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1.
New Phytol ; 242(5): 2163-2179, 2024 Jun.
Article En | MEDLINE | ID: mdl-38532564

The S-domain-type receptor-like kinase (SD-RLK) LIPOOLIGOSACCHARIDE-SPECIFIC REDUCED ELICITATION (LORE) from Arabidopsis thaliana is a pattern recognition receptor that senses medium-chain 3-hydroxy fatty acids, such as 3-hydroxydecanoic acid (3-OH-C10:0), to activate pattern-triggered immunity. Here, we show that LORE homomerization is required to activate 3-OH-C10:0-induced immune signaling. Fluorescence lifetime imaging in Nicotiana benthamiana demonstrates that AtLORE homomerizes via the extracellular and transmembrane domains. Co-expression of AtLORE truncations lacking the intracellular domain exerts a dominant negative effect on AtLORE signaling in both N. benthamiana and A. thaliana, highlighting that homomerization is essential for signaling. Screening for 3-OH-C10:0-induced reactive oxygen species production revealed natural variation within the Arabidopsis genus. Arabidopsis lyrata and Arabidopsis halleri do not respond to 3-OH-C10:0, although both possess a putative LORE ortholog. Both LORE orthologs have defective extracellular domains that bind 3-OH-C10:0 to a similar level as AtLORE, but lack the ability to homomerize. Thus, ligand binding is independent of LORE homomerization. Analysis of AtLORE and AlyrLORE chimera suggests that the loss of AlyrLORE homomerization is caused by several amino acid polymorphisms across the extracellular domain. Our findings shed light on the activation mechanism of LORE and the loss of 3-OH-C10:0 perception within the Arabidopsis genus.


Arabidopsis Proteins , Arabidopsis , Nicotiana , Protein Multimerization , Signal Transduction , Arabidopsis/immunology , Arabidopsis/genetics , Arabidopsis/metabolism , Arabidopsis Proteins/metabolism , Arabidopsis Proteins/genetics , Arabidopsis Proteins/chemistry , Nicotiana/genetics , Nicotiana/immunology , Nicotiana/metabolism , Reactive Oxygen Species/metabolism , Plant Immunity/drug effects , Protein Domains , Receptors, Pattern Recognition/metabolism , Decanoic Acids/metabolism , Decanoic Acids/pharmacology
2.
Molecules ; 28(23)2023 Nov 28.
Article En | MEDLINE | ID: mdl-38067561

Perfluorodecanoic acid (PFDA), an enduring and harmful organic pollutant, is widely employed in diverse food-related sectors. Our previous studies have provided evidence that PFDA has the potential to facilitate obesity and hepatic fat accumulation induced by high-fat diet (HFD) intake. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, has been suggested to possess potential preventive effects against metabolic abnormalities and fatty liver. The purpose of this research was to investigate the effects of EGCG on PFDA-exacerbated adiposity and hepatic lipid accumulation in HFD-fed mice. The results showed that EGCG reduced body weight gain; tissue and organ weights; blood glucose, serum insulin, HOMA-IR, leptin, and lipid parameters; serum inflammatory cytokines (IL-1ß, IL-18, IL-6, and TNF-α); and hepatic lipid accumulation in PFDA-exposed mice fed an HFD. Further work showed that EGCG improved liver function and glucose homeostasis in mice fed an HFD and co-exposed to PFDA. The elevated hepatic mRNA levels of SREBP-1 and associated lipogenic genes, NLRP3, and caspase-1 in PFDA-exposed mice fed an HFD were significantly decreased by EGCG. Our work provides evidence for the potential anti-obesity effect of EGCG on co-exposure to HFD and PFDA and may call for further research on the bioactivity of EGCG to attenuate the endocrine disruption effects of long-term exposure to pollutants.


Catechin , Diet, High-Fat , Male , Animals , Mice , Diet, High-Fat/adverse effects , Adiposity , Mice, Inbred C57BL , Obesity/etiology , Obesity/genetics , Liver , Decanoic Acids/pharmacology , Catechin/pharmacology , Catechin/metabolism
3.
Mol Pharm ; 20(2): 929-941, 2023 02 06.
Article En | MEDLINE | ID: mdl-36592951

Sodium caprate (C10) has been widely evaluated as an intestinal permeation enhancer for the oral delivery of macromolecules. However, the effect of C10 on the intestinal absorption of peptides with different physicochemical properties and its permeation-enhancing effect in vivo remains to be understood. Here, we evaluated the effects of C10 on intestinal absorption in rats with a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GIP-GLP1) dual agonist peptide (LY) and semaglutide with different enzymatic stabilities and self-association behaviors as well as the oral exposure of the LY peptide in minipigs. Furthermore, we investigated the mechanism of action (MoA) of C10 for improving the intestinal absorption of the LY peptide in vivo via live imaging of the rat intestinal epithelium and tissue distribution of the LY peptide in minipigs. The LY peptide showed higher proteolytic stability in pancreatin and was a monomer in solution compared to that in semaglutide. C10 increased in vitro permeability in the minipig intestinal organoid monolayer to a greater extent for the LY peptide than for semaglutide. In the rat jejunal closed-loop model, C10 increased the absorption of LY peptide better than that of semaglutide, which might be attributed to higher in vitro proteolytic stability and permeability of the LY peptide. Using confocal live imaging, we observed that C10 enabled the rapid oral absorption of a model macromolecule (FD4) in the rat intestine. In the duodenum tissues of minipigs, C10 was found to qualitatively reduce the tight junction protein level and allow peptide uptake to the intestinal cells. C10 decreased the transition temperature of the artificial lipid membrane, indicating an increase in membrane fluidity, which is consistent with the above in vivo imaging results. These data indicated that the LY's favorable physicochemical properties combined with the effects of C10 on the intestinal mucosa resulted in an ∼2% relative bioavailability in minipigs.


