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Neurology Oct 2021A monogenic etiology can be identified in up to 40% of people with severe epilepsy. To address earlier and more appropriate treatment strategies, clinicians are required... (Review)
Review
A monogenic etiology can be identified in up to 40% of people with severe epilepsy. To address earlier and more appropriate treatment strategies, clinicians are required to know the implications that specific genetic causes might have on pathophysiology, natural history, comorbidities, and treatment choices. In this narrative review, we summarize concepts on the genetic epilepsies based on the underlying pathophysiologic mechanisms and present the current knowledge on treatment options based on evidence provided by controlled trials or studies with lower classification of evidence. Overall, evidence robust enough to guide antiseizure medication (ASM) choices in genetic epilepsies remains limited to the more frequent conditions for which controlled trials and observational studies have been possible. Most monogenic disorders are very rare and ASM choices for them are still based on inferences drawn from observational studies and early, often anecdotal, experiences with precision therapies. Precision medicine remains applicable to only a narrow number of patients with monogenic epilepsies and may target only part of the actual functional defects. Phenotypic heterogeneity is remarkable, and some genetic mutations activate epileptogenesis through their developmental effects, which may not be reversed postnatally. Other genes seem to have pure functional consequences on excitability, acting through either loss- or gain-of-function effects, and these may have opposite treatment implications. In addition, the functional consequences of missense mutations may be difficult to predict, making precision treatment approaches considerably more complex than estimated by deterministic interpretations. Knowledge of genetic etiologies can influence the approach to surgical treatment of focal epilepsies. Identification of germline mutations in specific genes contraindicates surgery while mutations in other genes do not. Identification, quantification, and functional characterization of specific somatic mutations before surgery using CSF liquid biopsy or after surgery in brain specimens will likely be integrated in planning surgical strategies and reintervention after a first unsuccessful surgery as initial evidence suggests that mutational load may correlate with the epileptogenic zone. Promising future directions include gene manipulation by DNA or mRNA targeting; although most are still far from clinical use, some are in early phase clinical development.
Topics: Anticonvulsants; Epilepsy; Genetic Predisposition to Disease; Humans; Molecular Targeted Therapy; Precision Medicine
PubMed: 34493617
DOI: 10.1212/WNL.0000000000012744 -
Nutrients Oct 2023Coronary artery disease (CAD) is a cardiovascular disease with significant personal health and socioeconomic consequences. The biological functions of decanoic acid and...
BACKGROUND
Coronary artery disease (CAD) is a cardiovascular disease with significant personal health and socioeconomic consequences. The biological functions of decanoic acid and the pathogenesis of CAD overlap considerably; however, studies exploring their relationship are limited.
METHODS
Data from 34,186 Americans from the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2018 were analyzed. The relationship between dietary decanoic acid (DDA) and CAD prevalence was explored using weighted multivariate logistic regression models, generalized summation models, and fitted smoothing curves. Stratified analyses and interaction tests were conducted to explore the potential modifiers between them.
RESULTS
DDA was negatively associated with CAD prevalence, with each 1 g/d increase in the DDA being associated with a 21% reduction in CAD prevalence (odds ratio (OR) 0.79, 95% confidence interval (CI) 0.61-1.02). This relationship persisted after log10 and trinomial transformations, respectively. The OR after log10 transformation was 0.81 (95% CI 0.69-0.96), and the OR for tertile 3 compared with tertile 1 was 0.83 (95% CI 0.69-1.00). The subgroup analyses found this relationship to be significant among males and non-Hispanic white individuals, and there was a significant interaction (interaction -values of 0.011 and 0.012, respectively).
CONCLUSIONS
DDA was negatively associated with the prevalence of CAD, and both sex and race may modify this relationship.
Topics: Male; Humans; Coronary Artery Disease; Cross-Sectional Studies; Nutrition Surveys; Cardiovascular Diseases; Risk Factors
PubMed: 37892384
DOI: 10.3390/nu15204308 -
Proceedings of the National Academy of... Sep 2020Low-glucose and -insulin conditions, associated with ketogenic diets, can reduce the activity of the mechanistic target of rapamycin complex 1 (mTORC1) signaling...
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, , 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 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.
Topics: Adaptor Proteins, Signal Transducing; Animals; Astrocytes; Cell Cycle Proteins; Cells, Cultured; Decanoic Acids; Dictyostelium; Epilepsy; Glucose; Hippocampus; Humans; Insulin; Mechanistic Target of Rapamycin Complex 1; Peptide Initiation Factors; Phosphorylation; Rats
PubMed: 32879008
DOI: 10.1073/pnas.2008980117 -
Cells Oct 2021Ketogenic diets, used in epilepsy treatment, are considered to work through reduced glucose and ketone generation to regulate a range of cellular process including...
