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In Vivo (Athens, Greece) 2023Acute liver injury is the hallmark of organ failure in sepsis. Enteral nutrition (EN) is an important clinical therapeutic measure in septic patients. However, the...
BACKGROUND/AIM
Acute liver injury is the hallmark of organ failure in sepsis. Enteral nutrition (EN) is an important clinical therapeutic measure in septic patients. However, the therapeutic effect of EN alone is not obvious. Here, we investigated whether octanoic acid (OA)-rich EN alleviated acute liver injury through PPARγ/STAT-1/MyD88 pathway in endotoxemic rats.
MATERIALS AND METHODS
First, rats were randomly divided into four groups: Sham, Lipopolysaccharide (LPS), LPS+EN and LPS+EN+OA groups to investigate the effect of OA-rich EN on LPS-induced acute liver injury in endotoxemic rats. Then rats were randomly divided into five groups: Sham, LPS, LPS+EN+OA, LPS+EN+OA+SR202 (SR) and LPS+ pioglitazone (PI) groups to examine whether OA-rich EN alleviated acute liver injury through the PPARγ/STAT-1/MyD88 pathway. Rats received nutrition support via a gastric tube for 3 days. We evaluated the liver histology, apoptosis, liver enzymes and inflammatory cytokine levels in the liver and serum. PPARγ/STAT-1/MyD88 pathway was also measured.
RESULTS
OA-rich EN inhibited the phosphorylation of STAT-1 and the activity of MyD88 by activating PPARγ and alleviating LPS-induced acute liver injury more effectively than EN alone in endotoxemic rats. The use of SR counteracted the effect of OA-rich EN on acute liver injury. Meanwhile, PI showed effects similar to OA-rich EN in endotoxemic rats.
CONCLUSION
OA-rich EN alleviated acute liver injury through PPARγ/STAT-1/MyD88 pathway in endotoxemic rats.
Topics: Rats; Animals; Enteral Nutrition; Lipopolysaccharides; Myeloid Differentiation Factor 88; PPAR gamma; Liver
PubMed: 37369501
DOI: 10.21873/invivo.13246 -
Journal of Food Biochemistry Oct 2021Ketosis is a potentially beneficial metabolic state for health especially in neurological conditions including Parkinson's disease (PD). Medium-chain-triglycerides (MCT)...
Ketosis is a potentially beneficial metabolic state for health especially in neurological conditions including Parkinson's disease (PD). Medium-chain-triglycerides (MCT) have specific metabolic properties and they are described as ketogenic even without restriction of carbohydrate. Octanoic acid (C8) is the main MCT showing this effect. Rotenone is a neurotoxin that is used to induce experimental PD model. Rotenone inhibits mitochondrial respiratory complex 1 (MRC1) and causes reactive oxygen species formation. Mass spectrometry (MS)-based phosphoproteomic methods enable discovering specific signaling events in special molecular pathways through identification and quantification of phosphoproteins. Signaling networks involved in rotenone-mediated biological processes and beneficial effects of MCTs on neurodegenerative diseases are not well understood. We aimed to gain comprehensive molecular perspective on the global phosphoproteome differences in rotenone-exposed zebrafish treated with octanoic acid. Raw files obtained from MS analysis were processed and searched against the Danio rerio protein database using SEQUEST-HT algorithm to identify and quantify phosphopeptides with 2,569 unique phosphoproteins and 4,161 unique phosphopeptides corresponding to 2005 proteins. Microtubule-associated protein (MAP) family members were significantly lower in rotenone group. Phosphoproteins involved in ion binding (calcium, magnesium, zinc ion), oxygen binding, microtubule binding, ATP- and GTP-binding were among differentially expressed 347 proteins in rotenone group and they were reversed after octanoic acid treatments. Phosphoproteins and phosphorylation sites were identified for future exploration of signaling pathways involved in rotenone toxicity. We believe our findings might help in the formulation of effective therapeutic strategies for the treatment of PD using ketogenic formulations involving MCTs. PRACTICAL APPLICATIONS: Ketosis is a potentially beneficial metabolic state for health especially in neurological conditions including Parkinson's disease (PD). Medium-chain-triglycerides (MCT) (C6-C12) have specific metabolic properties making them described as ketogenic even without restriction of carbohydrate. Octanoic acid (caprylic acid, C8) is the main MCT showing this effect. Our findings might help in the formulation of effective therapeutic strategies for the treatment of Parkinson's disease using ketogenic formulations involving Medium-chain-triglycerides.
