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Biomolecules Aug 2022Palmitoylethanolamide (PEA), the naturally occurring amide of ethanolamine and palmitic acid, is an endogenous lipid compound endowed with a plethora of pharmacological... (Review)
Review
Palmitoylethanolamide (PEA), the naturally occurring amide of ethanolamine and palmitic acid, is an endogenous lipid compound endowed with a plethora of pharmacological functions, including analgesic, neuroprotective, immune-modulating, and anti-inflammatory effects. Although the properties of PEA were first characterized nearly 65 years ago, the identity of the receptor mediating these actions has long remained elusive, causing a period of research stasis. In the last two decades, a renewal of interest in PEA occurred, and a series of interesting studies have demonstrated the pharmacological properties of PEA and clarified its mechanisms of action. Recent findings showed the ability of formulations containing PEA in promoting oligodendrocyte differentiation, which represents the first step for the proper formation of myelin. This evidence opens new and promising research opportunities. White matter defects have been detected in a vast and heterogeneous group of diseases, including age-related neurodegenerative disorders. Here, we summarize the history and pharmacology of PEA and discuss its therapeutic potential in restoring white matter defects.
Topics: Amides; Analgesics; Anti-Inflammatory Agents; Ethanolamines; Palmitic Acid; Palmitic Acids; White Matter
PubMed: 36139030
DOI: 10.3390/biom12091191 -
Skin Pharmacology and Physiology 2023A disruption of sebocyte differentiation and lipogenesis has fatal consequences and can cause a wide spectrum of skin diseases, from acne vulgaris to sebaceous...
BACKGROUND
A disruption of sebocyte differentiation and lipogenesis has fatal consequences and can cause a wide spectrum of skin diseases, from acne vulgaris to sebaceous carcinoma, however, the relevant molecular mechanisms have not been fully clarified.
OBJECTIVES
The induction of autophagy and apoptosis in human sebocytes in response to biologically relevant fatty acids was investigated.
METHODS
Free fatty acids (arachidonic acid, linoleic acid, palmitic acid, and palmitoleic acid) and the pan-caspase inhibitor QVD-Oph were added to the supernatant of cultured human SZ95 sebocytes. Individual relevant proteins were analyzed by Western blotting. Apoptosis and cell viability were determined, and typical autophagy structures were detected through electron microscopy. To obtain cell growth curves, cell confluence was continuously monitored by real-time cell analysis.
RESULTS
Fatty acids induced the development of intracellular lipid droplets with subsequent apoptosis, whereas arachidonic acid caused the most rapid effect. Cleavage products of caspase-3 were only detected in arachidonic acid-induced apoptosis. The high basal apoptotic rate of cultured SZ95 sebocytes was strongly suppressed by QVD-Oph. Fatty acid-induced apoptosis was also markedly inhibited by QVD-Oph, whereas intracellular lipid droplets further accumulated. While cell viability after incubation with linoleic acid, palmitic acid, or palmitoleic acid and QVD-Oph was comparable with that of non-treated controls, arachidonic acid significantly reduced cell viability and cell density despite the concomitant pan-caspase inhibitor treatment. Using electron microscopy, typical autophagy structures were detected, such as autophagosomes and autolysosomes, at the basal level, which became more pronounced after treatment with fatty acids.
CONCLUSIONS
Our findings contribute to a better understanding of the inflammation-associated mechanisms of lipogenesis and cell death induction in human sebocytes and may help to unveil the effects of fatty acid-rich human nutrition.
Topics: Humans; Fatty Acids, Nonesterified; Sebaceous Glands; Palmitic Acid; Apoptosis; Caspases; Autophagy; Arachidonic Acids
PubMed: 36384913
DOI: 10.1159/000527471 -
Nature Communications Feb 2024Patients with Type 2 Diabetes Mellitus are increasingly susceptible to atherosclerotic plaque vulnerability, leading to severe cardiovascular events. In this study, we...
Patients with Type 2 Diabetes Mellitus are increasingly susceptible to atherosclerotic plaque vulnerability, leading to severe cardiovascular events. In this study, we demonstrate that elevated serum levels of palmitic acid, a type of saturated fatty acid, are significantly linked to this enhanced vulnerability in patients with Type 2 Diabetes Mellitus. Through a combination of human cohort studies and animal models, our research identifies a key mechanistic pathway: palmitic acid induces macrophage Delta-like ligand 4 signaling, which in turn triggers senescence in vascular smooth muscle cells. This process is critical for plaque instability due to reduced collagen synthesis and deposition. Importantly, our findings reveal that macrophage-specific knockout of Delta-like ligand 4 in atherosclerotic mice leads to reduced plaque burden and improved stability, highlighting the potential of targeting this pathway. These insights offer a promising direction for developing therapeutic strategies to mitigate cardiovascular risks in patients with Type 2 Diabetes Mellitus.
