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International Journal of Molecular... Dec 2023Ketone bodies (KBs), such as acetoacetate and β-hydroxybutyrate, serve as crucial alternative energy sources during glucose deficiency. KBs, generated through... (Review)
Review
Ketone bodies (KBs), such as acetoacetate and β-hydroxybutyrate, serve as crucial alternative energy sources during glucose deficiency. KBs, generated through ketogenesis in the liver, are metabolized into acetyl-CoA in extrahepatic tissues, entering the tricarboxylic acid cycle and electron transport chain for ATP production. Reduced glucose metabolism and mitochondrial dysfunction correlate with increased neuronal death and brain damage during cerebral ischemia and neurodegeneration. Both KBs and the ketogenic diet (KD) demonstrate neuroprotective effects by orchestrating various cellular processes through metabolic and signaling functions. They enhance mitochondrial function, mitigate oxidative stress and apoptosis, and regulate epigenetic and post-translational modifications of histones and non-histone proteins. Additionally, KBs and KD contribute to reducing neuroinflammation and modulating autophagy, neurotransmission systems, and gut microbiome. This review aims to explore the current understanding of the molecular mechanisms underpinning the neuroprotective effects of KBs and KD against brain damage in cerebral ischemia and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.
Topics: Humans; Ketone Bodies; Neurodegenerative Diseases; Neuroprotection; Neuroprotective Agents; Diet, Ketogenic; Cerebral Infarction; Brain Injuries
PubMed: 38203294
DOI: 10.3390/ijms25010124 -
Inorganic Chemistry Jan 2024We synthesized a stable and reusable Schiff base complex of copper immobilized on core-shell magnetic nanoparticles [Cu(II)-SB/GPTMS@SiO@FeO] with simple, efficient, and...
Schiff Base Complex of Copper Immobilized on Core-Shell Magnetic Nanoparticles Catalyzed One-Pot Syntheses of Polyhydroquinoline Derivatives under Mild Conditions Supported by a DFT Study.
We synthesized a stable and reusable Schiff base complex of copper immobilized on core-shell magnetic nanoparticles [Cu(II)-SB/GPTMS@SiO@FeO] with simple, efficient, and available materials. A variety of characterization analyses including Fourier transform infrared (FT-IR), X-ray photoelectron spectroscopy (XPS), field-emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), Brunauer-Emmett-Teller (BET), thermogravimetric analysis (TGA), X-ray diffraction (XRD), vibrating-sample magnetometry (VSM), energy-dispersive X-ray spectrometry (EDX), and inductively coupled plasma (ICP) confirm that our synthesized nanocatalyst was obtained. The particle size distribution from the TEM image was obtained in the range of 42-55 nm. The existence of cupric species (Cu) in the catalyst was determined with XPS analysis and clearly indicated two peaks at 933.7 and 953.7 eV for Cu 2p and Cu 2p, respectively. BET results showed that our catalyst synthesized with a mesoporous structure and with a specific area of 48.82 m g. After detailed characterization, the resulting nanocatalyst exhibited excellent catalytic performance for the explored catalytic reactions in the one-pot synthesis of polyhydroquinoline derivatives by the Hantzsch reaction of dimedone, ethyl acetoacetate, ammonium acetate, and various aldehydes under sustainable and mild conditions. The corresponding products - are achieved in yields of 88-97%. Additionally, density functional theory (DFT) calculations were carried out to investigate the electrostatic potential root (ESP), natural bond orbital (NBO), and molecular orbitals (MOs), drawing the reaction mechanism using the total energy of the reactant and product and the study of structural parameters.
PubMed: 38194483
DOI: 10.1021/acs.inorgchem.3c03861 -
Communications Biology Jan 2024Torpor and arousal cycles, both daily and seasonal (e.g. hibernation), are crucial for small mammals, including bats, to maintain the energy and water balance. The...
