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Heliyon Nov 2023Ketone bodies are pleotropic metabolites that play important roles in multiple biological processes ranging from bioenergetics to inflammation regulation via suppression...
BACKGROUND
Ketone bodies are pleotropic metabolites that play important roles in multiple biological processes ranging from bioenergetics to inflammation regulation via suppression of the NLRP3 inflammasome, and epigenetic modifications. Ketone bodies are elevated in left ventricular failure (LVF) and multiple approaches that increase ketone concentrations exert advantageous cardiac effects in rodents and humans. However, the relationships between ketone bodies and right ventricular failure (RVF) are relatively unexplored.
METHODS
51 PAH patients were dichotomized into preserved or impaired RV function based on a cardiac index of 2.2 L/min/m. Impaired RV function patients were further segmented into intermediate or severe RV dysfunction based on a right atrial pressure of 8 mm Hg. Serum ketone bodies acetoacetate (AcAc) and beta-hydroxybutyrate (βOHB) were quantified using ultra performance liquid chromatography and mass spectrometry. In rodent studies, male Sprague Dawley rats were assigned to three groups: control (saline injection), monocrotaline (MCT) standard chow diet (MCT-Standard), and MCT ketogenic diet (MCT-Keto). Immunoblots and confocal microscopy probed macrophage NLRP3 activation in RV extracts and sections. RV fibrosis was determined by Picrosirus Red. Echocardiography evaluated RV function. Pulmonary arteriole remodeling was assessed from histological specimens.
RESULTS
Human RVF patients lacked a compensatory ketosis as serum AcAc and βOHB levels were not associated with hemodynamic, echocardiographic, or biochemical measures of RV dysfunction. In rodent studies, AcAc and βOHB levels were also not elevated in MCT-mediated RVF, but the ketogenic diet significantly increased AcAc and βOHB levels. MCT-Keto exhibited suppressed NLRP3 activation with a reduction in NLRP3, ASC (apoptosis-associated speck-like protein), pro-caspase-1, and interleukin-1 beta on immunoblots. Moreover, the number of ASC-positive macrophage in RV sections was reduced, RV fibrosis was blunted, and RV function was augmented in MCT-Keto rats.
CONCLUSION
The ketogenic response is blunted in pulmonary arterial hypertension (PAH) patients with RVF. In the MCT rat model of PAH-mediated RVF, a dietary-induced ketosis improves RV function, suppresses NLRP3 inflammasome activation, and combats RV fibrosis. The summation of these data suggest ketogenic therapies may be particularly efficacious in RVF, and therefore future studies evaluating ketogenic interventions in human RVF are warranted.
PubMed: 38058654
DOI: 10.1016/j.heliyon.2023.e22227 -
Frontiers in Bioengineering and... 2023Acetate is a low-cost feedstock for the production of different bio-chemicals. Electrochemical reduction of CO into acetate and subsequent acetate fermentation is a...
Acetate is a low-cost feedstock for the production of different bio-chemicals. Electrochemical reduction of CO into acetate and subsequent acetate fermentation is a promising method for transforming CO into value-added chemicals. However, the significant inhibitory effect of acetate on microbial growth remains a barrier for acetate-based biorefinery. In this study, the deletion of genes involved in L-leucine degradation was found to be beneficial for the growth of A1501 in acetate. (Δ), in which the hydroxymethylglutaryl-CoA lyase catalyzing -hydroxy--methylglutaryl-CoA into acetyl-CoA and acetoacetate was deleted, grew faster than other mutants and exhibited increased tolerance to acetate. Then, the genes from H16 for poly-3-hydroxybutyrate (PHB) biosynthesis were overexpressed in (∆) and the recombinant strain (∆-) can accumulate 0.11 g L PHB from commercial acetate. Importantly, (∆-) can also use CO-derived acetate to produce PHB and the accumulated PHB accounted for 5.42% (w/w) of dried cell weight of (∆-).
