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Metabolites Jun 2023Opposing evidence exists for the source of the hydrogen ions (H) during ketoacidosis. Organic and computational chemistry using dissociation constants and alpha...
Opposing evidence exists for the source of the hydrogen ions (H) during ketoacidosis. Organic and computational chemistry using dissociation constants and alpha equations for all pertinent ionizable metabolites were used to (1) document the atomic changes in the chemical reactions of ketogenesis and ketolysis and (2) identify the sources and quantify added fractional (~) H exchange (~He). All computations were performed for pH conditions spanning from 6.0 to 7.6. Summation of the ~He for given pH conditions for all substrates and products of each reaction of ketogenesis and ketolysis resulted in net reaction and pathway ~He coefficients, where negative revealed ~H release and positive revealed ~H uptake. Results revealed that for the liver (pH = 7.0), the net ~He for the reactions of ketogenesis ending in each of acetoacetate (AcAc), β-hydroxybutyrate (β-HB), and acetone were -0.9990, 0.0026, and 0.0000, respectively. During ketogenesis, ~H release was only evident for HMG CoA production, which is caused by hydrolysis and not ~H dissociation. Nevertheless, there is a net ~H release during ketogenesis, though this diminishes with greater proportionality of acetone production. For reactions of ketolysis in muscle (pH = 7.1) and brain (pH = 7.2), net ~H coefficients for β-HB and AcAc oxidation were -0.9649 and 0.0363 (muscle), and -0.9719 and 0.0291 (brain), respectively. The larger ~H release values for β-HB oxidation result from covalent ~H release during the oxidation-reduction. For combined ketogenesis and ketolysis, which would be the metabolic condition in vivo, the net ~H coefficient depends once again on the proportionality of the final ketone body product. For ketone body production in the liver, transference to blood, and oxidation in the brain and muscle for a ratio of 0.6:0.2:0.2 for β-HB:AcAc:acetone, the net ~He coefficients for liver ketogenesis, blood transfer, brain ketolysis, and net total (ketosis) equate to -0.1983, -0.0003, -0.2872, and -0.4858, respectively. The traditional theory of ketone bodies being metabolic acids causing systemic acidosis is incorrect. Summation of ketogenesis and ketolysis yield H coefficients that differ depending on the proportionality of ketone body production, though, in general, there is a small net H release during ketosis. Products formed during ketogenesis (HMG-CoA, acetoacetate, β-hydroxybutyrate) are created as negatively charged bases, not acids, and the final ketone body, acetone, does not have pH-dependent ionizable groups. Proton release or uptake during ketogenesis and ketolysis are predominantly caused by covalent modification, not acid dissociation/association. Ketosis (ketogenesis and ketolysis) results in a net fractional H release. The extent of this release is dependent on the final proportionality between acetoacetate, β-hydroxybutyrate, and acetone.
PubMed: 37512510
DOI: 10.3390/metabo13070803 -
Cureus Jun 2023Ketone bodies are important energy sources for the body and are produced by the liver when the body is in a deficiency state of glucose, which is used in the peripheral...
Ketone bodies are important energy sources for the body and are produced by the liver when the body is in a deficiency state of glucose, which is used in the peripheral tissues to provide energy. There are several ketone bodies that are produced by the liver, of which two are important: acetoacetate and beta-hydroxybutyrate. Even though ketone bodies are always present in the body, they are minimal when a person is not fasting. Ketone bodies are produced by the oxidation of fatty acids to fulfill the metabolic needs of tissues, especially the brain. The biochemical reactions of forming ketone bodies are triggered by a lack of insulin and an elevated glucagon level in the blood. Both cause unopposed lipolysis and free fatty acid oxidation resulting in the production of ketone bodies and eventually high anion gap metabolic acidosis. We present a case of young healthy female who presented with euglycemic ketoacidosis after involving prolonged fasting for her religious ceremony. She also physically exerted quite more during her fasting. With a detailed history and excluding other possibilities, we made the diagnosis of starvation ketoacidosis. She improved well with the treatment and established her pre-morbid condition in our review.
