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Viruses Mar 2022Our previous studies have shown that cholesterol-conjugated, peptide-based pan-coronavirus (CoV) fusion inhibitors can potently inhibit human CoV infection. However,...
Our previous studies have shown that cholesterol-conjugated, peptide-based pan-coronavirus (CoV) fusion inhibitors can potently inhibit human CoV infection. However, only palmitic acid (C16)-based lipopeptide drugs have been tested clinically, suggesting that the development of C16-based lipopeptide drugs is feasible. Here, we designed and synthesized a C16-modified pan-CoV fusion inhibitor, EK1-C16, and found that it potently inhibited infection by SARS-CoV-2 and its variants of concern (VOCs), including Omicron, and other human CoVs and bat SARS-related CoVs (SARSr-CoVs). These results suggest that EK1-C16 could be further developed for clinical use to prevent and treat infection by the currently circulating MERS-CoV, SARS-CoV-2 and its VOCs, as well as any future emerging or re-emerging coronaviruses.
Topics: Humans; Lipopeptides; Middle East Respiratory Syndrome Coronavirus; Palmitic Acid; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35336956
DOI: 10.3390/v14030549 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Jan 2022To investigate the effect of palmitic acid (PA) on autophagy in neonatal rat cardiomyocytes (NRCMs) and explore the underlying mechanism.
OBJECTIVE
To investigate the effect of palmitic acid (PA) on autophagy in neonatal rat cardiomyocytes (NRCMs) and explore the underlying mechanism.
METHODS
NRCMs were isolated and cultured for 24 h before exposure to 10% BSA and 0.1, 0.3, 0.5, or 0.7 mmol/L PA for 24 h. After the treatments, the expressions of Parkin, PINK1, p62, LC3Ⅱ/ LC3Ⅰ, cGAS, STING and p-IRF3/IRF3 were detected using Western blotting and the cell viability was assessed with CCK8 assay, based on which 0.7 mmol/L was selected as the optimal concentration in subsequent experiments. The effects of cGAS knockdown mediated by cGAS siRNA in the presence of PA on autophagy-related proteins in the NRCMs were determined using Western blotting, and the expressions of P62 and LC3 in the treated cells were examined using immunofluorescence assay.
RESULTS
PA at different concentrations significantly lowered the expressions of Parkin, PINK1, LC3 Ⅱ/LC3 Ⅰ and LC3 Ⅱ/LC3 Ⅰ+Ⅱ ( < 0.05), increased the expression of p62 ( < 0.05), and inhibited the viability of NRCMs ( < 0.05). Knockdown of cGAS obviously blocked the autophagy-suppressing effect of PA and improved the viability of NRCMs ( < 0.05).
CONCLUSION
PA inhibits autophagy by activating the cGAS-STING-IRF3 pathway to reduce the viability of NRCMs.
Topics: Animals; Animals, Newborn; Autophagy; Myocytes, Cardiac; Nucleotidyltransferases; Palmitic Acid; Rats
PubMed: 35249868
DOI: 10.12122/j.issn.1673-4254.2022.01.04 -
Biochimica Et Biophysica Acta.... Aug 2022
Topics: Fatty Liver; Female; Granulosa Cells; Humans; Oleic Acid; Palmitic Acid; Progesterone
PubMed: 35421604
DOI: 10.1016/j.bbalip.2022.159159 -
Autophagy Jan 2022Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease globally. NAFLD is a consequence of fat accumulation in the liver leading to...