PubMed: 38026858
DOI: 10.3389/fbioe.2023.1297431 -
Aging Nov 2023A ketogenic diet (KD) and β-hydroxybutyrate (βOHB) have been widely reported as effective therapies for metabolic diseases. β-Hydroxybutyrate dehydrogenase 1 (BDH1)...
A ketogenic diet (KD) and β-hydroxybutyrate (βOHB) have been widely reported as effective therapies for metabolic diseases. β-Hydroxybutyrate dehydrogenase 1 (BDH1) is the rate-limiting enzyme in ketone metabolism. In this study, we examined the BDH1-mediated βOHB metabolic pathway in the pathogenesis of diabetic kidney disease (DKD). We found that BDH1 is downregulated in the kidneys in DKD mouse models, patients with diabetes, and high glucose- or palmitic acid-induced human renal tubular epithelial (HK-2) cells. BDH1 overexpression or βOHB treatment protects HK-2 cells from glucotoxicity and lipotoxicity by inhibiting reactive oxygen species overproduction. Mechanistically, BDH1-mediated βOHB metabolism activates NRF2 by enhancing the metabolic flux of βOHB-acetoacetate-succinate-fumarate. Moreover, studies showed that adeno-associated virus 9-mediated BDH1 renal expression successfully reverses fibrosis, inflammation, and apoptosis in the kidneys of C57 BKS mice. Either βOHB supplementation or KD feeding could elevate the renal expression of BDH1 and reverse the progression of DKD. Our results revealed a BDH1-mediated molecular mechanism in the pathogenesis of DKD and identified BDH1 as a potential therapeutic target for DKD.
Topics: Animals; Humans; Mice; 3-Hydroxybutyric Acid; Antioxidants; Diabetes Mellitus; Diabetic Nephropathies; Kidney; NF-E2-Related Factor 2; Hydroxybutyrate Dehydrogenase
PubMed: 38015723
DOI: 10.18632/aging.205248 -
Molecules (Basel, Switzerland) Nov 2023In this investigation, 4-antipyrinecarboxaldhyde was reacted with methyl hydrazinecarbodithioate to afford the carbodithioate derivative . The as-prepared carbodithioate...
In this investigation, 4-antipyrinecarboxaldhyde was reacted with methyl hydrazinecarbodithioate to afford the carbodithioate derivative . The as-prepared carbodithioate derivative is considered to be a key molecule for the preparation of new antipyrine-1,3,4-thiadiazole-based molecules (-) through its reaction with the appropriate hydrazonoyl halides. Furthermore, a typical Biginelli three-component cyclocondensation reaction involving ethyl acetoacetate, 4-antipyrinecarboxaldhyde, and thiourea under the standard conditions is carried out in the presence of sulfuric acid to afford the corresponding antipyrine-pyrimidine hybrid molecule (). The latter was submitted to react with hydrazine monohydrate to provide the corresponding hydrazide derivative () which, under reaction with ethyl acetoacetate in refluxing ethanol containing catalytic amount of acetic acid, afforded the corresponding derivative (). The structure of the newly synthesized compounds was affirmed by their spectral and microanalytical data. We also screened for their antimicrobial potential (ZOI and MIC) and conducted a kinetic study. Additionally, the mechanism of biological action was assessed by a membrane leakage assay and SEM imaging technique. Moreover, the biological activities and the binding modes of these compounds were further supplemented by an in silico docking study against β-carbonic anhydrase. The amount of cellular protein released by is directly correlated to the concentration of compound , which was found to be 177.99 µg/mL following treatment with 1.0 mg/mL of compound . This finding supports compound 's antibacterial properties and explains how the formation of holes in the cell membrane results in the release of proteins from the cytoplasm. The newly synthesized compounds represent acceptable antimicrobial activities with potential action against β-carbonic anhydrase. The docking studies and antimicrobial activity test proved that compound () declared a greater activity than the other synthesized compounds.