PubMed: 37416003
DOI: 10.7759/cureus.39962 -
Frontiers in Nutrition 2023COVID-19 infection causes cognitive changes in the acute phase, but also after apparent recovery. Over fifty post (long)-COVID symptoms are described, including...
COVID-19 infection causes cognitive changes in the acute phase, but also after apparent recovery. Over fifty post (long)-COVID symptoms are described, including cognitive dysfunction ("brain fog") precluding return to pre-COVID level of function, with rates twice as high in females. Additionally, the predominant demographic affected by these symptoms is younger and still in the workforce. Lack of ability to work, even for six months, has significant socio-economic consequences. This cognitive dysfunction is associated with impaired cerebral glucose metabolism, assessed using F-fluorodeoxyglucose-positron emission tomography (FDG-PET), showing brain regions that are abnormal compared to age and sex matched controls. In other cognitive conditions such as Alzheimer's disease (AD), typical patterns of cerebral glucose hypometabolism, frontal hypometabolism and cerebellar hypermetabolism are common. Similar FDG-PET changes have also been observed in post-COVID-19, raising the possibility of a similar etiology. Ketone bodies (B-hydroxybutyrate, acetoacetate and acetone) are produced with very low carbohydrate intake or fasting. They improve brain energy metabolism in the face of cerebral glucose hypometabolism in other conditions [mild cognitive impairment (MCI) and AD]. Long-term low carbohydrate intake or prolonged fasting is not usually feasible. Medium chain triglyceride (MCT) is an route to nutritional ketosis. Research has supported their efficacy in managing intractable seizures, and cognitive impairment in MCI and AD. We hypothesize that cerebral glucose hypometabolism associated with post COVID-19 infection can be mitigated with MCT supplementation, with the prediction that cognitive function would also improve. Although there is some suggestion that post COVID-19 cognitive symptoms may diminish over time, in many individuals this may take more than six months. If MCT supplementation is able to speed the cognitive recovery, this will impact importantly on quality of life. MCT is readily available and, compared to pharmaceutical interventions, is cost-effective. Research shows general tolerability with dose titration. MCT is a component of enteral and parenteral nutrition supplements, including in pediatrics, so has a long record of safety in vulnerable populations. It is not associated with weight gain or adverse changes in lipid profiles. This hypothesis serves to encourage the development of clinical trials evaluating the impact of MCT supplementation on the duration and severity of post COVID-19 cognitive symptoms.
PubMed: 37415915
DOI: 10.3389/fnut.2023.1126534 -
Frontiers in Nutrition 2023The New Nordic Diet (NND) has been shown to promote weight loss and lower blood pressure amongst obese people. This study investigates blood plasma metabolite and...
SCOPE
The New Nordic Diet (NND) has been shown to promote weight loss and lower blood pressure amongst obese people. This study investigates blood plasma metabolite and lipoprotein biomarkers differentiating subjects who followed Average Danish Diet (ADD) or NND. The study also evaluates how the individual response to the diet is reflected in the metabolic differences between NND subjects who lost or maintained their pre-intervention weight.
METHODS
Centrally obese Danes (BMI >25) followed NND (90 subjects) or ADD (56 subjects) for 6 months. Fasting blood plasma samples, collected at three time-points during the intervention, were screened for metabolites and lipoproteins (LPs) using proton nuclear magnetic resonance spectroscopy. In total, 154 metabolites and 65 lipoproteins were analysed.
RESULTS
The NND showed a relatively small but significant effect on the plasma metabolome and lipoprotein profiles, with explained variations ranging from 0.6% for lipoproteins to 4.8% for metabolites. A total of 38 metabolites and 11 lipoproteins were found to be affected by the NND. The primary biomarkers differentiating the two diets were found to be HDL-1 cholesterol, apolipoprotein A1, phospholipids, and ketone bodies (3-hydroxybutyric acid, acetone, and acetoacetic acid). The increased levels of ketone bodies detected in the NND group inversely associated with the decrease in diastolic blood pressure of the NND subjects. The study also showed that body weight loss among the NND subjects was weakly associated with plasma levels of citrate.
