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Metabolic Engineering May 2015Carboxylic acids are an attractive biorenewable chemical, but as with many biorenewables, their toxicity to microbial biocatalysts limits their fermentative production....
Carboxylic acids are an attractive biorenewable chemical, but as with many biorenewables, their toxicity to microbial biocatalysts limits their fermentative production. While it is generally accepted that membrane damage is the main mechanism of fatty acid toxicity, previous metabolic engineering efforts that increased membrane integrity did not enable increased carboxylic acid production. Here we used an evolutionary approach to improve tolerance to exogenous octanoic acid, with the goal of learning design strategies from this evolved strain. This evolution of an Escherichia coli MG1655 derivative at neutral pH in minimal media produced a strain with increased tolerance not only to octanoic acid, but also to hexanoic acid, decanoic acid, n-butanol and isobutanol. This evolved strain also produced carboxylic acids at a 5-fold higher titer than its parent strain when expressing the Anaerococcus tetradius thioesterase. While it has been previously suggested that intracellular acidification may contribute to carboxylic acid toxicity, we saw no evidence that the evolved strain has increased resistance to this acidification. Characterization of the evolved strain membrane showed that it had significantly altered membrane polarization (fluidity), integrity (leakage) and composition relative to its parent. The changes in membrane composition included a significant increase in average lipid length in a variety of growth conditions, including 30°C, 42°C, carboxylic acid challenge and ethanol challenge. The evolved strain has a more dynamic membrane composition, showing both a larger number of significant changes and larger fold changes in the relative abundance of membrane lipids. These results highlight the importance of the cell membrane in increasing microbial tolerance and production of biorenewable fuels and chemicals.
Topics: Bacterial Proteins; Caprylates; Directed Molecular Evolution; Drug Resistance, Bacterial; Escherichia coli; Firmicutes; Hydrogen-Ion Concentration; Thiolester Hydrolases
PubMed: 25839166
DOI: 10.1016/j.ymben.2015.03.014 -
Nutrition (Burbank, Los Angeles County,... Mar 2024Metabolic disorders and no response to intravenous nutrition because of sepsis have been urgent problems for clinical nutrition support. Enteral nutrition (EN) has been...
OBJECTIVES
Metabolic disorders and no response to intravenous nutrition because of sepsis have been urgent problems for clinical nutrition support. Enteral nutrition (EN) has been an important clinical therapeutic measure in septic patients; however, simple EN has not demonstrated good performance. This study aimed to investigate the effects of different concentrations of octanoic acid (OA)-rich EN on hypercatabolism in endotoxemic rats and test whether OA-rich EN could attenuate hypercatabolism through the acylated ghrelin-proopiomelanocortin (POMC) pathway.
METHODS
Rats were randomly divided into six groups: sham, lipopolysaccharide (LPS), LPS + EN and LPS + EN + OA (0.25, 0.5, and 1 g/kg, respectively) groups to investigate the effects of different concentrations of OA-rich EN on hypercatabolism in endotoxemic rats. The rats were then randomly divided into four groups: sham, LPS, LPS + OA, and LPS + OA + Go-CoA-Tat, to test whether OA-rich EN attenuated hypercatabolism through the acylated ghrelin-POMC pathway. Rats received nutrition support via a gastric tube for 3 d (100 kcal/kg daily). Insulin resistance, muscle protein synthesis and atrophy, inflammatory cytokines, ghrelin in circulation and hypothalamus, ghrelin O-acyltransferase (GOAT), and the adenosine 5'-monophosphate-activated protein kinase (AMPK)-autophagy-POMC pathway were measured.
RESULTS
Compared with simple EN, OA-rich EN promoted the acylation of ghrelin in a dose-dependent manner and attenuated POMC-mediated hypercatabolism in endotoxemic rats. Inhibition of GOAT activity decreased the level of acylated ghrelin and aggravated POMC-mediated hypercatabolism conferred by OA-rich EN.
CONCLUSIONS
OA-rich EN could increase the level of acylated ghrelin and attenuate hypercatabolism through the acylated ghrelin-POMC pathway compared with simple EN in endotoxemic rats.