Topics: Escherichia coli; Antipyrine; Carbonic Anhydrases; Anti-Infective Agents; Molecular Docking Simulation; Structure-Activity Relationship; Molecular Structure; Carbonic Anhydrase Inhibitors
PubMed: 38005213
DOI: 10.3390/molecules28227491 -
Metabolic Brain Disease Jan 2024To study the effects of different types of exercise on the plasma metabolomics of chronic unpredictable mild stress (CUMS)-induced depressed rats based on H-NMR...
To study the effects of different types of exercise on the plasma metabolomics of chronic unpredictable mild stress (CUMS)-induced depressed rats based on H-NMR metabolomics techniques, and to explore the potential mechanisms of exercise for the treatment of depression. Rats were randomly divided into blank control group (C), CUMS control group (D), pre-exercise with CUMS group (P), CUMS with aerobic exercise group, CUMS with resistance exercise group (R), and CUMS with aerobic + resistance exercise group (E). The corresponding protocol intervention was applied to each group of rats. Body weight, sucrose preference and open field tests were performed weekly during the experiment to evaluate the extent of depression in rats. Plasma samples from each group of rats were collected at the end of the experiment, and then the plasma was analyzed by H-NMR metabolomics combined with multivariate statistical analysis methods to identify differential metabolites and perform metabolic pathway analysis. (1) Compared with the group D, the body weight, sucrose preference rate, and the number of crossings and standings in the different types of exercise groups were significantly improved (p < 0.05 or p < 0.01). (2) Compared to group C, a total of 15 differential metabolites associated with depression were screened in the plasma of rats in group D, involving 6 metabolic pathways. Group P can regulate the levels of 6 metabolites: valine, lactate, inositol, glucose, phosphocreatine, acetoacetic acid. Group A can regulate the levels of 6 metabolites: N-acetylglycoprotein, leucine, lactate, low density lipoprotein, glucose and acetoacetic acid. Group R can regulate the levels of 6 metabolites: choline, lactate, inositol, glucose, phosphocreatine and acetoacetic acid. Group E can regulate the levels of 5 metabolites: choline, citric acid, glucose, acetone and acetoacetic acid. The different types of exercise groups can improve the depressive symptoms in CUMS rats, and there are common metabolites and metabolic pathways for their mechanism of effects. This study provides a powerful analytical tool to study the mechanism of the antidepressant effect of exercise, and provides an important method and basis for the early diagnosis, prevention and treatment of depression.
Topics: Rats; Animals; Depression; Phosphocreatine; Rats, Sprague-Dawley; Glucose; Metabolomics; Sucrose; Inositol; Lactates; Body Weight; Choline; Stress, Psychological; Disease Models, Animal; Acetoacetates
PubMed: 37999885
DOI: 10.1007/s11011-023-01310-7 -
American Journal of Physiology. Cell... Jan 2024Over the last decade, there has been a growing interest in the use of ketone supplements to improve athletic performance. These ketone supplements transiently elevate... (Review)
Review
Over the last decade, there has been a growing interest in the use of ketone supplements to improve athletic performance. These ketone supplements transiently elevate the concentrations of the ketone bodies acetoacetate (AcAc) and d-β-hydroxybutyrate (βHB) in the circulation. Early studies showed that ketone bodies can improve energetic efficiency in striated muscle compared with glucose oxidation and induce a glycogen-sparing effect during exercise. As such, most research has focused on the potential of ketone supplementation to improve athletic performance via ingestion of ketones immediately before or during exercise. However, subsequent studies generally observed no performance improvement, and particularly not under conditions that are relevant for most athletes. However, more and more studies are reporting beneficial effects when ketones are ingested after exercise. As such, the real potential of ketone supplementation may rather be in their ability to enhance postexercise recovery and training adaptations. For instance, recent studies observed that postexercise ketone supplementation (PEKS) blunts the development of overtraining symptoms, and improves sleep, muscle anabolic signaling, circulating erythropoietin levels, and skeletal muscle angiogenesis. In this review, we provide an overview of the current state-of-the-art about the impact of PEKS on aspects of exercise recovery and training adaptation, which is not only relevant for athletes but also in multiple clinical conditions. In addition, we highlight the underlying mechanisms by which PEKS may improve exercise recovery and training adaptation. This includes epigenetic effects, signaling via receptors, modulation of neurotransmitters, energy metabolism, and oxidative and anti-inflammatory pathways.