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease globally. NAFLD is a consequence of fat accumulation in the liver leading to lipotoxicity. Increasing evidence has demonstrated the critical role of autophagy in NAFLD. This study uncovers the unexpected role of immune surveillance protein DDX58/Rig-1 (DExD/H box helicase 58) in activating macroautophagy/autophagy and protecting from lipotoxicity associated with NAFLD. Here we show for the first time that DDX58 protein is significantly reduced in nonalcoholic steatohepatitis (NASH) mouse model, an aggressive form of NAFLD characterized by inflammation and fibrosis of the liver. In addition to decreased expression of DDX58, we found that DDX58 activity can be attenuated by treatments with palmitic acid (PA), a saturated fatty acid. To investigate whether PA inhibition of DDX58 is harmful to the cell, we characterized DDX58 function in hepatocytes when exposed to high doses of PA in the presence and/or absence of DDX58. We show that siRNA knockdown of DDX58 promotes apoptosis. Importantly, we show that stable overexpression of DDX58 is protective against toxic levels of PA and stimulates autophagy. This study begins to demonstrate the regulation of the autophagy receptor protein SQSTM1/p62 through DDX58. DDX58 expression directly influences mRNA and protein levels. This work proposes a model in which activating DDX58 increases an autophagic response and this aids in clearing toxic lipid inclusion bodies, which leads to inflammation and apoptosis. Activating a DDX58-induced autophagy response may be a strategy for treating NAFLD.5'pppdsRNA: 5' triphosphate double-stranded RNA; CDAHFD: choline-deficient, L-amino acid defined high-fat diet; CEBPB: CCAAT/enhancer binding protein (C/EBP), beta; CQ: chloroquine; DDX58/retinoic acid inducible gene 1/Rig-1: DExD/H box helicase 58; h: hours; IFIH1/MDA5: interferon induced with helicase C domain 1; IFNB/IFN-β: interferon beta 1, fibroblast; KO: knockout; MAVS: mitochondrial antiviral signaling protein; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; PA: palmitic acid; poly:IC: polyinosinic:polycytidylic acid; PRR: pattern recognition receptors; PSR: picrosirus red; RAP: rapamycin; RLR: RIG-I-like receptor; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK-binding kinase 1.
Topics: Animals; Autophagy; Cell Death; Inflammation; Mice; Non-alcoholic Fatty Liver Disease; Palmitic Acid; Sequestosome-1 Protein
PubMed: 33966599
DOI: 10.1080/15548627.2021.1920818 -
American Journal of Respiratory Cell... Dec 2019The impact of lipotoxicity on the development of lung fibrosis is unclear. Saturated fatty acids, such as palmitic acid (PA), activate endoplasmic reticulum (ER) stress,...
The impact of lipotoxicity on the development of lung fibrosis is unclear. Saturated fatty acids, such as palmitic acid (PA), activate endoplasmic reticulum (ER) stress, a cellular stress response associated with the development of idiopathic pulmonary fibrosis (IPF). We tested the hypothesis that PA increases susceptibility to lung epithelial cell death and experimental fibrosis by modulating ER stress. Total liquid chromatography and mass spectrometry were used to measure fatty acid content in IPF lungs. Wild-type mice were fed a high-fat diet (HFD) rich in PA or a standard diet and subjected to bleomycin-induced lung injury. Lung fibrosis was determined by hydroxyproline content. Mouse lung epithelial cells were treated with PA. ER stress and cell death were assessed by Western blotting, TUNEL staining, and cell viability assays. IPF lungs had a higher level of PA compared with controls. Bleomycin-exposed mice fed an HFD had significantly increased pulmonary fibrosis associated with increased cell death and ER stress compared with those fed a standard diet. PA increased apoptosis and activation of the unfolded protein response in lung epithelial cells. This was attenuated by genetic deletion and chemical inhibition of CD36, a fatty acid transporter. In conclusion, consumption of an HFD rich in saturated fat increases susceptibility to lung fibrosis and ER stress, and PA mediates lung epithelial cell death and ER stress via CD36. These findings demonstrate that lipotoxicity may have a significant impact on the development of lung injury and fibrosis by enhancing pro-death ER stress pathways.
Topics: Animals; Apoptosis; CD36 Antigens; Diet, High-Fat; Endoplasmic Reticulum Stress; Epithelial Cells; Lung; Male; Mice; Mice, Inbred C57BL; Palmitic Acid; Pulmonary Fibrosis
PubMed: 31461627
DOI: 10.1165/rcmb.2018-0324OC -
The American Journal of Clinical... May 2021Interesterified (IE) fats are widely used in place of trans fats; however, little is known about their metabolism. (Randomized Controlled Trial)
Randomized Controlled Trial
Palmitic acid-rich oils with and without interesterification lower postprandial lipemia and increase atherogenic lipoproteins compared with a MUFA-rich oil: A randomized controlled trial.
BACKGROUND
Interesterified (IE) fats are widely used in place of trans fats; however, little is known about their metabolism.
OBJECTIVES
To test the impact of a commonly consumed IE compared with a non-IE equivalent fat on in vivo postprandial and in vitro lipid metabolism, compared with a reference oil [rapeseed oil (RO)].
METHODS
A double-blinded, 3-phase crossover, randomized controlled trial was performed in healthy adults (n = 20) aged 45-75 y. Postprandial plasma triacylglycerol and lipoprotein responses (including stable isotope tracing) to a test meal (50 g fat) were evaluated over 8 h. The test fats were IE 80:20 palm stearin/palm kernel fat, an identical non-IE fat, and RO (control). In vitro, mechanisms of digestion were explored using a dynamic gastric model (DGM).
