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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 -
The American Journal of Clinical... May 2021Early applications of metabolomics in nutrition and health research identified associations between dietary patterns and metabolomic profiles. Twin studies show that...
BACKGROUND
Early applications of metabolomics in nutrition and health research identified associations between dietary patterns and metabolomic profiles. Twin studies show that diet-related phenotypes and diet-associated metabolites are influenced by genes. However, studies have not examined whether diet-metabolite associations are explained by genetic or environmental factors and whether these associations are reproducible over multiple time points.
OBJECTIVE
This research aims to examine the genetic and environmental factors influencing covariation in diet-metabolite associations that are reproducible over time in healthy twins.
METHODS
The UCD Twin Study is a semi-longitudinal classic twin study that collected repeated dietary, anthropometric, and urinary data over 2 months. Correlation analysis identified associations between diet quality measured using the Healthy Eating Index (HEI) and urinary metabolomic profiles at 3 time points. Diet-associated metabolites were examined using linear regression to identify those significantly influenced by familial factors between twins and those significantly influenced by unique factors. Cholesky decomposition modeling quantified the genetic and environmental path coefficients through associated dietary components onto the metabolites.
RESULTS
The HEI was associated with 14 urinary metabolites across 3 metabolomic profiles (r: ±0.15-0.49). For 8 diet-metabolite associations, genetic or shared environmental factors influencing HEI component scores significantly influenced variation in metabolites (β: 0.40-0.52). A significant relation was observed between dietary intakes of whole grain and acetoacetate (β: -0.50, P < 0.001) and β-hydroxybutyrate (β: -0.46, P < 0.001), as well as intakes of saturated fat and acetoacetate (β: 0.47, P < 0.001) and β-hydroxybutyrate (β: 0.52, P < 0.001). For these diet-metabolite associations a common shared environmental factor explained 66-69% of variance in the metabolites.
CONCLUSIONS
This study shows that diet-metabolite associations are reproducible in 3 urinary metabolomic profiles. Components of the HEI covary with metabolites, and covariation is largely due to the shared environment.
Topics: Adolescent; Adult; Biomarkers; Diet; Diet, Healthy; Feeding Behavior; Female; Humans; Male; Metabolomics; Middle Aged; Twins; Urinalysis; Young Adult
PubMed: 33826700
DOI: 10.1093/ajcn/nqaa378 -
Gut Microbes 2021Reduction of relative abundance in the gut microbiota is a widely accepted signature associated with obesity-related metabolic disorders. Using untargeted metabolomics... (Randomized Controlled Trial)
Randomized Controlled Trial
Reduction of relative abundance in the gut microbiota is a widely accepted signature associated with obesity-related metabolic disorders. Using untargeted metabolomics profiling of fasting plasma, our study aimed at identifying metabolic signatures associated with beneficial properties of alive and pasteurized when administrated to a cohort of insulin-resistant individuals with metabolic syndrome. Our data highlighted either shared or specific alterations in the metabolome according to the form of administered with respect to a control group. Common responses encompassed modulation of amino acid metabolism, characterized by reduced levels of arginine and alanine, alongside several intermediates of tyrosine, phenylalanine, tryptophan, and glutathione metabolism. The global increase in levels of acylcarnitines together with specific modulation of acetoacetate also suggested induction of ketogenesis through enhanced β-oxidation. Moreover, our data pinpointed some metabolites of interest considering their emergence as substantial compounds pertaining to health and diseases in the more recent literature.
Topics: Adolescent; Adult; Aged; Akkermansia; Amino Acids; Carnitine; Glycolysis; Humans; Insulin Resistance; Ketone Bodies; Lipid Metabolism; Liver; Metabolic Syndrome; Metabolome; Middle Aged; Probiotics; Young Adult
PubMed: 34812127
DOI: 10.1080/19490976.2021.1994270 -
Frontiers in Aging Neuroscience 2023Beta-amyloid (Abeta) and tau protein in cerebrospinal fluid (CSF) are established diagnostic biomarkers for Alzheimer's disease (AD). However, these biomarkers may not...