CONCLUSION
The main plasma metabolites associated with NND were acetate, methanol and 3-hydroxybutyrate. The metabolic changes associated with the NND-driven weight loss are mostly pronounced in energy and lipid metabolism.
PubMed: 37396134
DOI: 10.3389/fnut.2023.1198531 -
Advanced Science (Weinheim,... Sep 2023Ketone bodies have long been known as a group of lipid-derived alternative energy sources during glucose shortages. Nevertheless, the molecular mechanisms underlying...
Ketone bodies have long been known as a group of lipid-derived alternative energy sources during glucose shortages. Nevertheless, the molecular mechanisms underlying their non-metabolic functions remain largely elusive. This study identified acetoacetate as the precursor for lysine acetoacetylation (Kacac), a previously uncharacterized and evolutionarily conserved histone post-translational modification. This protein modification is comprehensively validated using chemical and biochemical approaches, including HPLC co-elution and MS/MS analysis using synthetic peptides, Western blot, and isotopic labeling. Histone Kacac can be dynamically regulated by acetoacetate concentration, possibly via acetoacetyl-CoA. Biochemical studies show that HBO1, traditionally known as an acetyltransferase, can also serve as an acetoacetyltransferase. In addition, 33 Kacac sites are identified on mammalian histones, depicting the landscape of histone Kacac marks across species and organs. In summary, this study thus discovers a physiologically relevant and enzymatically regulated histone mark that sheds light on the non-metabolic functions of ketone bodies.
Topics: Animals; Histones; Lysine; Acetoacetates; Tandem Mass Spectrometry; Protein Processing, Post-Translational; Mammals
PubMed: 37382194
DOI: 10.1002/advs.202300032 -
Molecules (Basel, Switzerland) Jun 2023Pyrimidines play an important role in modern medical fields. They have a wide spectrum of biological activities such as antimicrobial, anticancer, anti-allergic,...
Pyrimidines play an important role in modern medical fields. They have a wide spectrum of biological activities such as antimicrobial, anticancer, anti-allergic, anti-leishmanial, antioxidant agents and others. Moreover, in recent years, 3,4-dihydropyrimidin-2(1H)ones have attracted researchers to synthesize them via Biginelli reaction and evaluate their antihypertensive activities as bioisosters of Nifedipine, which is a famous calcium channel blocker. Our new target compounds were prepared through one-pot reaction of thiourea , ethyl acetoacetate and/or 1H-indole-2-carbaldehyde, 2-chloroquinoline-3-carbaldehyde, 1,3-diphenyl-1H-pyrazole-4-carbaldehyde, - in acid medium (HCl) yielding pyrimidines -, which in turn were hydrolyzed to carboxylic acid derivatives - which were chlorinated by SOCl to give acyl chlorides -. Finally, the latter were reacted with some selected aromatic amines, namely, aniline, p-toluidine and p-nitroaniline, producing amides -- and -. The purity of the prepared compounds was examined via TLC monitoring, and structures were confirmed by different spectroscopic techniques such as IR, HNMR, CNMR, and mass spectroscopy. The in vivo evaluation of the antihypertensive activity revealed that compounds and had comparable antihypertensive properties with Nifedipine. On the other hand, the in vitro calcium channel blocking activity was evaluated by IC measurement and results revealed that compounds and had comparable calcium channel blocking activity with the reference Nifedipine. Based on the aforementioned biological results, we selected compounds and to be docked onto Ryanodine and dihydropyridine receptors. Furthermore, we developed a structure-activity relationship. The designed compounds in this study show promising activity profiles in reducing blood pressure and as calcium channel blockers, and could be considered as new potential antihypertensive and/or antianginal agents.