Topics: Humans; Ketones; Ketone Bodies; Exercise; 3-Hydroxybutyric Acid; Dietary Supplements
PubMed: 37982172
DOI: 10.1152/ajpcell.00485.2023 -
-Arylation of Amino Acid Esters via an I-Mediated Metal-Free Multicomponent Benzannulation Strategy.The Journal of Organic Chemistry Dec 2023Herein, we present a novel method for the -arylation of amino acid esters using α-bromoacetaldehyde acetal and acetoacetate via an I-mediated metal-free benzannulation...
Herein, we present a novel method for the -arylation of amino acid esters using α-bromoacetaldehyde acetal and acetoacetate via an I-mediated metal-free benzannulation strategy, which disclosed the first synthetic application of -arylation of amino acids using nonaromatic building blocks. The synthesized -arylated amino acid derivatives were found to possess promising selective inhibition against human hepatocellular liver carcinoma cells, human melanoma cells, and human normal liver cells, with an IC value as low as 16.79 μg·mL.
Topics: Humans; Amino Acids; Esters; Metals
PubMed: 37967371
DOI: 10.1021/acs.joc.3c01907 -
The Journal of Clinical Endocrinology... Mar 2024Studies on human renal metabolism are scanty. Nowadays, functional imaging allows the characterization of renal metabolism in a noninvasive manner. We have recently...
CONTEXT
Studies on human renal metabolism are scanty. Nowadays, functional imaging allows the characterization of renal metabolism in a noninvasive manner. We have recently demonstrated that fluorodeoxyglucose F18 (18F FDG) positron emission tomography can be used to analyze renal glucose uptake (GU) rates, and that the renal cortex is an insulin-sensitive tissue.
OBJECTIVE
To confirm that renal GU is decreased in people with obesity and to test whether circulating metabolites are related to renal GU.
DESIGN, SETTING AND PARTICIPANTS
Eighteen people with obesity and 18 nonobese controls were studied with [18F]FDG positron emission tomography during insulin clamp. Renal scans were obtained ∼60 minutes after [18F]FDG injection. Renal GU was measured using fractional uptake rate and after correcting for residual intratubular [18F]FDG. Circulating metabolites were measured using high-throughput proton nuclear magnetic resonance metabolomics.
RESULTS
Cortical GU was higher in healthy nonobese controls compared with people with obesity (4.7 [3.4-5.6] vs 3.1 [2.2-4.3], P = .004, respectively), and it associated positively with the degree of insulin sensitivity (M value) (r = 0.42, P = .01). Moreover, cortical GU was inversely associated with circulating β-OH-butyrate (r = -0.58, P = .009), acetoacetate (r = -0.48, P = .008), citrate (r = -0.44, P = .01), and free fatty acids (r = -0.68, P < .0001), even when accounting for the M value. On the contrary, medullary GU was not associated with any clinical parameters.
CONCLUSION
These data confirm differences in renal cortical GU between people with obesity and healthy nonobese controls. Moreover, the negative correlations between renal cortex GU and free fatty acids, ketone bodies, and citrate are suggestive of substrate competition in the renal cortex.
Topics: Humans; Insulin Resistance; Fatty Acids, Nonesterified; Fluorodeoxyglucose F18; Glucose; Insulin; Positron-Emission Tomography; Obesity; Citrates; Radiopharmaceuticals
PubMed: 37955868
DOI: 10.1210/clinem/dgad663 -
Frontiers in Molecular Biosciences 2023This study aims to test the hypothesis that increased ketone body production resulting from a ketogenic diet (KD) will correlate with reductions in pro-inflammatory...