Gastric Inhibitory Polypeptide , Glucagon-Like Peptide 1 , Swine , Rats , Animals , Gastric Inhibitory Polypeptide/metabolism , Gastric Inhibitory Polypeptide/pharmacology , Glucagon-Like Peptide 1/metabolism , Swine, Miniature/metabolism , Decanoic Acids/pharmacology , Intestinal Absorption , Intestinal Mucosa/metabolism , Peptides/metabolism
4.
Food Funct ; 13(4): 2336-2353, 2022 Feb 21.
Article En | MEDLINE | ID: mdl-35142767

Alzheimer's disease (AD), the most common form of neurodegenerative dementia among the older population, is associated with acute or chronic inflammation. As a nonsteroidal anti-inflammatory drug, aspirin has recently been widely studied in the prevention and treatment of neurodegenerative diseases. However, there is a controversy about the efficacy as well as the adverse effects of aspirin. 10-Hydroxydecanoic acid (10-HDAA) is a characteristic fatty acid found in the honey bee product royal jelly. In this study, we found that 10-HDAA attenuated the activation of the NF-κB pathway, then targeted Ptgs-1/2, the well-known target of aspirin. Hence, combined therapy of 10-HDAA and aspirin was conducted. In vitro assays suggested that this combinatory group alleviated LPS-induced inflammation in BV-2 cells, as assessed by the downregulation of nitric oxide, COX-2, and IL-6 compared to 10-HDAA or aspirin treatment alone. In vivo assays showed that the combined treatment synergistically inhibited the overactivation of glial cells and decreased the levels of pro-inflammatory mediators. Moreover, 10-HDAA alleviated the adverse effects of aspirin on gastrointestinal injuries and microbiota dysbiosis. The Morris water maze test indicated that neither 10-HDAA nor aspirin effectively improved LPS-induced memory dysfunction, but the combined therapy showed synergistic effects. Altogether, our findings support 10-HDAA and aspirin combinatory therapy as the basis for future therapeutics for AD and other neuroinflammation-related diseases with minimal adverse effects.


Aspirin/pharmacology , Decanoic Acids/pharmacology , Memory Disorders/prevention & control , Neuroinflammatory Diseases/prevention & control , Neuroprotective Agents/pharmacology , Administration, Oral , Animals , Aspirin/administration & dosage , Aspirin/chemistry , Astrocytes/drug effects , Bees , Decanoic Acids/administration & dosage , Decanoic Acids/chemistry , Disease Models, Animal , Drug Synergism , Fatty Acids , Functional Food , Male , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/chemistry , Random Allocation
5.
Neuropsychopharmacol Rep ; 42(1): 59-69, 2022 03.
Article En | MEDLINE | ID: mdl-34994529

AIM: Capric acid (also known as decanoic acid or C10) is one of the fatty acids in the medium-chain triglycerides (MCTs) commonly found in dietary fats. Although dietary treatment with MCTs is recently of great interest for the potential therapeutic effects on neuropsychiatric disorders, the effects of oral administration of C10 on behavior remain to be examined. This study investigated acute and chronic effects of oral administration of C10 on locomotor activity and anxiety-like and depression-related behaviors in adult male C57BL/6J mice. METHODS: To explore the acute effects of C10 administration, mice were subjected to a series of behavioral tests in the following order: light/dark transition, open field, elevated plus maze, Porsolt forced swim, and tail suspension tests, 30 minutes after oral gavage of either vehicle or C10 solution (30 mmol/kg dose in Experiment 1; 0.1, 0.3, 1.0, 3.0 mmol/kg doses in Experiment 2). Next, to examine chronic effects of C10, mice repeatedly administered with either vehicle or C10 solution (0.3, 3.0 mmol/kg doses per day, for 21 days, in Experiment 3) were subjected to behavioral tests without oral administration immediately before each test. RESULTS: The mice administrated with the high dose of C10 (30 mmol/kg) showed lower body weights, shorter distance traveled, and more anxiety-like behavior than vehicle-treated mice, and the results reached study-wide statistical significance. The C10 administration at a lower dose of 0.3 mmol/kg had no significant effects on body weights and induced nominally significantly longer distance traveled than vehicle administration. Repeated administration of C10 at a dose of 3.0 mmol/kg for more than 21 days caused lower body weights and decreased depression-related behavior, although the behavioral differences did not reach study-wide significance. CONCLUSIONS: Although these results suggest dose-dependent effects of oral administration of capric acid on locomotor activity and anxiety-like and depression-related behaviors, further study will be needed to replicate the findings and explore the underlying brain mechanisms.