Topics: Humans; Rats; Animals; Pro-Opiomelanocortin; Lipopolysaccharides; Enteral Nutrition; Ghrelin; Goats; Acylation; Caprylates
PubMed: 38215672
DOI: 10.1016/j.nut.2023.112329 -
Die Naturwissenschaften Feb 2009The mite Varroa destructor Anderson & Trueman is a parasite of the honeybee Apis mellifera L. and represents a major threat for apiculture in the Western world....
The mite Varroa destructor Anderson & Trueman is a parasite of the honeybee Apis mellifera L. and represents a major threat for apiculture in the Western world. Reproduction takes place only inside bee brood cells that are invaded just before sealing; drone cells are preferred over worker cells, whereas queen cells are not normally invaded. Lower incidence of mites in queen cells is at least partly due to the deterrent activity of royal jelly. In this study, the repellent properties of royal jelly were investigated using a lab bioassay. Chemical analysis showed that octanoic acid is a major volatile component of royal jelly; by contrast, the concentration is much lower in drone and worker larval food. Bioassays, carried out under lab conditions, demonstrated that octanoic acid is repellent to the mite. Field studies in bee colonies confirmed that the compound may interfere with the process of cell invasion by the mite.
Topics: Animals; Bees; Caprylates; Fatty Acids; Female; Insect Hormones; Insecticide Resistance; Italy; Larva; Volatile Organic Compounds
PubMed: 19050844
DOI: 10.1007/s00114-008-0470-0 -
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 Neurochemistry Apr 1992Effects of octanoic acid on monoamines and their acidic metabolites in the rat brain were analyzed by HPLC. Octanoic acid (1,000 mg/kg i.p.) elevated homovanillic acid...
Effects of octanoic acid on monoamines and their acidic metabolites in the rat brain were analyzed by HPLC. Octanoic acid (1,000 mg/kg i.p.) elevated homovanillic acid levels by 54% in the caudate and 338% in the hypothalamus but increased 5-hydroxyindoleacetic acid (5-HIAA) levels in both the caudate and the hypothalamus by approximately 50% compared with the control. A lower dose of octanoic acid (500 mg/kg) increased 5-HIAA levels by 29% in the caudate and 20% in the hypothalamus. However, it did not produce any changes in the concentration of homovanillic acid in either the caudate or the hypothalamus. Treatment with octanoic acid also failed to change the level of dopamine, serotonin, and 3,4-dihydroxyphenylacetic acid in the caudate and the hypothalamus. The role of carrier-mediated transport in the clearance of 5-HIAA from the rabbit CSF was also evaluated in vivo by ventriculocisternal perfusion. Steady-state clearance of 5-HIAA from CSF exceeded that of inulin and was reduced in the presence of octanoic acid. Because this transport system in the choroid plexus is normally responsible for the excretion of the serotonin metabolite from the brain to the plasma, accumulation of endogenously produced organic acids in the brain, secondary to reduced clearance by the choroid plexus, could be a contributing factor in the development of encephalopathy in children with medium-chain acyl-CoA dehydrogenase deficiency who have elevated levels of octanoic acid systematically.
Topics: Acids; Animals; Anions; Biogenic Amines; Biological Transport; Brain; Caprylates; Choroid Plexus; Hydroxyindoleacetic Acid; Male; Osmolar Concentration; Rats; Rats, Inbred Strains
PubMed: 1372345
DOI: 10.1111/j.1471-4159.1992.tb11370.x -
Neurology Mar 2013To assess safety and efficacy of an oral, single, low dose of octanoic acid (OA) in subjects with alcohol-responsive essential tremor (ET). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To assess safety and efficacy of an oral, single, low dose of octanoic acid (OA) in subjects with alcohol-responsive essential tremor (ET).
METHODS
We conducted a double-blind, placebo-controlled, crossover, phase I/II clinical trial evaluating the effect of 4 mg/kg OA in 19 subjects with ET. The primary outcome was accelerometric postural tremor power of the dominant hand 80 minutes after administration. Secondary outcomes included digital spiral analysis, pharmacokinetic sampling, as well as safety measures.