Topics: Animals; Caprylates; Parkinson Disease; Rotenone; Zebrafish
PubMed: 34494670
DOI: 10.1111/jfbc.13923 -
Journal of Animal Science and... Mar 2023Dietary fat is important for energy provision and immune function of lactating sows and their progeny. However, knowledge on the impact of fat on mammary transcription...
BACKGROUND
Dietary fat is important for energy provision and immune function of lactating sows and their progeny. However, knowledge on the impact of fat on mammary transcription of lipogenic genes, de novo fat synthesis, and milk fatty acid (FA) output is sparse in sows. This study aimed to evaluate impacts of dietary fat levels and FA composition on these traits in sows. Forty second-parity sows (Danish Landrace × Yorkshire) were assigned to 1 of 5 dietary treatments from d 108 of gestation until weaning (d 28 of lactation): low-fat control diet (3% added animal fat); or 1 of 4 high-fat diets with 8% added fat: coconut oil (CO), fish oil (FO), sunflower oil (SO), or 4% octanoic acid plus 4% FO (OFO). Three approaches were taken to estimate de novo milk fat synthesis from glucose and body fat.
RESULTS
Daily intake of FA was lowest in low-fat sows within fat levels (P < 0.01) and in OFO and FO sows within high-fat diets (P < 0.01). Daily milk outputs of fat, FA, energy, and FA-derived carbon reflected to a large extent the intake of those. On average, estimates for de novo fat synthesis were 82 or 194 g/d from glucose according to method 1 or 2 and 255 g de novo + mobilized FA/d according to method 3. The low-fat diet increased mammary FAS expression (P < 0.05) and de novo fat synthesis (method 1; P = 0.13) within fat levels. The OFO diet increased de novo fat synthesis (method 1; P < 0.05) and numerically upregulated mammary FAS expression compared to the other high-fat diets. Across diets, a daily intake of 440 g digestible FA minimized milk fat originating from glucose and mobilized body fat.
CONCLUSIONS
Sows fed diets with low-fat or octanoic acid, through upregulating FAS expression, increased mammary de novo fat synthesis whereas the milk FA output remained low in sows fed the low-fat diet or high-fat OFO or FO diets, indicating that dietary FA intake, dietary fat level, and body fat mobilization in concert determine de novo fat synthesis, amount and profiles of FA in milk.
PubMed: 36899401
DOI: 10.1186/s40104-022-00815-y -
Biomedicines Nov 2022Characterising Alzheimer's disease (AD) as a metabolic disorder of the brain is gaining acceptance based on the pathophysiological commonalities between AD and major... (Review)
Review
Characterising Alzheimer's disease (AD) as a metabolic disorder of the brain is gaining acceptance based on the pathophysiological commonalities between AD and major metabolic disorders. Therefore, metabolic interventions have been explored as a strategy for brain energetic rescue. Amongst these, medium-chain fatty acid (MCFA) supplementations have been reported to rescue the energetic failure in brain cells as well as the cognitive decline in patients. Short-chain fatty acids (SCFA) have also been implicated in AD pathology. Due to the increasing therapeutic interest in metabolic interventions and brain energetic rescue in neurodegenerative disorders, in this review, we first summarise the role of SCFAs and MCFAs in AD. We provide a comparison of the main findings regarding these lipid species in established AD animal models and recently developed human cell-based models of this devastating disorder.
PubMed: 36359298
DOI: 10.3390/biomedicines10112778 -
Nutrients Feb 2023MCTs are increasingly being used to promote ketogenesis by patients on ketogenic diet therapy, but also by people with other conditions and by the general public for the...
Beta-Hydroxybutyrate (BHB), Glucose, Insulin, Octanoate (C8), and Decanoate (C10) Responses to a Medium-Chain Triglyceride (MCT) Oil with and without Glucose: A Single-Center Study in Healthy Adults.
