar residues (T289, H323, H449, and Y473) of PPARδ donate hydrogen bonds to these fatty acids. Interestingly, T289 does not donate a hydrogen bond to GLA, suggesting that bacterial modification of GLA introducing hydroxy and oxo group determines ligand selectivity. In human intestinal organoids, we determined γHYD and γKetoD increased the expression of PPARδ target genes, enhanced fatty acid β-oxidation, and reduced intracellular triglyceride accumulation. These findings suggest that γHYD and γKetoD, which gut lactic acid bacteria could generate, are naturally occurring PPARδ ligands in the intestinal tract and may improve lipid metabolism in the human intestine.
Topics: Humans; gamma-Linolenic Acid; Lactobacillales; Ligands; Organoids; PPAR delta; Intestine, Small
PubMed: 36162507
DOI: 10.1016/j.jbc.2022.102534 -
Scientific Reports Feb 2022Dysregulation of circadian rhythm can cause nocturia. Levels of fatty acid metabolites, such as palmitoylethanolamide (PEA), 9-hydroxy-10E,12Z-octadecadienoic acid...
Dysregulation of circadian rhythm can cause nocturia. Levels of fatty acid metabolites, such as palmitoylethanolamide (PEA), 9-hydroxy-10E,12Z-octadecadienoic acid (9-HODE), and 4-hydroxy-5E,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid (4-HDoHE), are higher in the serum of patients with nocturia; however, the reason remains unknown. Here, we investigated the circadian rhythm of fatty acid metabolites and their effect on voiding in mice. WT and Clock mutant (Clock) mice, a model for nocturia with circadian rhythm disorder, were used. Levels of serum PEA, 9-HODE, and 4-HDoHEl were measured every 8 h using LC/MS. Voiding pattern was recorded using metabolic cages after administration of PEA, 9-HODE, and 4-HDoHE to WT mice. Levels of serum PEA and 9-HODE fluctuated with circadian rhythm in WT mice, which were lower during the light phase. In contrast, circadian PEA and 9-HODE level deteriorated or retreated in Clock mice. Levels of serum PEA, 9-HODE, and 4-HDoHE were higher in Clock than in WT mice. Voiding frequency increased in PEA- and 4-HDoHE-administered mice. Bladder capacity decreased in PEA-administered mice. The changes of these bladder functions in mice were similar to those in elderly humans with nocturia. These findings highlighted the novel effect of lipids on the pathology of nocturia. These may be used for development of biomarkers and better therapies for nocturia.
Topics: Amides; Animals; CLOCK Proteins; Circadian Rhythm; Disease Models, Animal; Docosahexaenoic Acids; Ethanolamines; Fatty Acids; Injections, Intraperitoneal; Linoleic Acids, Conjugated; Male; Mice, Inbred C57BL; Nocturia; Palmitic Acids; Photoperiod; Urinary Bladder; Urination; Mice
PubMed: 35197540
DOI: 10.1038/s41598-022-07096-5 -
Mucosal Immunology Feb 2022Dietary ω3 fatty acids have important health benefits and exert their potent bioactivity through conversion to lipid mediators. Here, we demonstrate that microbiota...
Dietary ω3 fatty acids have important health benefits and exert their potent bioactivity through conversion to lipid mediators. Here, we demonstrate that microbiota play an essential role in the body's use of dietary lipids for the control of inflammatory diseases. We found that amounts of 10-hydroxy-cis-12-cis-15-octadecadienoic acid (αHYA) and 10-oxo-cis-12-cis-15-octadecadienoic acid (αKetoA) increased in the feces and serum of specific-pathogen-free, but not germ-free, mice when they were maintained on a linseed oil diet, which is high in α-linolenic acid. Intake of αKetoA, but not αHYA, exerted anti-inflammatory properties through a peroxisome proliferator-activated receptor (PPAR)γ-dependent pathway and ameliorated hapten-induced contact hypersensitivity by inhibiting the development of inducible skin-associated lymphoid tissue through suppression of chemokine secretion from macrophages and inhibition of NF-κB activation in mice and cynomolgus macaques. Administering αKetoA also improved diabetic glucose intolerance by inhibiting adipose tissue inflammation and fibrosis through decreased macrophage infiltration in adipose tissues and altering macrophage M1/M2 polarization in mice fed a high-fat diet. These results collectively indicate that αKetoA is a novel postbiotic derived from α-linolenic acid, which controls macrophage-associated inflammatory diseases and may have potential for developing therapeutic drugs as well as probiotic food products.