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 , 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.
Topics: Autophagosomes; Autophagy; Decanoic Acids; Dictyostelium; Phosphatidylinositol Phosphates; Proto-Oncogene Proteins c-akt
PubMed: 34831171
DOI: 10.3390/cells10112946 -
Frontiers in Nutrition 2021Medium-chain triacylglycerides (MCTs) are dietary supplements that can induce ketosis without the need for a traditional ketogenic diet or prolonged fasting. They have... (Review)
Review
Medium-chain triacylglycerides (MCTs) are dietary supplements that can induce ketosis without the need for a traditional ketogenic diet or prolonged fasting. They have the potential to marginally delay the progression of neurodegenerative diseases, such as Alzheimer's disease. However, there have been inconsistencies in reports of the MCT dose-response relationship, which may be due to differences in MCT composition, participant characteristics, and other factors that can influence ketone generation. To resolve these discrepancies, we reviewed studies that investigated the ketogenic effect of MCTs in healthy adults. Aside from the treatment dose, other factors that can influence the ketogenic response, such as accompanying meals, fasting duration, and caffeine intake, were assessed. Based on the available literature, four practical recommendations are made to optimize the ketogenic effect of MCTs and reduce unwanted side effects (primarily gastrointestinal discomfort and diarrhea). First, the starting dose should be either 5 g of octanoic acid [caprylic acid (C8); a component of MCTs] or 5 g of a combination of C8 and decanoic or capric acid (C10; another component of MCTs), and the dose should be progressively increased to 15-20 g of C8. Second, MCTs should be consumed after an overnight fast, without an accompanying meal if tolerable, or with a low-carbohydrate meal. Third, the addition of caffeine may slightly increase the ketogenic response. Fourth, emulsifying the MCTs might increase their ketogenic effect and alleviate side effects.
PubMed: 34888335
DOI: 10.3389/fnut.2021.747284 -
AMB Express May 2018Biotransformation of fatty acid methyl esters to dicarboxylic acids has attracted much attention in recent years; however, reports of sebacic acid production using such...
Biotransformation of fatty acid methyl esters to dicarboxylic acids has attracted much attention in recent years; however, reports of sebacic acid production using such biotransformation remain few. The toxicity of decanoic acid is the main challenge for this process. Decane induction has been reported to be essential to activate the enzymes involved in the α,ω-oxidation pathway before initiating the biotransformation of methyl decanoate to sebacic acid. However, we observed the accumulation of intermediates (decanoic acid and 10-hydroxydecanoic acid) during the induction period. In this study, we examined the effects of these intermediates on the biotransformation process. The presence of decanoic acid, even at a low concentration (0.2 g/L), inhibited the transformation of 10-hydroxydecanoic acid to sebacic acid. Moreover, about 24-32% reduction in the decanoic acid oxidation was observed in the presence of 0.5-1.5 g/L 10-hydroxydecanoic acid. To eliminate these inhibitory effects, we applied substrate-limiting conditions during the decane induction process, which eliminated the accumulation of decanoic acid. Although the productivity of sebacic acid (34.5 ± 1.10 g/L) was improved, by 28% over that achieved using the previously methods, after 54 h, the accumulation of 10-hydroxydecanoic acid was still detected. The accumulation of 10-hydroxydecanoic acid even under the decane limiting conditions could be an evidence that oxidation of 10-hydroxydecanoic acid could be the rate-limiting step in this process. The improvement of this reaction should be an important objective for further development of the production of sebacic acid using biotransformation.
PubMed: 29730843
DOI: 10.1186/s13568-018-0605-4 -
Scientific Reports Mar 2021Enhanced oxidative stress is a contributing factor in the pathogenesis of several neurodegenerative disorders such as Alzheimer´s disease. Beneficial effects have been...
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 HO 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 HO-induced cell death. It did not affect the level of the ketone body β-hydroxybutyrate (βHB). 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.
Topics: Animals; Cell Line, Tumor; Decanoic Acids; Fatty Acids; Humans; Lipid Metabolism; Mice; Neuroblastoma; Oxidative Stress; Triglycerides
PubMed: 33731759
DOI: 10.1038/s41598-021-85523-9 -
Biomolecules Sep 2023Alzheimer's disease (AD), a devastating neurodegenerative disease characterized by cognitive dysfunctions, is associated with high levels of amyloid beta 42 (Aβ), which...