Torpor and arousal cycles, both daily and seasonal (e.g. hibernation), are crucial for small mammals, including bats, to maintain the energy and water balance. The alternation between torpor and arousal leads to metabolic changes, leaving traceable evidence of metabolic wastes in urine. In this study we investigated urinary creatinine and acetoacetate (a ketone body) in the Eastern bent-wing bat (Miniopterus fuliginosus) in Mungyeong, South Korea. We found an increase in urinary creatinine during torpor in summer, indicating changes in renal water reabsorption rates during the active season. Although we could not confirm ketonuria in hibernating bats due to a methodological limitation caused by the small amount of urine, we verified an increase in urinary creatinine concentration during hibernation. This finding suggests that managing water stress resulting from evaporative water loss is one of key reasons for arousal during hibernation in Eastern bent-wing bats.
Topics: Animals; Hibernation; Chiroptera; Creatinine; Torpor; Republic of Korea
PubMed: 38182741
DOI: 10.1038/s42003-023-05713-1 -
Bioengineering (Basel, Switzerland) Nov 2023The depletion of fossil fuel resources and the CO emissions coupled with petroleum-based industrial processes present a relevant issue for the whole of society. An...
The depletion of fossil fuel resources and the CO emissions coupled with petroleum-based industrial processes present a relevant issue for the whole of society. An alternative to the fossil-based production of chemicals is microbial fermentation using acetogens. Acetogenic bacteria are able to metabolize CO or CO (+H) via the Wood-Ljungdahl pathway. As isopropanol is widely used in a variety of industrial branches, it is advantageous to find a fossil-independent production process. In this study, was employed to produce isopropanol via plasmid-based expression of the enzymes thiolase A, CoA-transferase, acetoacetate decarboxylase and secondary alcohol dehydrogenase. An examination of the enzymes originating from different organisms led to a maximum isopropanol production of 5.64 ± 1.08 mM using CO + H as the carbon and energy source. To this end, the genes (encoding thiolase A) and (encoding CoA-transferase) of , (encoding acetoacetate decarboxylase) originating from and (encoding secondary alcohol dehydrogenase) of DSM 6423 were employed. Since bottlenecks in the isopropanol production pathway are known, optimization of the strain was investigated, resulting in a 2.5-fold increase in isopropanol concentration.
PubMed: 38135972
DOI: 10.3390/bioengineering10121381 -
Metabolites Nov 2023H-NMR metabolomics data is increasingly used to track health and disease. Nightingale Health, a major supplier of H-NMR metabolomics, has recently updated the...
H-NMR metabolomics data is increasingly used to track health and disease. Nightingale Health, a major supplier of H-NMR metabolomics, has recently updated the quantification strategy to further align with clinical standards. Such updates, however, might influence backward replicability, particularly affecting studies with repeated measures. Using data from BBMRI-NL consortium (~28,000 samples from 28 cohorts), we compared Nightingale data, originally released in 2014 and 2016, with a re-quantified version released in 2020, of which both versions were based on the same NMR spectra. Apart from two discontinued and twenty-three new analytes, we generally observe a high concordance between quantification versions with 73 out of 222 (33%) analytes showing a mean ρ > 0.9 across all cohorts. Conversely, five analytes consistently showed lower Spearman's correlations (ρ < 0.7) between versions, namely acetoacetate, LDL-L, saturated fatty acids, S-HDL-C, and sphingomyelins. Furthermore, previously trained multi-analyte scores, such as or , might be particularly sensitive to platform changes. Whereas replicated well, the score had to be retrained due to use of discontinued analytes. Notably, both scores in the re-quantified data recapitulated mortality associations observed previously. Concluding, we urge caution in utilizing different platform versions to avoid mixing analytes, having different units, or simply being discontinued.
PubMed: 38132863
DOI: 10.3390/metabo13121181 -
MBio Feb 2024Acetone carboxylases (ACs) catalyze the metal- and ATP-dependent conversion of acetone and bicarbonate to form acetoacetate. Interestingly, two homologous ACs that have...