Topics: Calcium Channel Blockers; Antihypertensive Agents; Nifedipine; Structure-Activity Relationship; Pyrimidines; Calcium Channels; Molecular Structure
PubMed: 37375424
DOI: 10.3390/molecules28124869 -
Metabolites May 2023Insights into the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness, point towards a complex interplay of genetic and lifestyle...
Insights into the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness, point towards a complex interplay of genetic and lifestyle factors triggering various systemic pathways. This study aimed to characterize metabolomic profiles for AMD and to evaluate their position in the trias with genetics and lifestyle. This study included 5923 individuals from five European studies. Blood metabolomics were assessed using a nuclear magnetic resonance platform of 146 metabolites. Associations were studied using regression analyses. A genetic risk score (GRS) was calculated using β-values of 49 AMD variants, a lifestyle risk score (LRS) using smoking and diet data, and a metabolite risk score (MRS) using metabolite values. We identified 61 metabolites associated with early-intermediate AMD, of which 94% were lipid-related, with higher levels of HDL-subparticles and apolipoprotein-A1, and lower levels of VLDL-subparticles, triglycerides, and fatty acids (false discovery rate (FDR) -value < 1.4 × 10). Late AMD was associated with lower levels of the amino acids histidine, leucine, valine, tyrosine, and phenylalanine, and higher levels of the ketone bodies acetoacetate and 3-hydroxybutyrate (FDR -value < 1.5 × 10). A favorable lifestyle characterized by a healthy diet was associated with higher levels of amino acids and lower levels of ketone bodies, while an unfavorable lifestyle, including smoking, showed opposite effects (FDR -value < 2.7 × 10). The MRS mediated 5% of the effect of the GRS and 20% of that of the LRS on late AMD. Our findings show that metabolomic profiles differ between AMD stages and show that blood metabolites mostly reflect lifestyle. The severity-specific profiles spur further interest into the systemic effects related to disease conversion.
PubMed: 37367859
DOI: 10.3390/metabo13060701 -
Journal of Lipid Research Aug 2023Acetoacetyl-CoA synthetase (AACS) is the key enzyme in the anabolic utilization of ketone bodies (KBs) for denovo lipid synthesis, a process that bypasses citrate and... (Review)
Review
Acetoacetyl-CoA synthetase (AACS) is the key enzyme in the anabolic utilization of ketone bodies (KBs) for denovo lipid synthesis, a process that bypasses citrate and ATP citrate lyase. This review shows that AACS is a highly regulated, cytosolic, and lipogenic enzyme and that many tissues can readily use KBs for denovo lipid synthesis. AACS has a low micromolar K for acetoacetate, and supply of acetoacetate should not limit its activity in the fed state. In many tissues, AACS appears to be regulated in conjunction with the need for cholesterol, but in adipose tissue, it seems tied to fatty acid synthesis. KBs are readily utilized as substrates for lipid synthesis in lipogenic tissues, including liver, adipose tissue, lactating mammary gland, skin, intestinal mucosa, adrenals, and developing brain. In numerous studied cases, KBs served several-fold better than glucose as substrates for lipid synthesis, and when present, KBs suppressed the utilization of glucose for lipid synthesis. Here, it is hypothesized that a physiological role for the utilization of KBs for lipid synthesis is a metabolic process of lipid interconversion. Fatty acids are converted to KBs in liver, and then, the KBs are utilized to synthesize cholesterol and other long-chain fatty acids in liver and nonhepatic tissues. The conversion of fatty acids to cholesterol via the KBs may be a particularly important example of lipid interconversion. Utilizing KBs for lipid synthesis is glucose sparing and probably is important with low carbohydrate diets. Metabolic situations and tissues where this pathway may be important are discussed.
Topics: Female; Humans; Acetoacetates; Lactation; Ketone Bodies; Fatty Acids; Liver; Cholesterol; Glucose
PubMed: 37356666
DOI: 10.1016/j.jlr.2023.100407 -
Diabetes Sep 2023With rising incidence and prevalence of type 2 diabetes, prevention including identification of prospective biomarkers becomes increasingly relevant. Although ketone...