Behavior, Animal , Depression , Administration, Oral , Animals , Anxiety/drug therapy , Decanoic Acids/pharmacology , Depression/drug therapy , Fatty Acids/pharmacology , Locomotion , Male , Mice , Mice, Inbred C57BL
6.
Mol Pharm ; 19(1): 124-137, 2022 01 03.
Article En | MEDLINE | ID: mdl-34913341

Oral administration of drugs is generally considered convenient and patient-friendly. However, oral administration of biological drugs exhibits low oral bioavailability (BA) due to enzymatic degradation and low intestinal absorption. A possible approach to circumvent the low BA of oral peptide drugs is to coformulate the drugs with permeation enhancers (PEs). PEs have been studied since the 1960s and are molecules that enhance the absorption of hydrophilic molecules with low permeability over the gastrointestinal epithelium. In this study, we investigated the impact of six PEs on the structural properties of a model membrane using molecular dynamics (MD) simulations. The PEs included were the sodium salts of the medium chain fatty acids laurate, caprate, and caprylate and the caprylate derivative SNAC─all with a negative charge─and neutral caprate and neutral sucrose monolaurate. Our results indicated that the PEs, once incorporated into the membrane, could induce membrane leakiness in a concentration-dependent manner. Our simulations suggest that a PE concentration of at least 70-100 mM is needed to strongly affect transcellular permeability. The increased aggregation propensity seen for neutral PEs might provide a molecular-level mechanism for the membrane disruptions seen at higher concentrations in vivo. The ability for neutral PEs to flip-flop across the lipid bilayer is also suggestive of possible intracellular modes of action other than increasing membrane fluidity. Taken together, our results indicate that MD simulations are useful for gaining insights relevant to the design of oral dosage forms based around permeability enhancer molecules.


Fatty Acids/pharmacology , Intestinal Absorption/drug effects , Lipid Bilayers/metabolism , Caprylates/pharmacology , Computer Simulation , Decanoic Acids/pharmacology , Laurates/pharmacology , Molecular Docking Simulation , Permeability
7.
Mol Pharm ; 19(1): 200-212, 2022 01 03.
Article En | MEDLINE | ID: mdl-34928160

In this work, we set out to better understand how the permeation enhancer sodium caprate (C10) influences the intestinal absorption of macromolecules. FITC-dextran 4000 (FD4) was selected as a model compound and formulated with 50-300 mM C10. Absorption was studied after bolus instillation of liquid formulation to the duodenum of anesthetized rats and intravenously as a reference, whereafter plasma samples were taken and analyzed for FD4 content. It was found that the AUC and Cmax of FD4 increased with increasing C10 concentration. Higher C10 concentrations were associated with an increased and extended absorption but also increased epithelial damage. Depending on the C10 concentration, the intestinal epithelium showed significant recovery already at 60-120 min after administration. At the highest studied C10 concentrations (100 and 300 mM), the absorption of FD4 was not affected by the colloidal structures of C10, with similar absorption obtained when C10 was administered as micelles (pH 8.5) and as vesicles (pH 6.5). In contrast, the FD4 absorption was lower when C10 was administered at 50 mM formulated as micelles as compared to vesicles. Intestinal dilution of C10 and FD4 revealed a trend of decreasing FD4 absorption with increasing intestinal dilution. However, the effect was smaller than that of altering the total administered C10 dose. Absorption was similar when the formulations were prepared in simulated intestinal fluids containing mixed micelles of bile salts and phospholipids and in simple buffer solution. The findings in this study suggest that in order to optimally enhance the absorption of macromolecules, high (≥100 mM) initial intestinal C10 concentrations are likely needed and that both the concentration and total dose of C10 are important parameters.


Colloids/chemistry , Decanoic Acids/pharmacology , Intestinal Absorption/drug effects , Intestinal Mucosa/drug effects , Animals , Cryoelectron Microscopy , Decanoic Acids/analysis , Decanoic Acids/chemistry , Dextrans/pharmacology , Drug Synergism , Fluorescein-5-isothiocyanate/analogs & derivatives , Fluorescein-5-isothiocyanate/pharmacology , Intestinal Mucosa/chemistry , Male , Rats , Rats, Wistar
8.
Cells ; 10(11)2021 10 29.
Article En | MEDLINE | ID: mdl-34831171

Ketogenic diets, used in epilepsy treatment, are considered to work through reduced glucose and ketone generation to regulate a range of cellular process including autophagy induction. Recent studies into the medium-chain triglyceride (MCT) ketogenic diet have suggested that medium-chain fatty acids (MCFAs) provided in the diet, decanoic acid and octanoic acid, cause specific therapeutic effects independent of glucose reduction, although a role in autophagy has not been investigated. Both autophagy and MCFAs have been widely studied in Dictyostelium, with findings providing important advances in the study of autophagy-related pathologies such as neurodegenerative diseases. Here, we utilize this model to analyze a role for MCFAs in regulating autophagy. We show that treatment with decanoic acid but not octanoic acid induces autophagosome formation and modulates autophagic flux in high glucose conditions. To investigate this effect, decanoic acid, but not octanoic acid, was found to induce the expression of autophagy-inducing proteins (Atg1 and Atg8), providing a mechanism for this effect. Finally, we demonstrate a range of related fatty acid derivatives with seizure control activity, 4BCCA, 4EOA, and Epilim (valproic acid), also function to induce autophagosome formation in this model. Thus, our data suggest that decanoic acid and related compounds may provide a less-restrictive therapeutic approach to activate autophagy.