BACKGROUND
Beta-amyloid (Abeta) and tau protein in cerebrospinal fluid (CSF) are established diagnostic biomarkers for Alzheimer's disease (AD). However, these biomarkers may not the only ones existing parameters that reflect Alzheimer's disease neuropathological change. The use of quantitative metabolomics approach could provide novel insights into dementia progression and identify key metabolic alterations in CSF and serum.
METHODS
In the present study, we quantified a set of 45 metabolites in CSF (71 patients) and 27 in serum (76 patients) in patients with mild cognitive impairment (MCI), AD, and controls using nuclear magnetic resonance (NMR)-based metabolomics.
RESULTS
We found significantly reduced CSF (1.32-fold, = 0.0195) and serum (1.47-fold, = 0.0484) levels of the ketone body acetoacetate in AD and MCI patients. Additionally, we found decreased levels (1.20-fold, = 0.0438) of the branched-chain amino acid (BCAA) valine in the CSF of AD patients with increased valine degradation pathway metabolites (such as 3-hydroxyisobutyrate and α-ketoisovalerate). Moreover, we discovered that CSF 2-hydroxybutyrate is dramatically reduced in the MCI patient group (1.23-fold, = 0.039). On the other hand, vitamin C (ascorbate) was significantly raised in CSF of these patients ( = 0.008). We also identified altered CSF protein content, 1,5-anhydrosorbitol and fructose as further metabolic shifts distinguishing AD from MCI. Significantly decreased serum levels of the amino acid ornithine were seen in the AD dementia group when compared to healthy controls (1.36-fold, = 0.011). When investigating the effect of sex, we found for AD males the sign of decreased 2-hydroxybutyrate and acetoacetate in CSF while for AD females increased serum creatinine was identified.
CONCLUSION
Quantitative NMR metabolomics of CSF and serum was able to efficiently identify metabolic changes associated with dementia groups of MCI and AD patients. Further, we showed strong correlations between these changes and well-established metabolomic and clinical indicators like Abeta.
PubMed: 37693649
DOI: 10.3389/fnagi.2023.1219718 -
Biomedicine & Pharmacotherapy =... Aug 2020Diabetes mellitus is the most prevalent endocrine disease in the world and is likely to be the major epidemic in human history. In current years, many modern... (Review)
Review
Diabetes mellitus is the most prevalent endocrine disease in the world and is likely to be the major epidemic in human history. In current years, many modern anti-diabetic medicines have been produced and introduced into the markets, however, long-term treatment of diabetes using synthetic drugs is limited. Medicinal plants play a great role in the treatment of diabetes. Many medicinal plants and their related traditional treatments for diabetes are used throughout the world and represent promising alternatives for the management of diabetes treatment. Metabolomics researches on diabetes have contributed to many aspects of exploring biomarkers and understanding the progression of the disease at metabolic levels. In addition, in the last decade, a number of metabolomics studies have focused on investigating the action mechanism of various herbal medicines. This paper aims to highlight and review a series of metabolomics studies that carried out on the role of herbal medicines on obesity and diabetes, finding potential biomarkers and also characterizing the metabolic disturbances associated with diabetes development. The findings showed that the metabolism of glycolysis/gluconeogenesis (glucose, pyruvate, lactate), TCA cycle (succinate, citrate, β-hydroxybutyrate, 2-oxoglutarate), lipid metabolism (acetoacetate, acetate) and amino acid metabolic pathways (valine, leucine, and isoleucine, hippurate, creatine) were more significantly disturbed metabolic pathways and biomarkers in diabetic models and herbal medicines affect these metabolic pathways by different mechanisms.
Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Hypoglycemic Agents; Metabolomics; Plant Extracts; Plants, Medicinal
PubMed: 32450525
DOI: 10.1016/j.biopha.2020.110263 -
Materials (Basel, Switzerland) Jun 2022The durability of Portland cement mortars is often affected by environmental factors, which can cause physicochemical and mechanical degradation processes. In this...