Topics: Adipose Tissue; Animals; Diet, High-Fat; Lipids; Macaca fascicularis; Macrophages; Mice; Mice, Inbred C57BL; PPAR gamma
PubMed: 35013573
DOI: 10.1038/s41385-021-00477-5 -
Biochimica Et Biophysica Acta.... Mar 2021Linoleic acid (LNA)-derived 13-hydroxyoctadecadienoic acid (13-HODE) is a bioactive lipid mediator that regulates multiple signaling processes in vivo. 13-HODE is also...
Linoleic acid (LNA)-derived 13-hydroxyoctadecadienoic acid (13-HODE) is a bioactive lipid mediator that regulates multiple signaling processes in vivo. 13-HODE is also produced when LNA is oxidized during food processing. However, the absorption and incorporation kinetics of dietary 13-HODE into tissues is not known. The present study measured unesterified d4-13-HODE plasma bioavailability and incorporation into rat liver, adipose, heart and brain following gavage or intravenous (IV) injection (n = 3 per group). Mass spectrometry analysis revealed that d4-13-HODE was absorbed within 20 min of gavage, and continued to incorporate into plasma esterified lipid fractions throughout the 90 min monitoring period (incorporation half-life of 71 min). Following IV injection, unesterified d4-13-HODE was rapidly eliminated from plasma with a half-life of 1 min. Analysis of tracer incorporation kinetics into rat tissues following IV injection or gavage revealed that the esterified tracer preferentially incorporated into liver, adipose and heart compared to unesterified d4-13-HODE. No tracer was detected in the brain. This study demonstrates that dietary 13-HODE is absorbed, and incorporated into peripheral tissues from esterified plasma lipid pools. Understanding the chronic effects of dietary 13-HODE exposure on peripheral tissue physiology and metabolism merits future investigation.
Topics: Adipose Tissue; Animals; Brain; Esterification; Linoleic Acid; Linoleic Acids; Liver; Male; Myocardium; Rats; Rats, Inbred F344
PubMed: 33340768
DOI: 10.1016/j.bbalip.2020.158870 -
Biomedicines Nov 2022Plasma from patients with Parkinson's disease (PD) is a valuable source of information indicating altered metabolites associated with the risk or progression of the...
Plasma from patients with Parkinson's disease (PD) is a valuable source of information indicating altered metabolites associated with the risk or progression of the disease. Neurotoxicity of dopaminergic neurons, which is triggered by aggregation of α-synuclein, is the main pathogenic feature of PD. However, a growing body of scientific reports indicates that metabolic changes may precede and directly contribute to neurodegeneration. Identification and characterization of the abnormal metabolic pattern in patients' plasma are therefore crucial for the search for potential PD biomarkers. The aims of the present study were (1) to identify metabolic alterations in plasma metabolome in subjects with PD as compared with the controls; (2) to find new potential markers, some correlations among them; (3) to identify metabolic pathways relevant to the pathophysiology of PD. Plasma samples from patients with PD ( = 25) and control group ( = 12) were collected and the gas chromatography-time-of-flight-mass spectrometry GC-TOFMS-based metabolomics approach was used to evaluate the metabolic changes based on the identified 14 metabolites with significantly altered levels using univariate and multivariate statistical analysis. The panel, including 6 metabolites (L-3-methoxytyrosine, aconitic acid, L-methionine, 13-docosenamide, hippuric acid, 9,12-octadecadienoic acid), was identified to discriminate PD from controls with the area under the curve (AUC) of 0.975, with an accuracy of 92%. We also used statistical criteria to identify the significantly altered level of metabolites. The metabolic pathways involved were associated with linoleic acid metabolism, mitochondrial electron transport chain, glycerolipid metabolism, and bile acid biosynthesis. These abnormal metabolic changes in the plasma of patients with PD were mainly related to the amino acid metabolism, TCA cycle metabolism, and mitochondrial function.