Topics: Animals; Humans; Mice; Apolipoproteins E; Diabetes Mellitus, Type 2; Disease Models, Animal; Macrophages; Mice, Knockout; Myocytes, Smooth Muscle; Palmitic Acid; Plaque, Atherosclerotic
PubMed: 38346959
DOI: 10.1038/s41467-024-45582-8 -
Biochemical and Biophysical Research... May 2020Diacylglycerol kinase (DGK) α enhances the proliferation of melanoma and hepatocellular carcinoma cells whereas, in contrast, DGKα induces a nonproliferative state in...
Diacylglycerol kinase (DGK) α enhances the proliferation of melanoma and hepatocellular carcinoma cells whereas, in contrast, DGKα induces a nonproliferative state in T cells. We previously found that DGKα produces palmitic acid (16:0)-containing PA species, such as 16:0/16:0- and 16:0/18:0-PA, in melanoma cells under serum-starved (nonproliferative) conditions. In the present study, we identified the PA species generated by DGKα in T cells under serum-starved (nonproliferative) conditions. We found that serum starvation markedly increased the levels of many PA species, such as 14:1/16:1-, 14:0/16:1-, 14:0/16:0-, 16:1/16:2-, 16:1/16:1-, 16:0/16:1-, 16:0/16:0-, 16:1/18:2-, 16:1/18:1-, 16:0/18:1-, 16:0/18:0-, 18:1/18:2-, 18:1/18:1- and 18:0/18:1-PA, in Jurkat T cells. In lysates from serum-starved Jurkat T cells, DGKα activity, which was Ca-dependent and sensitive to a DGKα-specific inhibitor (CU-3), was substantially increased, indicating its activation. Moreover, CU-3 (1-10 μM) significantly reduced the amounts of palmitic acid- and/or palmitoleic acid (16:1)-containing PA species, such as 14:1/16:1-, 14:0/16:1-, 14:0/16:0-, 16:1/16:2-, 16:1/16:1-, 16:0/16:1-, 16:0/16:0-, 16:0/18:1- and 16:0/18:0-PA, which were increased by serum starvation. These results indicate that DGKα generates different PA species in starved melanoma cells (palmitic acid-containing PA species) and T cells (palmitic acid- and/or palmitoleic acid (16:1)-containing PA species). Therefore, the differences in the PA molecular species may account for the opposing functions of DGKα in melanoma and T cells.
Topics: Calcium; Cell Proliferation; Chromatography, Liquid; Diacylglycerol Kinase; Fatty Acids, Monounsaturated; Humans; Jurkat Cells; Melanoma; Palmitic Acid; Phosphatidic Acids; Rhodanine; Sulfonamides; T-Lymphocytes; Tandem Mass Spectrometry
PubMed: 32184022
DOI: 10.1016/j.bbrc.2020.02.162 -
The Journal of Biological Chemistry Nov 2023A high-fat diet (HFD) plays a critical role in hepatocyte insulin resistance. Numerous models and factors have been proposed to elucidate the mechanism of palmitic acid...
A high-fat diet (HFD) plays a critical role in hepatocyte insulin resistance. Numerous models and factors have been proposed to elucidate the mechanism of palmitic acid (PA)-induced insulin resistance. However, proteomic studies of insulin resistance by HFD stimulation are usually performed under insulin conditions, leading to an unclear understanding of how a HFD alone affects hepatocytes. Here, we mapped the phosphorylation rewiring events in PA-stimulated HepG2 cells and found PA decreased the phosphorylation level of the eukaryotic translation initiation factor 4E-binding protein 2 (4EBP2) at S65/T70. Further experiments identified 4EBP2 as a key node of insulin resistance in either HFD mice or PA-treated cells. Reduced 4EBP2 levels increased glucose uptake and insulin sensitivity, whereas the 4EBP2_S65A/T70A mutation exacerbated PA-induced insulin resistance. Additionally, the nascent proteome revealed many glycolysis-related proteins translationally regulated by 4EBP2 such as hexokinase-2, pyruvate kinase PKM, TBC1 domain family member 4, and glucose-6-phosphate 1-dehydrogenase. In summary, we report the critical role of 4EBP2 in regulating HFD-stimulated insulin resistance in hepatocytes.
Topics: Animals; Male; Mice; Carrier Proteins; Cell Line; Diet, High-Fat; Hepatocytes; Insulin; Insulin Resistance; Mice, Inbred C57BL; Palmitic Acid; Protein Biosynthesis; Proteomics
PubMed: 37797700
DOI: 10.1016/j.jbc.2023.105315 -
Cell Proliferation Nov 2023This study aimed to investigate the role of the gut microbiota (GM)-bile acid (BA)-fibroblast growth factor (FGF) 19 axis in patients with atrial fibrillation (AF). Gut...