RESULTS
OA was safe and well tolerated. Nonserious adverse events were mild (Common Terminology Criteria for Adverse Events grade 1) and equally present after OA and placebo. At the primary outcome, OA effects were not different from placebo. Secondary outcome analyses of digital spiral analysis, comparison across the entire time course in weighted and nonweighted accelerometry, as well as nondominant hand tremor power did not show a benefit of OA over placebo. The analysis of individual time points showed that OA improved tremor at 300 minutes (dominant hand, F = 5.49, p = 0.032 vs placebo), with a maximum benefit at 180 minutes after OA (both hands, F = 6.1, p = 0.025).
CONCLUSIONS
Although the effects of OA and placebo at the primary outcome were not different, secondary outcome measures suggest superiority of OA in reducing tremor at later time points, warranting further trials at higher dose levels.
CLASSIFICATION OF EVIDENCE
This study provides Class I evidence that a single 4-mg/kg dose of OA is not effective in reducing postural tremor in patients with ET at a primary outcome of 80 minutes, but is effective for a secondary outcome after 180 minutes.
Topics: Alcoholic Beverages; Caprylates; Double-Blind Method; Essential Tremor; Female; Humans; Male; Middle Aged; Time
PubMed: 23408867
DOI: 10.1212/WNL.0b013e3182840c4f -
Journal of Biochemical and Molecular... May 2022Rotenone is used to generate Parkinson's disease (PD)-like symptoms in experimental animals. Octanoic acid (C8), is the principal fatty acid of medium-chain...
Rotenone is used to generate Parkinson's disease (PD)-like symptoms in experimental animals. Octanoic acid (C8), is the principal fatty acid of medium-chain triglycerides in ketogenic diets. Beneficial effects of ketogenic diets were shown in PD. We applied proteomic methods to reveal the effects of octanoic acid in rotenone toxicity in zebrafish to gain information on the use of ketogenic diets in PD. Zebrafish were exposed to 5 μg/ml rotenone and octanoic acid (20 and 60 mg/ml) for 30 days. LC-MS/MS analysis was performed. Raw files were analyzed by Proteome Discoverer 2.4 software, peptide lists were searched against Danio rerio proteins. STRING database was used for protein annotations or interactions. 2317 unique proteins were quantified, 302 proteins were differentially expressed. Proteins involved in cell organization, biogenesis, transport, response to stimulus were most frequently expressed. Our study is first to report that the alterations in the expressions of proteins related to energy and redox system, stress response, and cytoskeleton proteins caused by rotenone exposure were normalized by octanoic acid treatment in zebrafish.
Topics: Animals; Caprylates; Chromatography, Liquid; Cytoskeletal Proteins; Cytoskeleton; Oxidation-Reduction; Parkinson Disease; Proteomics; Rotenone; Tandem Mass Spectrometry; Zebrafish
PubMed: 35218269
DOI: 10.1002/jbt.23024 -
Prostaglandins, Leukotrienes, and... Aug 2018Caprylic acid (octanoic acid, C8:0) belongs to the class of medium-chain saturated fatty acids (MCFAs). Dairy products and specific oils such as coconut oil are natural... (Review)
Review
Caprylic acid (octanoic acid, C8:0) belongs to the class of medium-chain saturated fatty acids (MCFAs). Dairy products and specific oils such as coconut oil are natural sources of dietary caprylic acid. MCFAs display distinct chemico-physical and metabolic properties from those of long-chain saturated fatty acids (LCFAs ≥ 12 carbons) and potential beneficial physiological effects of dietary C8:0 have been studied for many years. More recently, caprylic acid was shown to octanoylate ghrelin, the only known peptide hormone with an orexigenic effect. Through its covalent binding to the ghrelin peptide, caprylic acid exhibits an emerging and specific role in modulating physiological functions themselves regulated by octanoylated ghrelin. Dietary caprylic acid is therefore now suspected to provide the ghrelin O-acyltransferase (GOAT) enzyme with octanoyl-CoA co-substrates necessary for the acyl modification of ghrelin. Recent studies suggest that decreasing the circulating octanoylated ghrelin level through the inhibition of GOAT activity, or simply by modulating the availability of its C8:0 substrate, might constitute a therapeutic strategy against obesity. Both dietary caprylic acid availability and GOAT activity may indeed be important to modulate octanoylated ghrelin concentration and functions. This review highlights recent findings in the field of nutrition.