Alzheimer's disease (AD), a devastating neurodegenerative disease characterized by cognitive dysfunctions, is associated with high levels of amyloid beta 42 (Aβ), which is believed to play a role in cellular damage and signaling changes in AD. Decanoic acid has been shown to be therapeutic in AD. Glutamatergic signaling within neurons and astrocytes of the CA1 region of the hippocampus is critical in cognitive processes, and previous work has indicated deficiencies in this signaling in a mouse model of AD. In this study, we investigated glutamate-mediated signaling by evaluating AMPA-mediated calcium rises in female and male CA1 neurons and astrocytes in a mouse model of AD and examined the potential of decanoic acid to normalize this signaling. In brain slices from 5xFAD mice in which there are five mutations leading to increasing levels of Aβ, AMPA-mediated calcium transients in CA1 neurons and astrocytes were significantly lower than that seen in wildtype controls in both females and males. Interestingly, incubation of 5xFAD slices in decanoic acid restored AMPA-mediated calcium levels in neurons and astrocytes in both females and males to levels indistinguishable from those seen in wildtype, whereas similar exposure to decanoic acid did not result in changes in AMPA-mediated transients in neurons or astrocytes in either sex in the wildtype. Our data indicate that one mechanism by which decanoic acid could improve cognitive functioning is through normalizing AMPA-mediated signaling in CA1 hippocampal cells.
Topics: Male; Mice; Female; Animals; Alzheimer Disease; Amyloid beta-Peptides; Astrocytes; Calcium; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Neurodegenerative Diseases; Hippocampus; Neurons; Disease Models, Animal
PubMed: 37892143
DOI: 10.3390/biom13101461 -
Frontiers in Neuroscience 2020Medium-chain fatty acids (MCFA) are dietary components with a chain length ranging from 6 to 12 carbon atoms. MCFA can cross the blood-brain barrier and in the brain can...
Medium-chain fatty acids (MCFA) are dietary components with a chain length ranging from 6 to 12 carbon atoms. MCFA can cross the blood-brain barrier and in the brain can be oxidized through mitochondrial β-oxidation. As components of ketogenic diets, MCFA have demonstrated beneficial effects on different brain diseases, such as traumatic brain injury, Alzheimer's disease, drug-resistant epilepsy, diabetes, and cancer. Despite the interest in MCFA effects, not much information is available about MCFA metabolism in the brain. In this study, with a gas chromatography-mass spectrometry (GC-MS)-based metabolomics approach, coupled with multivariate data analyses, we followed the metabolic changes of U87MG glioblastoma cells after the addition of octanoic (C8), or decanoic (C10) acids for 24 h. Our analysis highlighted significant differences in the metabolism of U87MG cells after the addition of C8 or C10 and identified several metabolites whose amount changed between the two groups of treated cells. Overall, metabolic pathway analyses suggested the citric acid cycle, Warburg effect, glutamine/glutamate metabolism, and ketone body metabolism as pathways influenced by C8 or C10 addition to U87MG cells. Our data demonstrated that, while C8 affected mitochondrial metabolism resulting in increased ketone body production, C10 mainly influenced cytosolic pathways by stimulating fatty acid synthesis. Moreover, glutamine might be the main substrate to support fatty acids synthesis in C10-treated cells. In conclusion, we identified a metabolic signature associated with C8 or C10 addition to U87MG cells that can be used to decipher metabolic responses of glioblastoma cells to MCFA treatment.
PubMed: 32792906
DOI: 10.3389/fnins.2020.00783 -
Pathogens (Basel, Switzerland) Jan 2022This study aims to investigate six food additives (octanoic acid, decanoic acid, acesulfame K, aspartame, saccharin, and sucralose) used in foods for the elderly or...
This study aims to investigate six food additives (octanoic acid, decanoic acid, acesulfame K, aspartame, saccharin, and sucralose) used in foods for the elderly or people with dysphagia because of the effect of these food additives on (), which is a keystone pathogen of periodontal diseases. The growth of was inhibited by 5 mM octanoic acid, 1.25 mM decanoic acid, 1.25% acesulfame K, 0.0625% aspartame, 0.03125% saccharin, and 0.625% sucralose. In addition, these food additives showed bactericidal activity for planktonic (5 mM octanoic acid, 5 mM decanoic acid, 0.25% aspartame, 0.25% saccharin, and 5% sucralose). Moreover, biofilm formation was inhibited by 10 mM octanoic acid, 10 mM decanoic acid, 10% acesulfame K, 0.35% aspartame, 0.5% saccharin, and 7.5% sucralose. Moreover, the same concentration of these food additives without aspartame killed in the biofilm. Aspartame and sucralose did not show cytotoxicity to human cell lines at concentrations that affected These findings may be useful in clarifying the effects of food additives on periodontopathogenic bacteria.
PubMed: 35056013
DOI: 10.3390/pathogens11010065