The durability of Portland cement mortars is often affected by environmental factors, which can cause physicochemical and mechanical degradation processes. In this study, the performance of three products, calcium acetoacetate and calcium tetrahydrofurfuryloxide dissolved in two different solvents developed and tested as stone consolidants, was evaluated in terms of crack filling or sealing and consolidation. Realistic cracks were induced in quasibrittle cement mortar prisms using a custom-designed test rig. The effectiveness and the performance of the considered treatments, investigated on specimens, were evaluated by optical and scanning electron microscopy, colourimetry, water absorption rate, ultrasonic pulse velocity, and surface hardness measurements. Results revealed that, in the examined conditions, the products were more suitable as surface consolidants than as crack fillers.
PubMed: 35744104
DOI: 10.3390/ma15124044 -
Free Radical Biology & Medicine Jun 2016Diets that boost ketone production are increasingly used for treating several neurological disorders. Elevation in ketones in most cases is considered favorable, as they... (Review)
Review
Diets that boost ketone production are increasingly used for treating several neurological disorders. Elevation in ketones in most cases is considered favorable, as they provide energy and are efficient in fueling the body's energy needs. Despite all the benefits from ketones, the above normal elevation in the concentration of ketones in the circulation tend to illicit various pathological complications by activating injurious pathways leading to cellular damage. Recent literature demonstrates a plausible link between elevated levels of circulating ketones and oxidative stress, linking hyperketonemia to innumerable morbid conditions. Ketone bodies are produced by the oxidation of fatty acids in the liver as a source of alternative energy that generally occurs in glucose limiting conditions. Regulation of ketogenesis and ketolysis plays an important role in dictating ketone concentrations in the blood. Hyperketonemia is a condition with elevated blood levels of acetoacetate, 3-β-hydroxybutyrate, and acetone. Several physiological and pathological triggers, such as fasting, ketogenic diet, and diabetes cause an accumulation and elevation of circulating ketones. Complications of the brain, kidney, liver, and microvasculature were found to be elevated in diabetic patients who had elevated ketones compared to those diabetics with normal ketone levels. This review summarizes the mechanisms by which hyperketonemia and ketoacidosis cause an increase in redox imbalance and thereby increase the risk of morbidity and mortality in patients.
Topics: Acetoacetates; Diabetes Mellitus, Type 1; Energy Metabolism; Glucose; Humans; Ketone Bodies; Ketones; Ketosis; Oxidative Stress; Risk Factors
PubMed: 27036365
DOI: 10.1016/j.freeradbiomed.2016.03.020 -
Frontiers in Public Health 2022In previous questionnaire surveys of miners, sleep disorders were found among underground workers. The influence of the special deep-underground environment and its...
BACKGROUND
In previous questionnaire surveys of miners, sleep disorders were found among underground workers. The influence of the special deep-underground environment and its potential mechanism are still unclear. Therefore, this study intends to utilize LC-MS metabolomics to study the potential differences between different environments and different sleep qualities.
METHODS
Twenty-seven miners working at 645-1,500 m deep wells were investigated in this study, and 12 local ground volunteers were recruited as the control group. The Pittsburgh Sleep Quality Index (PSQI) was used to examine and evaluate the sleep status of the subjects in the past month, and valuable basic information about the participants was collected. PSQI scores were obtained according to specific calculation rules, and the corresponding sleep grouping and subsequent analysis were carried out. Through liquid chromatography-mass spectrometry (LC-MS) non-targeted metabolomics analysis, differences in metabolism were found by bioinformatics analysis in different environments.