This study aims to test the hypothesis that increased ketone body production resulting from a ketogenic diet (KD) will correlate with reductions in pro-inflammatory cytokines and lipid subspecies and improved clinical outcomes in adults treated with an adjunctive ketogenic diet for super-refractory status epilepticus (SRSE). Adults (18 years or older) were treated with a 4:1 (fat: carbohydrate and protein) ratio of enteral KD as adjunctive therapy to pharmacologic seizure suppression in SRSE. Blood and urine samples and clinical measurements were collected at baseline ( = 10), after 1 week ( = 8), and after 2 weeks of KD ( = 5). In addition, urine acetoacetate, serum -hydroxybutyrate, lipidomics, pro-inflammatory cytokines (IL-1β and IL-6), chemokines (CCL3, CCL4, and CXCL13), and clinical measurements were obtained at these three time points. Univariate and multivariate data analyses were performed to determine the correlation between ketone body production and circulating lipids, inflammatory biomarkers, and clinical outcomes. Changes in lipids included an increase in ceramides, mono-hexosylceramide, sphingomyelin, phosphocholine, and phosphoserines, and there was a significant reduction in pro-inflammatory mediators, IL-6 and CXCL13, seen at 1 and 2 weeks of KD. Higher blood -hydroxybutyrate levels at baseline correlated with better clinical outcomes; however, ketone body production did not correlate with other variables during treatment. Higher chemokine CCL3 levels following treatment correlated with a longer stay in the intensive care unit and a higher modified Rankin Scale score (worse neurologic disability) at discharge and 6-month follow up. Adults receiving an adjunctive enteral ketogenic diet for super-refractory status epilepticus exhibit alterations in select pro-inflammatory cytokines and lipid species that may predict their response to treatment.
PubMed: 37936721
DOI: 10.3389/fmolb.2023.1173039 -
Journal of Chromatography. B,... Nov 2023An important area within clinical research is in vivo metabolism of ketone bodies (β-hydroxybutyrate and acetoacetate) and in connection metabolites that may affect...
LC-MS/MS method for quantitative profiling of ketone bodies, α-keto acids, lactate, pyruvate and their stable isotopically labelled tracers in human plasma: An analytical panel for clinical metabolic kinetics and interactions.
An important area within clinical research is in vivo metabolism of ketone bodies (β-hydroxybutyrate and acetoacetate) and in connection metabolites that may affect their production and/or cellular transport such as the keto-acids from the branched-chain amino acids, lactate and pyruvate. To determine in vivo metabolite turnover, availability of accurate and sensitive methods for analyzing the plasma concentrations of these metabolites and their stable isotopically labeled enrichments is mandatory. Therefore, the present study describes a high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous analysis of ketone bodies, α-keto acids, lactate, pyruvate, and their tracer enrichments in humans using 2 different derivatization techniques with 4-bromo-N-methylbenzylamine and O-benzylhydroxylamine as derivatization reagents, and 1-ethyl-3-dimethylaminopropyl carbodiimide as coupling compound followed by a single LC-MS/MS run. The method was validated for matrix effects, linearity, accuracy, precision, recovery, stability, and enrichment (ratio) analysis of a stable isotopically labelled analytes (tracers) continuously infused in humans divided by the unlabeled endogenous analyte (tracee) that makes it possible to quantify the analyte in vivo synthesis and degradation rates. The applied parallel derivatization procedure yielded good sensitivity for all analytes of interest and their tracers. Despite the double derivatization method, mixing the ethyl acetate portions at the final stage made it possible to simultaneously analyze all compounds in a single LC-MS/MS run. Moreover, the liquid chromatography method was optimized to robustly quantify the keto acids derived from leucine (α-keto-isocaproic acid) and isoleucine (α-keto-β-methylvaleric acid), the compounds with similar chemical structure and identical molecular weights. The presented method is designed and validated for human plasma. However, care should be taken in blood sampling and processing procedures as well as quick freezing and storage at -80 °C due to the instability of especially acetoacetate.
Topics: Humans; Lactic Acid; Pyruvic Acid; Acetoacetates; Ketone Bodies; Chromatography, Liquid; Tandem Mass Spectrometry; Keto Acids
PubMed: 37925904
DOI: 10.1016/j.jchromb.2023.123906