Autophagy , Decanoic Acids/pharmacology , Dictyostelium/cytology , Autophagosomes/drug effects , Autophagosomes/metabolism , Autophagy/drug effects , Dictyostelium/drug effects , Dictyostelium/metabolism , Phosphatidylinositol Phosphates/metabolism , Proto-Oncogene Proteins c-akt/metabolism
9.
Int J Mol Sci ; 22(18)2021 Sep 17.
Article En | MEDLINE | ID: mdl-34576224

Delivery of substances into the inner ear via local routes is increasingly being used in clinical treatment. Studies have focused on methods to increase permeability through the round window membrane (RWM) and enhance drug diffusion into the inner ear. However, the clinical applications of those methods have been unclear and few studies have investigated the efficacy of methods in an inner ear injury model. Here, we employed the medium chain fatty acid caprate, a biologically safe, clinically applicable substance, to modulate tight junctions of the RWM. Intratympanic treatment of sodium caprate (SC) induced transient, but wider, gaps in intercellular spaces of the RWM epithelial layer and enhanced the perilymph and cochlear concentrations/uptake of dexamethasone. Importantly, dexamethasone co-administered with SC led to significantly more rapid recovery from noise-induced hearing loss at 4 and 8 kHz, compared with the dexamethasone-only group. Taken together, our data indicate that junctional modulation of the RWM by SC enhances dexamethasone uptake into the inner ear, thereby hastening the recovery of hearing sensitivity after noise trauma.


Dexamethasone/pharmacokinetics , Ear, Inner/drug effects , Hearing Loss, Noise-Induced/drug therapy , Round Window, Ear/drug effects , Animals , Cochlea/drug effects , Decanoic Acids/pharmacology , Dexamethasone/administration & dosage , Diffusion , Drug Delivery Systems/methods , Evoked Potentials, Auditory, Brain Stem/drug effects , Fatty Acids/chemistry , Hearing , Male , Microscopy, Electron, Transmission , Perilymph/drug effects , Permeability , Rats
10.
Chem Res Toxicol ; 34(6): 1542-1555, 2021 06 21.
Article En | MEDLINE | ID: mdl-34081457

Perfluorotridecanoic acid (PFTrDA) is a long-chain (C13) perfluoroalkyl carboxylic acid. Here, we report the influence of PFTrDA exposure on the maturation of rat Leydig cells in late puberty in vivo. Male Sprague-Dawley rats were administered PFTrDA by gavage of 0, 1, 5, and 10 mg/kg/day from 35 days to 56 days postpartum. PFTrDA had no effect on body weight, testis weight, and epididymis weight. It significantly decreased the serum testosterone level after 5 and 10 mg/kg exposure, while it did not alter the serum estradiol level. The serum luteinizing hormone level was markedly reduced after 10 mg/kg PFTrDA exposure, while the follicle-stimulating hormone level was unchanged. Star, Cyp11a1, Cyp17a1, Hsd3b1, and Insl3 transcript levels in the testis were markedly lowered in the 1-5 mg/kg PFTrDA group and the Lhb transcript level in the pituitary in the 10 mg/kg group. CYP11A1 and HSD11B1-positive Leydig cell numbers were markedly reduced after 10 mg/kg PFTrDA exposure. Testicular triglyceride and free fatty acid (palmitic acid, oleic acid, and linoleic acid) levels were significantly reduced by PFTrDA, while Mgll (up-regulation) and Scarb1 and Elovl5 (down-regulation) expression were altered. AKT1 and AMPK phosphorylation was stimulated after 10 PFTrDA mg/kg exposure. In conclusion, PFTrDA delays the maturation of Leydig cells in late puberty mainly by altering the free fatty acid profile.