UNLABELLED
With rising incidence and prevalence of type 2 diabetes, prevention including identification of prospective biomarkers becomes increasingly relevant. Although ketone bodies recently received a renewed interest as potential biomarkers, data linking these metabolites to diabetes risk are scarce. Therefore, the present prospective study investigated a potential association between fasting ketone bodies and incident type 2 diabetes in the general population. This study from the PREVEND cohort included 3,307 participants from the general population initially free of diabetes or impaired fasting glucose. Baseline fasting ketone body concentrations were measured by nuclear magnetic resonance spectroscopy. One hundred twenty-six participants (3.8%) developed type 2 diabetes during a median (interquartile range) follow-up of 7.3 (6.3-7.6) years. In Kaplan-Meier analysis, sex-stratified ketone body levels strongly positively associated with incident type 2 diabetes, which was confirmed in Cox regression analyses adjusted for several potential confounders. There was no significant interaction by sex. Both 3-β-hydroxybutyrate and acetoacetate+acetone individually associated with incident type 2 diabetes. In conclusion, fasting plasma ketone body levels are strongly positively associated with incident type 2 diabetes in the general population independent of several other recognized risk factors. These results may have important implications for diabetes prevention including dietary strategies.
ARTICLE HIGHLIGHTS
The identification of biomarkers that predict type 2 diabetes is increasingly relevant for personalized medicine strategies. Data regarding ketone bodies and incident type 2 diabetes are scarce. This study shows that ketone bodies, either combined or as individual subspecies, are strongly associated with incident type 2 diabetes in the general population, independent of potential confounders. These results may have important implications for diabetes prevention including dietary strategies.
Topics: Humans; Diabetes Mellitus, Type 2; Ketone Bodies; Blood Glucose; Prospective Studies; 3-Hydroxybutyric Acid; Fasting; Biomarkers
PubMed: 37352012
DOI: 10.2337/db22-0826 -
Frontiers in Psychiatry 2023Increasing evidence indicates that metabolites are closely related to human diseases. Identifying disease-related metabolites is especially important for the diagnosis...
BACKGROUND
Increasing evidence indicates that metabolites are closely related to human diseases. Identifying disease-related metabolites is especially important for the diagnosis and treatment of disease. Previous works have mainly focused on the global topological information of metabolite and disease similarity networks. However, the local tiny structure of metabolites and diseases may have been ignored, leading to insufficiency and inaccuracy in the latent metabolite-disease interaction mining.
METHODS
To solve the aforementioned problem, we propose a novel metabolite-disease interaction prediction method with logical matrix factorization and local nearest neighbor constraints (LMFLNC). First, the algorithm constructs metabolite-metabolite and disease-disease similarity networks by integrating multi-source heterogeneous microbiome data. Then, the local spectral matrices based on these two networks are established and used as the input of the model, together with the known metabolite-disease interaction network. Finally, the probability of metabolite-disease interaction is calculated according to the learned latent representations of metabolites and diseases.
RESULTS
Extensive experiments on the metabolite-disease interaction data were conducted. The results show that the proposed LMFLNC method outperformed the second-best algorithm by 5.28 and 5.61% in the AUPR and F1, respectively. The LMFLNC method also exhibited several potential metabolite-disease interactions, such as "Cortisol" (HMDB0000063), relating to "21-Hydroxylase deficiency," and "3-Hydroxybutyric acid" (HMDB0000011) and "Acetoacetic acid" (HMDB0000060), both relating to "3-Hydroxy-3-methylglutaryl-CoA lyase deficiency."
CONCLUSION
The proposed LMFLNC method can well preserve the geometrical structure of original data and can thus effectively predict the underlying associations between metabolites and diseases. The experimental results show its effectiveness in metabolite-disease interaction prediction.
PubMed: 37342171
DOI: 10.3389/fpsyt.2023.1149947