MCTs are increasingly being used to promote ketogenesis by patients on ketogenic diet therapy, but also by people with other conditions and by the general public for the perceived potential benefits. However, consumption of carbohydrates with MCTs and untoward gastrointestinal side effects, especially at higher doses, could decrease the sustainability of the ketogenic response. This single-center study investigated the impact of consuming carbohydrate as glucose with MCT oil compared to MCT alone on the BHB response. The effects of MCT oil versus MCT oil plus glucose on blood glucose, insulin response, levels of C8, C10, BHB, and cognitive function were determined, and side effects were monitored. A significant plasma BHB increase with a peak at 60 min was observed in 19 healthy participants (24.4 ± 3.9 years) after consuming MCT oil alone, and a more delayed but slightly higher peak was observed after consuming MCT oil plus glucose. A significant increase in blood glucose and insulin levels occurred only after MCT oil plus glucose intake. The overall mean plasma levels of C8 and C10 were higher with the intake of MCT oil alone. MCT oil plus glucose consumption showed improved scores for the arithmetic and vocabulary subtests.
Topics: Humans; Adult; 3-Hydroxybutyric Acid; Glucose; Caprylates; Blood Glucose; Insulin; Decanoates; Triglycerides; Ketone Bodies
PubMed: 36904147
DOI: 10.3390/nu15051148 -
Microbial Cell Factories Feb 2024The improvement of yeast tolerance to acetic, butyric, and octanoic acids is an important step for the implementation of economically and technologically sustainable...
BACKGROUND
The improvement of yeast tolerance to acetic, butyric, and octanoic acids is an important step for the implementation of economically and technologically sustainable bioprocesses for the bioconversion of renewable biomass resources and wastes. To guide genome engineering of promising yeast cell factories toward highly robust superior strains, it is instrumental to identify molecular targets and understand the mechanisms underlying tolerance to those monocarboxylic fatty acids. A chemogenomic analysis was performed, complemented with physiological studies, to unveil genetic tolerance determinants in the model yeast and cell factory Saccharomyces cerevisiae exposed to equivalent moderate inhibitory concentrations of acetic, butyric, or octanoic acids.
RESULTS
Results indicate the existence of multiple shared genetic determinants and pathways underlying tolerance to these short- and medium-chain fatty acids, such as vacuolar acidification, intracellular trafficking, autophagy, and protein synthesis. The number of tolerance genes identified increased with the linear chain length and the datasets for butyric and octanoic acids include the highest number of genes in common suggesting the existence of more similar toxicity and tolerance mechanisms. Results of this analysis, at the systems level, point to a more marked deleterious effect of an equivalent inhibitory concentration of the more lipophilic octanoic acid, followed by butyric acid, on the cell envelope and on cellular membranes function and lipid remodeling. The importance of mitochondrial genome maintenance and functional mitochondria to obtain ATP for energy-dependent detoxification processes also emerged from this chemogenomic analysis, especially for octanoic acid.
CONCLUSIONS
This study provides new biological knowledge of interest to gain further mechanistic insights into toxicity and tolerance to linear-chain monocarboxylic acids of increasing liposolubility and reports the first lists of tolerance genes, at the genome scale, for butyric and octanoic acids. These genes and biological functions are potential targets for synthetic biology approaches applied to promising yeast cell factories, toward more robust superior strains, a highly desirable phenotype to increase the economic viability of bioprocesses based on mixtures of volatiles/medium-chain fatty acids derived from low-cost biodegradable substrates or lignocellulose hydrolysates.
Topics: Saccharomyces cerevisiae; Caprylates; Fatty Acids; Saccharomyces cerevisiae Proteins
PubMed: 38419072
DOI: 10.1186/s12934-024-02309-0 -
Applied and Environmental Microbiology Oct 2018Fermentative production of many attractive biorenewable fuels and chemicals is limited by product toxicity in the form of damage to the microbial cell membrane....