Decanoic Acids/pharmacology , Fluorocarbons/pharmacology , Leydig Cells/drug effects , Lipids/analysis , Pituitary Gland/drug effects , Testis/drug effects , Administration, Oral , Animals , Decanoic Acids/administration & dosage , Dose-Response Relationship, Drug , Fluorocarbons/administration & dosage , Male , Pituitary Gland/pathology , Rats , Rats, Sprague-Dawley , Testis/pathology
11.
Eur J Pharmacol ; 901: 174095, 2021 Jun 15.
Article En | MEDLINE | ID: mdl-33862063

Previous clinical studies have shown that anisodamine could improve no-reflow phenomenon and prevent reperfusion arrhythmias, but whether this protective effect is related to the antagonism of the M-type cholinergic receptor or other potential mechanisms is uncertain. The aim of the present study was to investigate the role of the mitochondrial ATP-sensitive potassium channel (mitoK ATP ) in cardioprotective effect of anisodamine against ischemia/reperfusion injury. Anisodamine and 5- hydroxydecanoic acid were used to explore the relationship between anisodamine and mitoK ATP . Using a Langendorff isolated heart ischemia/reperfusion injury model, hemodynamic parameters and reperfusion ventricular arrhythmia were evaluated; in addition, changes in myocardial infarct size, cTnI from coronary effluent and myocardial ultrastructure, as well as ATP, MDA and SOD in myocardial tissues, were detected. In the hypoxia/reoxygenation injury model of neonatal rat cardiomyocyte, cTnI release in the culture medium and levels of ATP, MDA and SOD in cardiomyocytes and mitochondrial membrane potential, were analyzed. Overall, anisodamine could significantly improve the hemodynamic indexes of isolated rat heart injured by ischemia/reperfusion, reduce the occurrence of ventricular reperfusion arrhythmia and myocardial infarction area, and improve the ultrastructural damage of myocardium and mitochondria. The in vitro results demonstrated that anisodamine could improve mitochondrial energy metabolism, reduce oxidative stress and stabilize mitochondrial membrane potential. The cardioprotective effects were significantly inhibited by 5-hydroxydecanoic acid. In conclusion, this study suggests that the opening of mitoK ATP could play an important role in the protective effect of anisodamine against myocardial ischemia/reperfusion injury.


Cardiotonic Agents/therapeutic use , Mitochondria, Heart/drug effects , Myocardial Reperfusion Injury/prevention & control , Potassium Channels/drug effects , Reperfusion Injury/prevention & control , Solanaceous Alkaloids/therapeutic use , Adenosine Triphosphate/metabolism , Animals , Arrhythmias, Cardiac/prevention & control , Decanoic Acids/pharmacology , Energy Metabolism/drug effects , Hemodynamics/drug effects , Hydroxy Acids/pharmacology , In Vitro Techniques , Male , Malondialdehyde/metabolism , Rats , Rats, Sprague-Dawley , Solanaceous Alkaloids/antagonists & inhibitors , Superoxide Dismutase/metabolism
12.
Sci Rep ; 11(1): 7003, 2021 03 26.
Article En | MEDLINE | ID: mdl-33772066

Octanoic acid is a medium-chained saturated fatty acid found abundantly in the ketogenic dietary supplements containing medium chained triglycerides (MCT) along with decanoic acid. The MCT ketogenic diet is commonly consumed for weight loss but has also showcased neuroprotective potential against neurodegenerative disorders. However, recent clinical findings have reported a critical disadvantage with the long-term consumption of ketogenic diet i.e. bone loss. The following study was employed to investigate whether the two major components of MCT diet also possess bone loss potential as observed with classical ketogenic diet. Swiss albino mice aged between 10 and 12 weeks, were divided into 3 treatment groups that were administered with oral suspensions of octanoic acid, decanoic acid and a combination of both for 4 weeks. Bone specific markers, microarchitectural parameters, using micro computed tomography, and biomechanical strength were analyzed. Remarkably deleterious alterations in the trabecular bone microarchitecture, and on bone markers were observed in the octanoic acid treated groups. Our results suggest significant negative effects on bone health by octanoic acid. These findings require further investigation and validation in order to provide significant clinically relevant data to possibly modify dietary composition of the MCT ketogenic diet.


Bone Resorption/chemically induced , Cancellous Bone/physiopathology , Caprylates/adverse effects , Decanoic Acids/pharmacology , Diet, Ketogenic/adverse effects , Dietary Supplements/adverse effects , Animals , Biomechanical Phenomena/drug effects , Bone Density/drug effects , Diet, High-Protein Low-Carbohydrate/adverse effects , Femur/physiopathology , Ketone Bodies/urine , Male , Mice , Neuroprotective Agents/adverse effects , Osteoclasts/drug effects , Random Allocation , Tibia/physiopathology , Triglycerides/administration & dosage
13.
Sci Rep ; 11(1): 6519, 2021 03 22.
Article En | MEDLINE | ID: mdl-33753842

The effect of capric acid, secreted by the probiotic yeasts Saccharomyces boulardii, was evaluated on the activities of fluconazole (FLC) and amphotericin B (AMB) against pathogenic Candida albicans fungus. The findings indicated that capric acid may be a promising additive for use in combination with FLC. A FLC-capric acid combination led to reduced efflux activity of multidrug resistance (MDR) transporter Cdr1p by causing it to relocalize from the plasma membrane (PM) to the interior of the cell. The above effect occurred due to inhibitory effect of FLC-capric acid combination of ergosterol biosynthesis. However, capric acid alone stimulated ergosterol production in C. albicans, which in turn generated cross resistance towards AMB and inhibited its action (PM permeabilization and cytoplasm leakage) against C. albicans cells. This concluded that AMB should not be administered among dietary supplements containing capric acid or S. boulardii cells.