This study aimed to investigate the role of the gut microbiota (GM)-bile acid (BA)-fibroblast growth factor (FGF) 19 axis in patients with atrial fibrillation (AF). Gut bacterial metabolisms of BAs were determined in an AF metagenomic dataset. The composition of faecal BAs pools was characterized by targeted metabolomics in an independent AF cross-sectional cohort. Circulating levels of FGF19 were measured by ELISA. In vitro cell experiments were conducted to validate the regulatory role of FGF19 in atrial cardiomyocytes stimulated with palmitic acid. First, metagenomic profiling revealed that gut microbial biotransformation from primary to secondary BAs was dysregulated in AF patients. Second, the proportion of secondary BAs decreased in the faeces of patients with AF. Also, eight BAs were identified as AF-associated BAs, including seven AF-enriched BAs (ursodeoxycholic acid, chenodeoxycholic acid, etc.), and AF-decreased dehydrolithocholic acid. Third, reduced levels of circulating FGF19 were observed in patients with AF. Subsequently, FGF19 was found to protect against palmitic acid-induced lipid accumulation and dysregulated signalling in atrial cardiomyocytes, including attenuated phosphorylation of YAP and Ca /calmodulin-dependent protein kinases II and secretion of interleukin-1β, mediated via peroxisome proliferator-activated receptor α. Our data found decreased levels of secondary BAs and circulating FGF19, resulting in the impaired protective function of FGF19 against lipid accumulation in atrial cardiomyocytes.
Topics: Humans; Bile Acids and Salts; Gastrointestinal Microbiome; Atrial Fibrillation; Cross-Sectional Studies; Palmitic Acid; Fibroblast Growth Factors
PubMed: 37186335
DOI: 10.1111/cpr.13488 -
Biomedicine & Pharmacotherapy =... Jan 2021Nosocomial Candida colonization causes Systemic candidiasis in human with invasive infections in immunocompromised patients. Of all Candida spp., C. albicans is dominant...
Nosocomial Candida colonization causes Systemic candidiasis in human with invasive infections in immunocompromised patients. Of all Candida spp., C. albicans is dominant in morbidity of all systemic candidiasis but C. tropicalis is phenomenal in mortality, virulence aspects and resistance development against antifungal drugs. The present study investigated the synergistic anti-virulent activity of myristic acid (MA) and palmitic acid (PA) against insidious dimorphic Candida spp. (C. albicans and C. tropicalis). In vitro and qPCR results revealed the mechanisms of MA-PA combination effectively inhibiting various virulence aspects such as biofilm, hyphal formation, secreted aspartyl proteases, lipases, ergosterol biosynthesis and drug effluxes. Further, in Danio rerio (Zebrafish), the MA-PA treatment increased the survival of animals and also the treated groups showed decreased level of fungal burden compared to the infected controls, after 3 day of post infection. Histopathology of vital organs and SEM analysis of skin revealed a drastic recovery and reduced the inflammation of both Candida spp. infections in MA-PA treated animals. In addition, MA-PA treatment reduced the haemolysin and increased the susceptibility of Candida spp. in human blood model. Hence, this study suggested the therapeutic utilization of MA-PA as synergistic combination for their anti-inflammatory potency against systemic candidiasis and candidemia.
Topics: Animals; Anti-Inflammatory Agents; Antifungal Agents; Candida albicans; Candida tropicalis; Candidiasis; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Humans; Microbial Viability; Myristic Acid; Palmitic Acid; Virulence; Zebrafish
PubMed: 33378951
DOI: 10.1016/j.biopha.2020.111043 -
Translational Research : the Journal of... Feb 2024To investigate the role of S-palmitoylation in pyroptosis following acute myocardial infarction (AMI). Myocardial ischemic injury is mainly related to the death of...
To investigate the role of S-palmitoylation in pyroptosis following acute myocardial infarction (AMI). Myocardial ischemic injury is mainly related to the death of terminally differentiated cardiomyocytes. Pyroptosis is a new form of programmed cell death and recently is identified a potential mechanism of cardiomyocyte loss. However, the role of S-palmitoylation in pyroptosis following MI remains elusive. AMI was mimicked by permanent left anterior descending artery ligation. The palmitoylated proteins labeled by Click-iT palmitic acid were precipitated using streptavidin magnetic bead conjugate. The short-term palmitic acid dietary intake by modified western diet with palm oil for 7 days is compared with modified western diet with olive oil. Palmitoylation is increased in myocardial infarction and anoxic cardiomyocytes. Pyroptosis, but not apoptosis and necrosis, is more relevant with palmitoylation in the process of myocardial ischemia injury. The gasdermin D (GSDMD) Cys192 palmitoylation promotes its cytomembrane localization by ZDHHC14. GSDMD Cys192 palmitoylation aggravates in vitro cardiomyocyte pyroptosis. The short-term palmitic acid dietary intake or ML348 deteriorates myocardial pyroptosis, infarct size and cardiac function in AMI mice by GSDMD palmitoylation. Disulfiram antagonizes Cys192 palmitoylation of GSDMD-N-terminal and reduces myocardial pyroptosis and injury in AMI mice. We identifies ZHDDC14 induced palmitoylation as a crucial node for modulating GSDMD-N-terminal cytomembrane localization and establishes Disulfiram targeting GSDMD Cys192 palmitoylation as a potential clinical intervention for myocardial pyroptosis.