Acetone carboxylases (ACs) catalyze the metal- and ATP-dependent conversion of acetone and bicarbonate to form acetoacetate. Interestingly, two homologous ACs that have been biochemically characterized have been reported to have different metal complements, implicating different metal dependencies in catalysis. ACs from proteobacteria and share 68% sequence identity but have been proposed to have different catalytic metals. In this work, the two ACs were expressed under the same conditions in and were subjected to parallel chelation and reconstitution experiments with Mn(II) or Fe(II). Electron paramagnetic and Mössbauer spectroscopies identified signatures, respectively, of Mn(II) or Fe(II) bound at the active site. These experiments showed that the respective ACs, without the assistance of chaperones, second metal sites, or post-translational modifications facilitate correct metal incorporation, and despite the expected thermodynamic preference for Fe(II), each preferred a distinct metal. Catalysis was likewise associated uniquely with the cognate metal, though either could potentially serve the proposed Lewis acidic role. Subtle differences in the protein structure are implicated in serving as a selectivity filter for Mn(II) or Fe(II).IMPORTANCEThe Irving-Williams series refers to the predicted stabilities of transition metal complexes where the observed general stability for divalent first-row transition metal complexes increase across the row. Acetone carboxylases (ACs) use a coordinated divalent metal at their active site in the catalytic conversion of bicarbonate and acetone to form acetoacetate. Highly homologous ACs discriminate among different divalent metals at their active sites such that variations of the enzyme prefer Mn(II) over Fe(II), defying Irving-Williams-predicted behavior. Defining the determinants that promote metal discrimination within the first-row transition metals is of broad fundamental importance in understanding metal-mediated catalysis and metal catalyst design.
Topics: Acetone; Acetoacetates; Manganese; Bicarbonates; Coordination Complexes; Metals; Ferrous Compounds; Catalysis
PubMed: 38126751
DOI: 10.1128/mbio.02987-23 -
ACS Omega Dec 2023An efficient synthesis of 5,7-dihydroxy-4-methylcoumarin from phloroglucinol with ethyl acetoacetate in the UiO-66-SOH metal-organic framework is reported. The potential...
An efficient synthesis of 5,7-dihydroxy-4-methylcoumarin from phloroglucinol with ethyl acetoacetate in the UiO-66-SOH metal-organic framework is reported. The potential of UiO-66-SOH as a solid catalyst was determined through optimized-condition experiments and quantum molecular calculations. The optimal conditions for the synthesis of 5,7-dihydroxy-4-methylcoumarin with UiO-66-SOH were as follows: phloroglucinol/ethyl acetoacetate molar ratio = 1:1.6, reaction time = 4 h, and temperature = 140 °C, for which the reaction yield reached 66.0%. The reusability of UiO-66-SOH catalysts for Pechmann condensation was examined. The activation energy of the reaction occurring on a sulfonic group of the UiO-66-SOH catalyst was 12.6 kcal/mol, which was significantly lower than 22.6 kcal/mol of the same reaction on the UiO-66 catalyst. To comprehend the reaction mechanism, density functional theory with the ONIOM approach was applied for the synthesis of coumarin on the UiO-66-SOH and UiO-66 clusters. A possible reaction mechanism was proposed involving three steps: a trans-esterification step, an intramolecular hydroxyalkylation step, and a dehydration step. The rate-determining step was suggested to be the first step which acquired an activation energy of 15.7 and 29.5 kcal/mol, respectively. Information from this study can be used as guidelines to develop more efficient catalytic metal-organic frameworks for various organic syntheses.
PubMed: 38107951
DOI: 10.1021/acsomega.3c06624 -
MedComm Dec 2023Lung adenocarcinoma (LUAD) is the most common form of lung cancer, with a consistently low 5-year survival rate. Therefore, we aim to identify key genes involved in LUAD...