RESULTS
Between the deep-underground and ground (DUvsG) group, 316 differential metabolites were identified and 125 differential metabolites were identified in the good sleep quality vs. poor sleep quality (GSQvsPSQ) group. The metabolic pathways of Phenylalanine, tyrosine and tryptophan biosynthesis ( = 0.0102) and D-Glutamine and D-glutamate metabolism ( = 0.0241) were significantly enriched in DUvsG. For GSQvsPSQ group, Butanoate metabolism was statistically significant ( = 0.0276). L-Phenylalanine, L-Tyrosine and L-Glutamine were highly expressed in the deep-underground group. Acetoacetic acid was poorly expressed, and 2-hydroxyglutaric acid was highly expressed in good sleep quality.
CONCLUSIONS
The influence of the underground environment on the human body is more likely to induce specific amino acid metabolism processes, and regulate the sleep-wake state by promoting the production of excitatory neurotransmitters. The difference in sleep quality may be related to the enhancement of glycolytic metabolism, the increase in excitatory neurotransmitters and the activation of proinflammation. L-phenylalanine, L-tyrosine and L-glutamine, Acetoacetic acid and 2-hydroxyglutaric acid may be potential biomarkers correspondingly.
Topics: Glutamine; Humans; Neurotransmitter Agents; Phenylalanine; Pilot Projects; Sleep Quality; Tyrosine
PubMed: 36062104
DOI: 10.3389/fpubh.2022.969113 -
The Journal of Experimental Biology Nov 2021Odontocete cetaceans exhibit genomic mutations in key ketogenesis genes. In order to validate an inferred lack of ketogenesis made by observations from genome...
Odontocete cetaceans exhibit genomic mutations in key ketogenesis genes. In order to validate an inferred lack of ketogenesis made by observations from genome sequencing, we biochemically analyzed tissues from several odontocete cetacean species and demonstrate that they indeed do not exhibit appreciable hepatic β-hydroxybutyrate (βHB) or its carnitine ester. Furthermore, liver tissue exhibited significantly lower long chain acylcarnitines and increased odd chain acylcarnitines indicative of a decreased reliance on hepatic long chain fatty acid oxidation in these carnivorous mammals. Finally, we performed single molecule, real-time next generation sequencing of liver and brain RNA of Tursiops truncatus and demonstrate that the succinyl-CoA transferase required for acetoacetate catabolism is expressed in the nervous system. These data show that odontocete cetaceans have lost the ability to perform ketogenesis and suggest a hepatocentric coenzyme A recycling function rather than a predominantly systemic-bioenergetic role for ketogenesis in other ketogenic competent mammals such as humans.
Topics: Animals; Cetacea; Fatty Acids; Humans; Ketone Bodies; Liver; Oxidation-Reduction
PubMed: 34605907
DOI: 10.1242/jeb.243062 -
Nutrients Sep 2022Ketone bodies are small compounds derived from fatty acids that behave as an alternative mitochondrial energy source when insulin levels are low, such as during fasting... (Review)
Review
Ketone bodies are small compounds derived from fatty acids that behave as an alternative mitochondrial energy source when insulin levels are low, such as during fasting or strenuous exercise. In addition to the metabolic function of ketone bodies, they also have several signaling functions separate from energy production. In this perspective, we review the main current data referring to ketone bodies in correlation with nutrition and metabolic pathways as well as to the signaling functions and the potential impact on clinical conditions. Data were selected following eligibility criteria accordingly to the reviewed topic. We used a set of electronic databases (Medline/PubMed, Scopus, Web of Sciences (WOS), Cochrane Library) for a systematic search until July 2022 using MeSH keywords/terms (i.e., ketone bodies, BHB, acetoacetate, inflammation, antioxidant, etc.). The literature data reported in this review need confirmation with consistent clinical trials that might validate the results obtained in in vitro and in vivo in animal models. However, the data on exogenous ketone consumption and the effect on the ketone bodies' brain uptake and metabolism might spur the research to define the acute and chronic effects of ketone bodies in humans and pursue the possible implication in the prevention and treatment of human diseases. Therefore, additional studies are required to examine the potential systemic and metabolic consequences of ketone bodies.
Topics: Animals; Antioxidants; Brain; Fasting; Humans; Ketone Bodies; Ketosis
PubMed: 36079870
DOI: 10.3390/nu14173613