Amphotericin B/pharmacology , Candida albicans/drug effects , Decanoic Acids/pharmacology , Fluconazole/pharmacology , ATP-Binding Cassette Transporters/genetics , Candida albicans/pathogenicity , Cell Membrane/drug effects , Cell Membrane Permeability/drug effects , Drug Resistance, Multiple/drug effects , Humans , Saccharomyces boulardii/genetics , Saccharomyces cerevisiae Proteins/genetics
14.
Sci Rep ; 11(1): 6135, 2021 03 17.
Article En | MEDLINE | ID: mdl-33731759

Enhanced oxidative stress is a contributing factor in the pathogenesis of several neurodegenerative disorders such as Alzheimer´s disease. Beneficial effects have been demonstrated for medium-chain fatty acids (MCFAs) nutritionally administered as medium-chain triglycerides (MCTs) or coconut oil (CO). The observed effects on cognitive impairment are generally attributed to the hepatic metabolism of MCFAs, where resulting ketone bodies serve as an alternate energy source to compensate for the impaired glucose utilisation in the human brain. Here we show that the saturated MCFA decanoic acid (10:0) reduces the oxidative stress level in two different neuroblastoma cell lines. Phosphatidylcholine (PC) containing decanoic acid (10:0) (PC10:0/10:0) reduced the cellular H2O2 release in comparison to solvent, L-α-Glycerophosphorylcholine and PC containing the long-chain fatty acid (LCFA) arachidic acid (20:0). This effect seems to be at least partially based on an upregulation of catalase activity, independent of alterations in catalase gene expression. Further, PC10:0/10:0 decreased the intracellular oxidative stress level and attenuated the H2O2-induced cell death. It did not affect the level of the ketone body ß-hydroxybutyrate (ßHB). These results indicate that decanoic acid (10:0) and possibly MCFAs in general directly reduce oxidative stress levels independent of ketone levels and thus may promote neuronal health.


Decanoic Acids/pharmacology , Fatty Acids/metabolism , Lipid Metabolism/drug effects , Neuroblastoma/metabolism , Oxidative Stress , Triglycerides , Animals , Cell Line, Tumor , Humans , Mice , Neuroblastoma/pathology , Triglycerides/metabolism , Triglycerides/pharmacology
15.
Clin Exp Hypertens ; 43(5): 462-473, 2021 Jul 04.
Article En | MEDLINE | ID: mdl-33775188

BACKGROUND: Signal transduction of Angiotensin II (Ang II) induced autophagy and its role in Ang II-induced dysfunction of HUVECs are still unclear. METHODS: HUVECs are stimulated with different doses of Ang II (10-9-10-5 mol/L) for different time (6-48 hours). Autophagy-related protein markers: LC3, Beclin-1 and SQSTM1/p62 are measured by western blot. RESULTS: Incubation with Ang II increases autophagic flux (Beclin-1, autophagosomes formation, and degradation of SQSTM1/p62, LC3-I). Increased autophagic levels are inhibited by pretreatment with Ang II type 1 receptor (AT1) blocker (Candesartan), NADPH Oxidase inhibitor (apocycin), mitochondrial KATP channels inhibitor (5-hydroxydecanoate, 5HD). 3-Methyladenine (inhibitors of autophagy) and rapamycin (activator of autophagy) respectively inhibits or activates Ang II-induced autophagy levels. Ang II decreases phosphorylation of endothelial nitric oxide synthase (eNOS) and NO production in HUVECs. L-NAME (NOS inhibitor) totally mimics the actions of Ang II on eNOS, NO production and autophagy levels. Rapamycin further decreases NO production combined with Ang II. Silence Atg5 completely reverses Ang II-activated autophagy levels. CONCLUSIONS: Our results demonstrate that Ang II stimulation increases autophagy levels via AT1 receptor, NADPH oxidase, mitochondrial KATP channel, eNOS, Atg5 signal pathway in HUVECs, and activation of autophagy contributes to Ang II induced dysfunction of HUVECs.


Angiotensin II/toxicity , Autophagy , Human Umbilical Vein Endothelial Cells/pathology , Acetophenones/pharmacology , Adenine/analogs & derivatives , Adenine/pharmacology , Animals , Autophagosomes/drug effects , Autophagosomes/metabolism , Autophagy/drug effects , Autophagy-Related Proteins/metabolism , Benzimidazoles/pharmacology , Biphenyl Compounds/pharmacology , Decanoic Acids/pharmacology , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Hydroxy Acids/pharmacology , Models, Biological , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide/metabolism , Nitric Oxide Synthase Type III/metabolism , Phosphorylation/drug effects , Signal Transduction/drug effects , Sirolimus/pharmacology , Tetrazoles/pharmacology , Time Factors
16.
Biomed Res Int ; 2020: 3039184, 2020.
Article En | MEDLINE | ID: mdl-33134375