Fermentative production of many attractive biorenewable fuels and chemicals is limited by product toxicity in the form of damage to the microbial cell membrane. Metabolic engineering of the production organism can help mitigate this problem, but there is a need for identification and prioritization of the most effective engineering targets. Here, we use a set of previously characterized environmental isolates with high tolerance and production of octanoic acid, a model membrane-damaging biorenewable product, as a case study for identifying and prioritizing membrane engineering strategies. This characterization identified differences in the membrane lipid composition, fluidity, integrity, and cell surface hydrophobicity from those of the lab strain MG1655. Consistent with previous publications, decreased membrane fluidity was associated with increased fatty acid production ability. Maintenance of high membrane integrity or longer membrane lipids seemed to be of less importance than fluidity. Cell surface hydrophobicity was also directly associated with fatty acid production titers, with the strength of this association demonstrated by plasmid-based expression of the multiple stress resistance outer membrane protein BhsA. This expression of was effective in altering hydrophobicity, but the direction and magnitude of the change differed between strains. Thus, additional strategies are needed to reliably engineer cell surface hydrophobicity. This work demonstrates the ability of environmental microbiological studies to impact the metabolic engineering design-build-test-learn cycle and possibly increase the economic viability of fermentative bioprocesses. The production of bulk fuels and chemicals in a bio-based fermentation process requires high product titers. This is often difficult to achieve, because many of the target molecules damage the membrane of the microbial cell factory. Engineering the composition of the membrane in order to decrease its vulnerability to this damage has proven to be an effective strategy for improving bioproduction, but additional strategies and engineering targets are needed. Here, we studied a small set of environmental isolates that have higher production titers of octanoic acid, a model biorenewable chemical, than those of the lab strain MG1655. We found that membrane fluidity and cell surface hydrophobicity are strongly associated with improved octanoic acid production. Fewer genetic modification strategies have been demonstrated for tuning hydrophobicity relative to fluidity, leading to the conclusion that there is a need for expanding hydrophobicity engineering strategies in .
Topics: Caprylates; Cell Membrane; Environmental Microbiology; Escherichia coli; Fatty Acids; Hydrophobic and Hydrophilic Interactions; Membrane Fluidity; Membrane Lipids; Metabolic Engineering
PubMed: 30030228
DOI: 10.1128/AEM.01285-18 -
Journal of Oleo Science 2015Ghrelin is a growth hormone-releasing peptide that also displays orexigenic activity. Since serine-3 acylation with octanoylate (octanoylation) is essential for the...
Ghrelin is a growth hormone-releasing peptide that also displays orexigenic activity. Since serine-3 acylation with octanoylate (octanoylation) is essential for the orexigenic activity of ghrelin, suppression of octanoylation could lead to amelioration or prevention of obesity. To enable the exploration of inhibitors of octanoylated ghrelin production, we developed a cell-based assay system using AGS-GHRL8 cells, in which octanoylated ghrelin concentration increases in the presence of octanoic acid. Using this assay system, we investigated whether fatty acids contained in foods or oils, such as acetic acid, stearic acid, oleic acid, linoleic acid, and α-linolenic acid, have inhibitory effects on octanoylated ghrelin production. Acetic acid did not suppress the increase in octanoylated ghrelin production in AGS-GHRL8 cells, which was induced by the addition of octanoic acid. However, stearic acid, oleic acid, linoleic acid, and α-linolenic acid significantly suppressed octanoylated ghrelin production, with the effect of oleic acid being the strongest. Additionally, oleic acid decreased the serum concentration of octanoylated ghrelin in mice. The serum concentration of des-acyl ghrelin (without acyl modification) was also decreased, but the decrease was smaller than that of octanoylated ghrelin. Decreased octanoylated ghrelin production likely resulted from post-translational ghrelin processing, as there were no significant differences in gene expression in the stomach between oleic acid-treated mice and controls. These results suggest that oleic acid is a potential inhibitor of octanoylated ghrelin production and that our assay system is a valuable tool for screening compounds with suppressive effects on octanoylated ghrelin production.
Topics: Animals; Biological Assay; Caprylates; Cells, Cultured; Fatty Acids; Ghrelin; Mice; Oleic Acid; Protein Processing, Post-Translational
PubMed: 26521811
DOI: 10.5650/jos.ess15137 -
Experimental and Clinical Endocrinology... Nov 2022Breath tests utilising C-labelled substrates for the assessment of gastric emptying have been applied widely. Wagner-Nelson analysis is a pharmacokinetic model that can...