Lung adenocarcinoma (LUAD) is the most common form of lung cancer, with a consistently low 5-year survival rate. Therefore, we aim to identify key genes involved in LUAD progression to pave the way for targeted therapies in the future. BDH1 plays a critical role in the conversion between acetoacetate and β-hydroxybutyrate. The presence of β-hydroxybutyrate is essential for initiating lysine β-hydroxybutyrylation (Kbhb) modifications. Histone Kbhb at the H3K9 site is attributed to transcriptional activation. We unveiled that β-hydroxybutyrate dehydrogenase 1 (BDH1) is not only conspicuously overexpressed in LUAD, but it also modulates the overall intracellular Kbhb modification levels. The RNA sequencing analysis revealed leucine-rich repeat-containing protein 31 (LRRC31) as a downstream target gene regulated by BDH1. Ecologically expressed BDH1 hinders the accumulation of H3K9bhb in the transcription start site of LRRC31, consequently repressing the transcriptional expression of LRRC31. Furthermore, we identified potential BDH1 inhibitors, namely pimozide and crizotinib, which exhibit a synergistic inhibitory effect on the proliferation of LUAD cells exhibiting high expression of BDH1. In summary, this study elucidates the molecular mechanism by which BDH1 mediates LUAD progression through the H3K9bhb/LRRC31 axis and proposes a therapeutic strategy targeting BDH1-high-expressing LUAD, providing a fresh perspective for LUAD treatment.
PubMed: 38098610
DOI: 10.1002/mco2.449 -
Nature Metabolism Dec 2023Prospective molecular targets and therapeutic applications for ketone body metabolism have increased exponentially in the past decade. Initially considered to be... (Review)
Review
Prospective molecular targets and therapeutic applications for ketone body metabolism have increased exponentially in the past decade. Initially considered to be restricted in scope as liver-derived alternative fuel sources during periods of carbohydrate restriction or as toxic mediators during diabetic ketotic states, ketogenesis and ketone bodies modulate cellular homeostasis in multiple physiological states through a diversity of mechanisms. Selective signalling functions also complement the metabolic fates of the ketone bodies acetoacetate and D-β-hydroxybutyrate. Here we discuss recent discoveries revealing the pleiotropic roles of ketone bodies, their endogenous sourcing, signalling mechanisms and impact on target organs, and considerations for when they are either stimulated for endogenous production by diets or pharmacological agents or administered as exogenous wellness-promoting agents.
Topics: Ketone Bodies; 3-Hydroxybutyric Acid; Diet; Liver; Homeostasis
PubMed: 38092961
DOI: 10.1038/s42255-023-00935-3 -
Nanoscale Advances Dec 2023In this research, we present a post-synthetic method for synthesizing a novel nanomagnetic Cu Schiff base complex and investigate its efficiency in catalytic organic...
In this research, we present a post-synthetic method for synthesizing a novel nanomagnetic Cu Schiff base complex and investigate its efficiency in catalytic organic conversion reactions. Various spectroscopic analyses were employed to characterize the physiochemical characteristics of the resulting nanocomposite. The experimental results successfully demonstrate the catalytic application of the prepared Cu-complex in the preparation of pyrano[2,3-]pyrazole heterocycles. This synthesis involved a one-pot three-component condensation reaction, wherein hydrazine hydrate, ethyl acetoacetate, malononitrile, and aromatic aldehydes were combined under reflux conditions using water as the solvent. Notably, the heterogenized complex exhibited exceptional catalytic performance, achieving remarkable conversion rates and selectivity, all accomplished using only 12 mg of the catalyst. Furthermore, thorough stability assessments of this catalyst were conducted through reusability and hot filtration tests, which confirmed its non-leaching properties and demonstrated excellent results over the course of five consecutive runs.
PubMed: 38059019
DOI: 10.1039/d3na00906h