Inflammatory response during myocardial ischemia reperfusion injury (MIRI) is essential for cardiac healing, while excessive inflammation extends the infarction and promotes adverse cardiac remodeling. Understanding the mechanism of these uncontrolled inflammatory processes has a significant impact during the MIRI therapy. Here, we found a critical role of ATP-sensitive potassium channels (KATP) in the inflammatory response of MIRI and its potential mechanism and explored the effects of Panax Notoginseng Saponins (PNS) during this possess. Rats underwent 40 min ischemia by occlusion of the left anterior descending (LAD) coronary artery and 60 min of reperfusion. PNS was treated at the corresponding time point before operation; 5-hydroxydecanoate (5-HD) and glybenclamide (Gly) (or Nicorandil (Nic)) were used as pharmacological blocker (or nonselective opener) of KATP. Cardiac function and pathomorphology were evaluated and a set of molecular signaling experiments was tested. KATP current density was measured by patch-clamp. Results revealed that in MIRI, PNS pretreatment restored cardiac function, reduced infarct size, and ameliorated inflammation through KATP. However, inhibiting KATP by 5-HD and Gly significantly reversed the effects, including NLRP3 inflammasome and inflammatory mediators IL-6, MPO, TNF-α, and MCP-1. Moreover, PNS inhibited the phosphorylation and nuclear translocation of NF-κB in I/R myocardium when the KATP was activated. Importantly, PNS promoted the expression of subunits and activation of KATP. The study uncovered KATP served as a new potential mechanism during PNS modulating MIRI-induced inflammation and promoting injured heart recovery. The manipulation of KATP could be a potential therapeutic approach for MIRI and other inflammatory diseases.


Cardiotonic Agents/pharmacology , Drugs, Chinese Herbal/chemistry , KATP Channels/genetics , Myocardial Infarction/prevention & control , Myocardial Reperfusion Injury/drug therapy , Saponins/pharmacology , Animals , Cardiotonic Agents/isolation & purification , Chemokine CCL2/genetics , Chemokine CCL2/metabolism , Decanoic Acids/pharmacology , Gene Expression Regulation , Glyburide/pharmacology , Hydroxy Acids/pharmacology , Inflammation , Interleukin-6/genetics , Interleukin-6/metabolism , KATP Channels/agonists , KATP Channels/antagonists & inhibitors , KATP Channels/metabolism , Male , Myocardial Infarction/genetics , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Myocardial Reperfusion Injury/genetics , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/pathology , Myocardium/metabolism , Myocardium/pathology , NF-kappa B/genetics , NF-kappa B/metabolism , Nicorandil/pharmacology , Patch-Clamp Techniques , Peroxidase/genetics , Peroxidase/metabolism , Rats , Rats, Sprague-Dawley , Saponins/isolation & purification , Signal Transduction , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism
17.
Nutrients ; 12(10)2020 Oct 11.
Article En | MEDLINE | ID: mdl-33050588

Honeybees produce royal jelly (RJ) from their cephalic glands. Royal jelly is a source of nutrition for the queen honey bee throughout its lifespan and is also involved in fertility and longevity. Royal jelly has long been considered beneficial to human health. We recently observed that RJ delayed impairment of motor function during aging, affecting muscle fiber size. However, how RJ affects skeletal muscle metabolism and the functional component of RJ is as of yet unidentified. We demonstrate that feeding mice with RJ daily prevents a decrease in myofiber size following denervation without affecting total muscle weight. RJ did not affect atrophy-related genes but stimulated the expression of myogenesis-related genes, including IGF-1 and IGF receptor. Trans-10-hydroxy-2-decenoic acid (10H2DA) and 10-hydroxydecanoic acid (10HDAA), two major fatty acids contained in RJ. After ingestion, 10H2DA and 10HDAA are metabolized into 2-decenedioic acid (2DA) and sebacic acid (SA) respectively. We found that 10H2DA, 10HDAA, 2DA, and SA all regulated myogenesis of C2C12 cells, murine myoblast cells. These novel findings may be useful for potential preventative and therapeutic applications for muscle atrophy disease included in Sarcopenia, an age-related decline in skeletal muscle mass and strength.


Decanoic Acids/pharmacology , Denervation/adverse effects , Fatty Acids, Monounsaturated/pharmacology , Fatty Acids/administration & dosage , Muscle Development/drug effects , Muscle, Skeletal/physiology , Muscular Atrophy/prevention & control , Muscular Atrophy/therapy , Myoblasts/physiology , Peptide Hydrolases/administration & dosage , Administration, Oral , Animals , Cells, Cultured , Decanoic Acids/administration & dosage , Decanoic Acids/isolation & purification , Fatty Acids/chemistry , Fatty Acids, Monounsaturated/administration & dosage , Fatty Acids, Monounsaturated/isolation & purification , Insulin-Like Growth Factor I/metabolism , Mice, Inbred C57BL , Muscle Development/genetics , Muscle, Skeletal/physiopathology , Muscular Atrophy/etiology , Receptor, IGF Type 1/metabolism , Sarcopenia/prevention & control , Sarcopenia/therapy
18.
Proc Natl Acad Sci U S A ; 117(38): 23617-23625, 2020 09 22.
Article En | MEDLINE | ID: mdl-32879008