RESULTS
Plasma triacylglycerol 8-h incremental area under the curves were lower following non-IE compared with RO [-1.7 mmol/L⋅h (95% CI: -3.3, -0.0)], but there were no differences between IE and RO or IE and non-IE. LDL particles were smaller following IE and non-IE compared with RO (P = 0.005). Extra extra large, extra large, and large VLDL particle concentrations were higher following IE and non-IE compared with RO at 6-8 h (P < 0.05). No differences in the appearance of [13C]palmitic acid in plasma triacylglycerol were observed between IE and non-IE fats. DGM revealed differences in phase separation of the IE and non-IE meals and delayed release of SFAs compared with RO.
CONCLUSIONS
Interesterification did not modify fat digestion, postprandial lipemia, or lipid metabolism measured by stable isotope and DGM analysis. Despite the lower lipemia following the SFA-rich fats, increased proatherogenic large triacylglycerol-rich lipoprotein remnant and small LDL particles following the SFA-rich fats relative to RO adds a new postprandial dimension to the mechanistic evidence linking SFAs to cardiovascular disease risk.
Topics: Aged; Apolipoprotein B-48; Atherosclerosis; Chylomicrons; Cross-Over Studies; Dietary Fats, Unsaturated; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Humans; Hyperlipidemias; Lipoproteins; Male; Middle Aged; Palmitic Acid; Postprandial Period; Triglycerides
PubMed: 33675343
DOI: 10.1093/ajcn/nqaa413 -
Nutrition Research Reviews Jun 2009The position of fatty acids in the TAG molecule (sn-1, sn-2 and sn-3) determines the physical properties of the fat, which affects its absorption, metabolism and... (Review)
Review
The position of fatty acids in the TAG molecule (sn-1, sn-2 and sn-3) determines the physical properties of the fat, which affects its absorption, metabolism and distribution into tissues, which may have implications for the risk of CHD. The TAG structure of fats can be manipulated by the process of interesterification, which is of increasing commercial importance, as it can be used to change the physical characteristics of a fat without the generation of trans-fatty acids. Interesterified fats rich in long-chain SFA are commercially important, but few studies have investigated their health effects. Evidence from animal and human infant studies suggests that TAG structure and interesterification affect digestibility, atherogenicity and fasting lipid levels, with fats containing palmitic and stearic acid in the sn-2 position being better digested and considered to be more atherogenic. However, chronic studies in human adults suggest that TAG structure has no effect on digestibility or fasting lipids. The postprandial effects of fats with differing TAG structure are better characterised but the evidence is inconclusive; it is probable that differences in the physical characteristics of fats resulting from interesterification and changes in TAG structure are key determinants of the level of postprandial lipaemia, rather than the position of fatty acids in the TAG. The present review gives an overview of TAG structure and interesterified palmitic and stearic acid-rich fats, their physical properties and their acute and chronic effects in human adults in relation to CHD.
Topics: Adult; Animals; Coronary Disease; Diet, Atherogenic; Dietary Fats; Esterification; Humans; Hyperlipidemias; Infant; Lipid Metabolism; Lipids; Palmitic Acid; Plant Oils; Stearic Acids; Trans Fatty Acids; Triglycerides
PubMed: 19442321
DOI: 10.1017/S0954422409369267 -
Endocrine Regulations Apr 2022Due to insulin resistance and oxidative stress that are associated with type 2 diabetes mellitus (T2DM), T2DM has become a prevalent metabolic disorder that presents...
Due to insulin resistance and oxidative stress that are associated with type 2 diabetes mellitus (T2DM), T2DM has become a prevalent metabolic disorder that presents various side effects. However, alternative antidiabetic treatment has commonly been used in treating diabetes mellitus in diabetic patients. In our previous studies, bredemolic acid has been reported as an antidiabetic agent that improves glucose uptake, ameliorates insulin resistance, and oxidative stress in the liver, heart, kidney, and skeletal muscle of prediabetic rats. However, these effects have not been validated . Therefore, this study was aimed to investigate the effects of bredemolic acid on insulin-mediated glucose utilization, lipid peroxidation, and the total antioxidant capacity (TOAC) in palmitic acid-induced insulin-resistant C2C12 skeletal muscle cells . Insulin resistance was induced in the skeletal muscle cells after 4 h of exposure to palmitic acid (0.5 mmol/l). Different cell groups were incubated in culture media DMEM supplemented with fetal calf serum (10%), penicillin/streptomycin (1%), and L-glutamine (1%) and then treated with either insulin (4 µg/ml) or bredemolic acid (12.5 mmol/l) or with both. Thereafter, the cells were seeded in 24- or 96-well plates for determination of the cell viability, glucose utilization, glycogen formation, and antioxidant capacity. The results showed that bredemolic acid significantly improved TOAC and promoted glucose utilization via attenuation of lipid peroxidation and increased glycogen formation in the insulin-resistant cells, respectively. This study showed that bredemolic acid restored the insulin resistance through improved glucose utilization, glycogen formation, and TOAC in the skeletal muscle cells.
