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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 -
Nature Metabolism Oct 2023Chronic inflammation due to islet-residing macrophages plays key roles in the development of type 2 diabetes mellitus. By systematically profiling intra-islet...
Chronic inflammation due to islet-residing macrophages plays key roles in the development of type 2 diabetes mellitus. By systematically profiling intra-islet lipid-transmembrane receptor signalling in islet-resident macrophages, we identified endogenous 9(S)-hydroxy-10,12-octadecadienoic acid-G-protein-coupled receptor 132 (GPR132)-Gi signalling as a significant contributor to islet macrophage reprogramming and found that GPR132 deficiency in macrophages reversed metabolic disorders in mice fed a high-fat diet. The cryo-electron microscopy structures of GPR132 bound with two endogenous agonists, N-palmitoylglycine and 9(S)-hydroxy-10,12-octadecadienoic acid, enabled us to rationally design both GPR132 agonists and antagonists with high potency and selectivity through stepwise translational approaches. We ultimately identified a selective GPR132 antagonist, NOX-6-18, that modulates macrophage reprogramming within pancreatic islets, decreases weight gain and enhances glucose metabolism in mice fed a high-fat diet. Our study not only illustrates that intra-islet lipid signalling contributes to islet macrophage reprogramming but also provides a broadly applicable strategy for the identification of important G-protein-coupled receptor targets in pathophysiological processes, followed by the rational design of therapeutic leads for refractory diseases such as diabetes.
Topics: Mice; Animals; Diabetes Mellitus, Type 2; Cryoelectron Microscopy; Islets of Langerhans; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 37770763
DOI: 10.1038/s42255-023-00899-4 -
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 -
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 -
Lipids Mar 2017Many uncommon non-methylene-interrupted fatty acids (NMI FA) are present in limpet gonads, but their biological properties remain unknown. To investigate new biological...
Many uncommon non-methylene-interrupted fatty acids (NMI FA) are present in limpet gonads, but their biological properties remain unknown. To investigate new biological effects of naturally occurring NMI FA in eukaryotic cells, the biological activities of structurally analogous (4Z,15Z)-octadecadienoic acid (1), (9Z,20Z)-tricosadienoic acid (2), and (12Z,23Z)-hexacosadienoic acid (3) were examined by using a yeast-based drug-screening system using the Ca-sensitive mutant strain, Saccharomyces cerevisiae (zds1Δ erg3Δ pdr1Δ pdr3Δ). Among 1-3, 1 showed restored growth activity at a dose of 80 µg/disc in the mutant yeast strain. This phenotype suggests that 1 suppresses Ca-signaling of the mutant yeast through inhibition of glycogen synthase kinase-3β (GSK-3β) or calcineurin pathways or both. From this result, the inhibitory activity of 1-3 against GSK-3β was further determined. 1-3 showed potent inhibitory activity against GSK-3β with IC values ranging from 8.7 to 21.9 µM. Inhibition of GSK-3β reduces gene expression of the gluconeogenic key enzymes in liver, so we analyzed glucose production in rat hepatoma H4IIE cells to assess GSK-3β inhibitory activity of 1-3. Acid 1 inhibited glucose production at 25 µM in H4IIE cells. Our results would open up new possibilities for an anti-diabetic effect of 1 and might provide important insights into understanding the biological properties of naturally occurring NMI FA.
Topics: Animals; Calcineurin; Calcium; Cell Line; Cell Survival; Drug Evaluation, Preclinical; Fatty Acids, Unsaturated; Glucose; Glycogen Synthase Kinase 3 beta; HL-60 Cells; Humans; Rats; Saccharomyces cerevisiae
PubMed: 28194557
DOI: 10.1007/s11745-017-4236-3 -
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 -
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 -
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 -
Cancer Cell International Nov 2023"Inflammatory bowel disease" (IBD) is a chronic, relapsing inflammatory disease of the intestinal tract that typically begins at a young age and might transit to... (Review)
Review
BACKGROUND AND AIM
"Inflammatory bowel disease" (IBD) is a chronic, relapsing inflammatory disease of the intestinal tract that typically begins at a young age and might transit to colorectal cancer (CRC). In this manuscript, we discussed the epigenetic and metabolic change to present a extensive view of IBDs transition to CRC. This study discusses the possible biomarkers for evaluating the condition of IBDs patients, especially before the transition to CRC.
RESEARCH APPROACH
We searched "PubMed" and "Google Scholar" using the keywords from 2000 to 2022.
DISCUSSION
In this manuscript, interesting titles associated with IBD and CRC are discussed to present a broad view regarding the epigenetic and metabolic reprogramming and the biomarkers.
CONCLUSION
Epigenetics can be the main reason in IBD transition to CRC, and Hypermethylation of several genes, such as VIM, OSM4, SEPT9, GATA4 and GATA5, NDRG4, BMP3, ITGA4 and plus hypomethylation of LINE1 can be used in IBD and CRC management. Epigenetic, metabolisms and microbiome-derived biomarkers, such as Linoleic acid and 12 hydroxy 8,10-octadecadienoic acid, Serum M2-pyruvate kinase and Six metabolic genes (NAT2, XDH, GPX3, AKR1C4, SPHK and ADCY5) expression are valuable biomarkers for early detection and transition to CRC condition. Some miRs, such as miR-31, miR-139-5p, miR -155, miR-17, miR-223, miR-370-3p, miR-31, miR -106a, miR -135b and miR-320 can be used as biomarkers to estimate IBD transition to CRC condition.
PubMed: 37936149
DOI: 10.1186/s12935-023-03117-z