PubMed: 36551761
DOI: 10.3390/biomedicines10123005 -
Neurobiology of Pain (Cambridge, Mass.) 2020Endogenous lipid mediators are proposed to contribute to headache and facial pain by activating trigeminal neurons (TN). We recently identified 11-hydroxy-epoxide- and...
Endogenous lipid mediators are proposed to contribute to headache and facial pain by activating trigeminal neurons (TN). We recently identified 11-hydroxy-epoxide- and 11-keto-epoxide derivatives of linoleic acid (LA) that are present in human skin and plasma and potentially contribute to nociception. Here we expand upon initial findings by examining the effects of 11-hydroxy- and 11-keto-epoxide-LA derivatives on TN activation in comparison to LA, the LA derivative [9-hydroxy-octadecadienoic acid (9-HODE)] and prostaglandin E (PGE). 11-hydroxy- and 11-keto-epoxide-LA derivatives elicited Ca transients in TN subpopulations. The proportion of neurons responding to test compounds (5 μM, 5 min) ranged from 16.2 ± 3.8 cells (11 K-9,10E-LA) to 34.1 ± 2.4 cells (11H-12,13E-LA). LA and 9-HODE (5 μM, 5 min) elicited responses in 11.6 ± 3.1% and 9.7 ± 3.4% of neurons, respectively. 11H-12,13E-LA, 11K-12,13E-LA, and 11H-9,10E-LA produced Ca responses in significantly higher proportions of neurons compared to either LA or 9-HODE (F (6, 36) = 5.12, P = 0.0007). 11H-12,13E-LA and 11H-9,10E-LA increased proportions of responsive neurons in a concentration-dependent fashion, similar to PGE. Most sensitive neurons responded to additional algesic agents (32.9% to capsaicin, 40.1% to PGE, 58.0% to AITC), however 20.6% did not respond to any other agent. In summary, 11-hydroxy-epoxide derivatives of LA increase trigeminal neuron excitability, suggesting a potential role in headache or facial pain.
PubMed: 32478201
DOI: 10.1016/j.ynpai.2020.100046 -
Heliyon Feb 2022Twenty medicinal plants with previously established anti-viral activity against a wild-type RVFV were further investigated using bio-chemometric and analytical...
Twenty medicinal plants with previously established anti-viral activity against a wild-type RVFV were further investigated using bio-chemometric and analytical techniques. The aim being to identify compounds common in plants with anti-RVFV activity, potentially being the major contributors to the anti-viral effect. Proton nuclear magnetic resonance (H NMR) spectroscopy coupled with multivariate data analysis (MVDA) was applied to characterize metabolite profiles of twenty antiviral medicinal plants. Discrimination and prediction of metabolome data of active anti-RVFV from the less-active samples was assessed using the multivariate statistical models by constructing a robust principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) regression model. Annotation of metabolites in the samples with higher activity were performed by Chenomx software and the compounds confirmed using Ultra-High-Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry (UHPLC-qTOF-MS). Both the PCA and OPLS-DA score plots showed clustering of samples; however, the OPLS-DA plot indicated a clear separation among active and less-active samples. Metabolic biomarkers were screened by -value < 0.05 and variable importance in the projection (VIP) value >1 and S-plot. Among active samples, the most prominent metabolites putatively identified by NMR include trigonelline, vanillic acid, fumarate, chlorogenic acid, ferulate, and formate. The presence of the compounds were confirmed by UHPLC-qTOF-MS, and two hydroxylated fatty acids were additionally detected indicated by peaks at 293.2116 and 295.2274 13S-Hydroxy-9Z,11E,15Z-octadecatrienoic acid and 13-Hydroxy-9Z,11E-octadecadienoic acid were annotated for the first time in all the antiviral active samples and are considered potential metabolites responsible for the antiviral activity. The study provides a metabolomic profile of anti-RVFV plant extracts and report for the first time the presence of hydroxylated fatty acids 13S-Hydroxy-9Z,11E,15Z-octadecatrienoic acid and 13-Hydroxy-9Z,11E-octadecadienoic acid, present in all the tested medicinal plants with high anti-RVFV activity and is a potential target for the future development of antiviral therapeutic agents.
PubMed: 35243061
DOI: 10.1016/j.heliyon.2022.e08936