Topics: Animals; Antioxidants; Diabetes Mellitus, Type 2; Glucose; Glycogen; Humans; Insulin; Insulin Resistance; Oxidative Stress; Palmitic Acid; Rats; Triterpenes
PubMed: 35489052
DOI: 10.2478/enr-2022-0014 -
Genes Sep 2022Lipotoxicity is known to cause cellular dysfunction and death in non-adipose tissue. A major cause of lipotoxicity is the accumulation of saturated free fatty acids...
Lipotoxicity is known to cause cellular dysfunction and death in non-adipose tissue. A major cause of lipotoxicity is the accumulation of saturated free fatty acids (FFA). Palmitic acid (PA) is the most common saturated fatty acid found in the human body. Endothelial cells form the blood vessels and are the first non-adipose cells to encounter FFA in the bloodstream. FFA overload has a direct impact on metabolism, which is evident through the changes occurring in mitochondria. To study these changes, the PA-treated human coronary artery endothelial cell (HCAEC) dataset was obtained from the Gene Expression Omnibus (GEO), and it was analyzed to obtain differentially expressed genes (DEGs) from the nucleus and mitochondria. Functional and pathway enrichment analyses were performed on DEGs. Results showed that nuclear and mitochondrial DEGs were implicated in several processes, e.g., reactive oxygen species (ROS) production, mitochondrial fusion and fission, Ca sequestering, membrane transport, the electron transport chain and the process of apoptosis. To better understand the role of FFA in endothelial cell damage, these DEGs can lead to future experiments based on these findings.
Topics: Humans; Palmitic Acid; Reactive Oxygen Species; Fatty Acids, Nonesterified; Endothelial Cells; Mitochondria; Fatty Acids; Gene Expression
PubMed: 36292589
DOI: 10.3390/genes13101704 -
Autoimmunity Dec 2023Impaired insulin secretion due to pancreatic β-cell injury is an important cause of type 2 diabetes (T2D). Regulators of guanine nucleotide binding protein (G protein)...
Impaired insulin secretion due to pancreatic β-cell injury is an important cause of type 2 diabetes (T2D). Regulators of guanine nucleotide binding protein (G protein) signaling proteins played a key role in regulating insulin sensitivity . To explore the role of RGS7 on palmitic acid-induced pancreatic β-cell injury, pancreatic β-cells Beta-TC-6 and Min6 were treated with palmitic acid (PA) to similar type 2 diabetes (T2D) injury . The 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), and flow cytometry were used to analyze cell viability, proliferation, and apoptosis, respectively. Enzyme-linked immunosorbent assay (ELISA) kits were used to analyze the changes of inflammation-related cytokines. The expression of gene and protein was measured by quantitative real-time PCR (qRT-PCR) and western blot. PA modeling induced apoptosis, increased levels of inflammation-related cytokines, and suppressed cell viability and proliferation of pancreatic β-cells. RGS7 silence markedly alleviated the cell injury induced by PA. RGS7 overexpression further aggravated apoptosis and inflammatory response in PA-induced pancreatic β-cells and inhibited cell viability and proliferation. It is worth noting that RGS7 activated the chemokine signaling pathway. Silence of the key gene of the chemokine signaling pathway could eliminate the negative effect of RGS7 on PA-induced pancreatic β-cells. RGS7 silence protects pancreatic β-cells from PA-induced injury by inactivating the chemokine signaling pathway.
Topics: Humans; Palmitic Acid; Signal Transduction; Diabetes Mellitus, Type 2; Insulin-Secreting Cells; Apoptosis; Cytokines; Inflammation; Chemokines; RGS Proteins
PubMed: 36999276
DOI: 10.1080/08916934.2023.2194584