Low-glucose and -insulin conditions, associated with ketogenic diets, can reduce the activity of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, potentially leading to a range of positive medical and health-related effects. Here, we determined whether mTORC1 signaling is also a target for decanoic acid, a key component of the medium-chain triglyceride (MCT) ketogenic diet. Using a tractable model system, Dictyostelium, we show that decanoic acid can decrease mTORC1 activity, under conditions of constant glucose and in the absence of insulin, measured by phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). We determine that this effect of decanoic acid is dependent on a ubiquitin regulatory X domain-containing protein, mediating inhibition of a conserved Dictyostelium AAA ATPase, p97, a homolog of the human transitional endoplasmic reticulum ATPase (VCP/p97) protein. We then demonstrate that decanoic acid decreases mTORC1 activity in the absence of insulin and under high-glucose conditions in ex vivo rat hippocampus and in tuberous sclerosis complex (TSC) patient-derived astrocytes. Our data therefore indicate that dietary decanoic acid may provide a new therapeutic approach to down-regulate mTORC1 signaling.


Decanoic Acids/pharmacology , Mechanistic Target of Rapamycin Complex 1 , Adaptor Proteins, Signal Transducing/metabolism , Animals , Astrocytes/metabolism , Cell Cycle Proteins/metabolism , Cells, Cultured , Dictyostelium/drug effects , Dictyostelium/growth & development , Dictyostelium/metabolism , Epilepsy , Glucose/metabolism , Hippocampus/chemistry , Hippocampus/metabolism , Humans , Insulin/metabolism , Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors , Mechanistic Target of Rapamycin Complex 1/metabolism , Mechanistic Target of Rapamycin Complex 1/pharmacology , Peptide Initiation Factors , Phosphorylation , Rats
19.
Nutrients ; 12(8)2020 Aug 08.
Article En | MEDLINE | ID: mdl-32784510

The ketogenic diet (KD), a high-lipid and low-carbohydrate diet, has been used in the treatment of epilepsy, neurodegenerative disorders, inborn errors of metabolism and cancer; however, the exact mechanism/s of its therapeutic effect is not completely known. We hypothesized that sirtuins (SIRT)-a group of seven NAD-dependent enzymes and important regulators of energy metabolism may be altered under KD treatment. HT22 hippocampal murine neurons were incubated with two important KD metabolites-beta-hydroxybutyrate (BHB) (the predominant ketone body) and decanoic acid (C10), both accumulating under KD. Enzyme activity, protein, and gene expressions of SIRT 1-4, enzyme capacities of the mitochondrial respiratory chain complexes (MRC), citrate synthase (CS) and gene expression of monocarboxylate transporters were measured in control (untreated) and KD-treated cells. Incubation with both-BHB and C10 resulted in significant elevation of SIRT1 enzyme activity and an overall upregulation of the MRC. C10 incubation showed prominent increases in maximal activities of complexes I + III and complex IV of the MRC and ratios of their activities to that of CS, pointing towards a more efficient functioning of the mitochondria in C10-treated cells.


3-Hydroxybutyric Acid/pharmacology , Decanoic Acids/pharmacology , Diet, Ketogenic , Energy Metabolism/drug effects , Hippocampus/drug effects , Animals , Citrate (si)-Synthase/metabolism , Gene Expression/drug effects , Mice , Mitochondria/enzymology , Multienzyme Complexes/drug effects , Neurons/drug effects , Sirtuins/drug effects
20.
Biol Pharm Bull ; 43(8): 1202-1209, 2020.
Article En | MEDLINE | ID: mdl-32741940

The effective antigen (Ag) uptake by microfold cells (M-cells) is important for the induction of an efficient mucosal immune responses. Here, we show that 10-hydroxydecanoic acid (10-HDAA) from royal jelly (RJ) potentially supports M-cell differentiation and induces effective antigen-specific mucosal immune responses in cynomolgus macaques. 10-HDAA increases the expression level of receptor activator of nuclear factor-kappaB (NF-κB) (RANK) in Caco-2 cells, which suggests that 10-HDAA potentially prompts the differentiation of Caco-2 cells into M-cells and increased transcytosis efficiency. This idea is supported by the following observations. Intranasal administration of 10-HDAA increased the number of M-cells in the epithelium overlying nasopharynx-associated lymphoid tissue (NALT) in macaques. Oral administration of 10-HDAA increased the number of M-cells in the follicle-associated epithelium (FAE) covering Peyer's patches (PPs) and significantly increased the antigen-specific immunoglobulin A (IgA) level in macaques. These findings suggest that the exogenous honeybee-derived medium-chain fatty acid 10-HDAA may effectively enhance antigen-specific immune responses.


Decanoic Acids/pharmacology , Immunity, Mucosal/drug effects , Immunoglobulin A/biosynthesis , Animals , Antigens/immunology , Caco-2 Cells , Cell Differentiation , Epithelial Cells/drug effects , Epithelial Cells/immunology , Humans , Intestinal Mucosa/immunology , Macaca fascicularis , Male , RANK Ligand/genetics
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