INTRODUCTION
Breath tests utilising C-labelled substrates for the assessment of gastric emptying have been applied widely. Wagner-Nelson analysis is a pharmacokinetic model that can be utilised to generate a gastric emptying curve from the % CO measured in breath samples. We compared Wagner-Nelson analysis with (i) scintigraphy and (ii) conventional breath test modelling to quantify gastric emptying in type 2 diabetes.
METHODS
Thirteen patients (age 68.1±1.5 years, body mass index 31.0±0.9 kg/m, HbA1c 6.3±0.2%) consumed a mashed potato meal comprising 65 g powdered potato, 20 g glucose, 250 ml water, an egg yolk labelled with 100 μL C-octanoic acid and 20MBq Tc-calcium phytate. Scintigraphic data were acquired and breath samples collected for 4 hours after the meal. Gastric emptying curves were derived based on each technique; the 50% emptying time and intragastric retention at 60 min were also calculated.
RESULTS
With Wagner-Nelson analysis, a K=0.60 (the elimination constant) best approximated the scintigraphic gastric emptying curve. There was a relationship between the T50 calculated with scintigraphy and by both Wagner-Nelson K=0.60 (r=0.45, P<0.05) and conventional analysis (r=0.44, P<0.05). There was no significant difference in the 50% gastric emptying time for scintigraphy (68.5±4.8 min) and Wagner-Nelson K=0.60 (71.3±4.5 min), however, the 50% gastric emptying time calculated by conventional analysis was much greater at 164.7±6.0 min (P<0.001).
CONCLUSION
In type 2 diabetes, gastric emptying of a mashed potato meal measured using a C-octanoic acid breath test analysed with Wagner-Nelson K=0.60 closely reflects measurements obtained with scintigraphy, whereas, in absolute terms, the conventional breath test analysis does not.
Topics: Humans; Aged; Gastric Emptying; Carbon Isotopes; Diabetes Mellitus, Type 2; Breath Tests; Radionuclide Imaging
PubMed: 35231948
DOI: 10.1055/a-1784-6185 -
MSystems Sep 2020Multispecies microbial communities determine the fate of materials in the environment and can be harnessed to produce beneficial products from renewable resources. In a...
Multispecies microbial communities determine the fate of materials in the environment and can be harnessed to produce beneficial products from renewable resources. In a recent example, fermentations by microbial communities have produced medium-chain fatty acids (MCFAs). Tools to predict, assess, and improve the performance of these communities, however, are limited. To provide such tools, we constructed two metabolic models of MCFA-producing microbial communities based on available genomic, transcriptomic, and metabolomic data. The first model is a unicellular model (iFermCell215), while the second model (iFermGuilds789) separates fermentation activities into functional guilds. Ethanol and lactate are fermentation products known to serve as substrates for MCFA production, while acetate is another common cometabolite during MCFA production. Simulations with iFermCell215 predict that low molar ratios of acetate to ethanol favor MCFA production, whereas the products of lactate and acetate coutilization are less dependent on the acetate-to-lactate ratio. In simulations of an MCFA-producing community fed a complex organic mixture derived from lignocellulose, iFermGuilds789 predicted that lactate was an extracellular cometabolite that served as a substrate for butyrate (C4) production. Extracellular hexanoic (C6) and octanoic (C8) acids were predicted by iFermGuilds789 to be from community members that directly metabolize sugars. Modeling results provide several hypotheses that can improve our understanding of microbial roles in an MCFA-producing microbiome and inform strategies to increase MCFA production. Further, these models represent novel tools for exploring the role of mixed microbial communities in carbon recycling in the environment, as well as in beneficial reuse of organic residues. Microbiomes are vital to human health, agriculture, and protecting the environment. Predicting behavior of self-assembled or synthetic microbiomes, however, remains a challenge. In this work, we used unicellular and guild-based metabolic models to investigate production of medium-chain fatty acids by a mixed microbial community that is fed multiple organic substrates. Modeling results provided insights into metabolic pathways of three medium-chain fatty acid-producing guilds and identified potential strategies to increase production of medium-chain fatty acids. This work demonstrates the role of metabolic models in augmenting multi-omic studies to gain greater insights into microbiome behavior.
PubMed: 32994290
DOI: 10.1128/mSystems.00755-20