Topics: Mice; Animals; Disulfiram; Intracellular Signaling Peptides and Proteins; Gasdermins; Lipoylation; Palmitic Acid; Myocardial Infarction
PubMed: 37769810
DOI: 10.1016/j.trsl.2023.09.007 -
Journal of Agricultural and Food... Nov 2023Wheat alkylresorcinols (ARs) consumption has been evidenced to improve obesity and its associated insulin resistance. However, the effect of ARs on glucagon-like peptide...
Wheat alkylresorcinols (ARs) consumption has been evidenced to improve obesity and its associated insulin resistance. However, the effect of ARs on glucagon-like peptide 1 (GLP-1) secretion and the underlying mechanism of action are still unclear. In this study, C57BL/6J mice were fed low-fat diet (LFD), high-fat diet (HFD), and HFD supplemented with 0.4% (w/w) ARs separately for 9 weeks. The results showed that ARs intervention significantly improved glucose homeostasis and restored the serum level of GLP-1 compared with the HFD control group. Moreover, ARs treatment alleviated HFD-induced ileal epithelium damage according to TUNEL staining, immunofluorescence, and transmission electron microscopy observation. The alleviative effect was further verified by apoptosis analysis and mitochondrial function evaluation. Furthermore, palmitic acid (PA) was administered to the intestinal secretin tumor cell line (STC-1) to clarify the protective effect of ARs on GLP-1 secretion in vitro. In consistence with the results of animal studies, ARs treatment could significantly improve GLP-1 secretion in STC-1 cells compared with PA treatment alone in a dose-dependent manner, accompanied by a reduction in apoptosis and mitochondrial dysfunction. In addition, ARs treatment notably enhanced the abundance of SCFA (short-chain fatty acid)-producing bacteria, such as , , and The increased levels of intestinal SCFAs, such as acetic acid, propionic acid, and butyric acid, improved the expression of short-chain fatty acid receptors (FFAR3) and glucagon-like peptide-1 receptor (GLP-1R), enhancing the secretion of the intestinal hormones GLP-1. Thus, this study provides potential clinical implications of whole wheat as a dietary strategy to improve glucose homeostasis for obese populations.
Topics: Mice; Animals; Diet, High-Fat; Glucagon-Like Peptide 1; Mice, Obese; Triticum; Mice, Inbred C57BL; Obesity; Fatty Acids, Volatile; Gastrointestinal Hormones; Palmitic Acid; Glucose; Homeostasis
PubMed: 37857386
DOI: 10.1021/acs.jafc.3c04664 -
International Journal of Molecular... Jun 2023One of the largest health problems worldwide is the development of chronic noncommunicable diseases due to the consumption of hypercaloric diets. Among the most common...
One of the largest health problems worldwide is the development of chronic noncommunicable diseases due to the consumption of hypercaloric diets. Among the most common alterations are cardiovascular diseases, and a high correlation between overnutrition and neurodegenerative diseases has also been found. The urgency in the study of specific damage to tissues such as the brain and intestine led us to use to study the metabolic effects caused by the consumption of fructose and palmitic acid in specific tissues. Thus, third instar larvae (96 ± 4 h) of the wild Canton-S strain of were used to perform transcriptomic profiling in brain and midgut tissues to test for the potential metabolic effects of a diet supplemented with fructose and palmitic acid. Our data infer that this diet can alter the biosynthesis of proteins at the mRNA level that participate in the synthesis of amino acids, as well as fundamental enzymes for the dopaminergic and GABAergic systems in the midgut and brain. These also demonstrated alterations in the tissues of flies that may help explain the development of various reported human diseases associated with the consumption of fructose and palmitic acid in humans. These studies will not only help to better understand the mechanisms by which the consumption of these alimentary products is related to the development of neuronal diseases but may also contribute to the prevention of these conditions.
Topics: Animals; Humans; Drosophila melanogaster; Fructose; Palmitic Acid; Larva; Neurodegenerative Diseases; Gene Expression
PubMed: 37373426
DOI: 10.3390/ijms241210279