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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 -
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 -
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 -
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 -
Nutrients Oct 2023While one-third of the population can be affected by anxiety disorders during their lifetime, our knowledge of the pathophysiology of these disorders is far from...
While one-third of the population can be affected by anxiety disorders during their lifetime, our knowledge of the pathophysiology of these disorders is far from complete. Previously, it has been demonstrated in male animals that exogenous ketone supplement-evoked ketosis can decrease anxiety levels in preclinical rodent models, such as Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats. Thus, in this study, we investigated whether intragastric gavage of the exogenous ketone supplement KEMCT (mix of 1,3-butanediol-acetoacetate diester/ketone ester/KE and medium-chain triglyceride/MCT oil in 1:1 ratio) for 7 days can alter the anxiety levels of female WAG/Rij rats using the light-dark box (LDB) test. We demonstrated that a lower dose of KEMCT (3 g/kg/day) increased blood R-βHB (R-β-hydroxybutyrate) levels and significantly decreased anxiety levels (e.g., increased the time spent in the light compartment) in female WAG/Rij rats on the seventh day of administration. Although the higher KEMCT dose (5 g/kg/day) increased blood R-βHB levels more effectively, compared with the lower KEMCT dose, anxiety levels did not improve significantly. We conclude that ketone supplementation might be an effective strategy to induce anxiolytic effects not only in male but also in female WAG/Rij rats. However, these results suggest that the optimal level may be moderately, not highly, elevated blood R-βHB levels when the goal is to alleviate symptoms of anxiety. More studies are needed to understand the exact mechanism of action of ketone supplementation on anxiety levels and to investigate their use in other animal models and humans for the treatment of anxiety disorders and other mental health conditions.
Topics: Rats; Animals; Humans; Male; Female; Rats, Wistar; Ketones; Ketosis; Anxiety; Dietary Supplements; Disease Models, Animal
PubMed: 37892486
DOI: 10.3390/nu15204412