Topics: Acyltransferases; Animals; Caprylates; Coconut Oil; Dairy Products; Dietary Fats; Ghrelin; Humans; Nutritional Status; Obesity
PubMed: 30103923
DOI: 10.1016/j.plefa.2018.07.009 -
PloS One 2013In a previous study, we provided evidence for the presence in hypothalamus and Brockmann bodies (BB) of rainbow trout Oncorhynchus mykiss of sensing systems responding...
In a previous study, we provided evidence for the presence in hypothalamus and Brockmann bodies (BB) of rainbow trout Oncorhynchus mykiss of sensing systems responding to changes in levels of oleic acid (long-chain fatty acid, LCFA) or octanoic acid (medium-chain fatty acid, MCFA). Since those effects could be attributed to an indirect effect, in the present study, we evaluated in vitro if hypothalamus and BB respond to changes in FA in a way similar to that observed in vivo. In a first set of experiments, we evaluated in hypothalamus and BB exposed to increased oleic acic or octanoic acid concentrations changes in parameters related to FA metabolism, FA transport, nuclear receptors and transcription factors, reactive oxygen species (ROS) effectors, components of the KATP channel, and (in hypothalamus) neuropeptides related to food intake. In a second set of experiments, we evaluated in hypothalamus the response of those parameters to oleic acid or octanoic acid in the presence of inhibitors of fatty acid sensing components. The responses observed in vitro in hypothalamus are comparable to those previously observed in vivo and specific inhibitors counteracted in many cases the effects of FA. These results support the capacity of rainbow trout hypothalamus to directly sense changes in MCFA or LCFA levels. In BB increased concentrations of oleic acid or octanoic acid induced changes that in general were comparable to those observed in hypothalamus supporting direct FA sensing in this tissue. However, those changes were not coincident with those observed in vivo allowing us to suggest that the FA sensing capacity of BB previously characterized in vivo is influenced by other neuroendocrine systems.
Topics: Animals; Caprylates; Fatty Acids; Hypothalamus; Oleic Acid; Oncorhynchus mykiss
PubMed: 23533628
DOI: 10.1371/journal.pone.0059507 -
Biological & Pharmaceutical Bulletin Mar 2007Breath test using 13C-labeled compound has been used as a convenient method to evaluate gastric emptying. 13C-Labeled acetic acid or octanoic acid has been used in... (Comparative Study)
Comparative Study
Breath test using 13C-labeled compound has been used as a convenient method to evaluate gastric emptying. 13C-Labeled acetic acid or octanoic acid has been used in clinic. However, there is few report comparing two compounds. This study aimed to compare 13C-acetic acid and 13C-octanoic acid in newly-constituted breath test for monitoring gastric emptying in conscious rats. After fasting, rats were orally administered Racol (liquid enteral nutrient formula) containing 13C-labeled compound (same molar of 13C-acetic acid or 13C-octanoic acid) and housed in a chamber. The expired air in the chamber was collected in a breath-sampling bag using a tube and aspiration pump. The level of 13CO2 in the expired air was measured using an infrared spectrometer at appropriate intervals for 120 min. Expired 13CO2 air from 13C-acetic acid changed at significantly higher levels than that from 13C-octanoic acid. Cmax and AUC120 min values of expired 13CO2 from 13C-acetic acid were significantly higher than those from 13C-octanoic acid, but Tmax was not different between them. These results show that 13C-acetic acid is more sensitive for monitoring gastric emptying than 13C-octanoic acid in liquid test meal although both acids clearly monitored gastric emptying.
Topics: Acetic Acid; Administration, Oral; Animals; Area Under Curve; Breath Tests; Caprylates; Carbon Isotopes; Consciousness; Enteral Nutrition; Gastric Emptying; Male; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Spectrophotometry, Infrared
PubMed: 17329843
DOI: 10.1248/bpb.30.487