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Frontiers in Endocrinology 2023Obesity poses an increased risk for the onset of Nonalcoholic fatty liver disease (NAFLD). The influence of other factors, such as sex in the incidence and severity of...
OBJECTIVE
Obesity poses an increased risk for the onset of Nonalcoholic fatty liver disease (NAFLD). The influence of other factors, such as sex in the incidence and severity of this liver disease has not yet been fully elucidated. Thus, we aimed to identify the NAFLD serum metabolic signatures associated with sex in normal, overweight and obese patients and to associate the metabolite fluctuations across the increasing liver steatosis stages.
METHODS AND RESULTS
Using nuclear magnetic resonance (NMR) serum samples of 210 NAFLD cases and control individuals diagnosed with liver U/S, our untargeted metabolomics enquiry provided a sex distinct metabolic bouquet. Increased levels of alanine, histidine and tyrosine are associated with severity of NAFLD in both men and women. Moreover, higher serum concentrations of valine, aspartic acid and mannose were positively associated with the progression of NAFLD among the male subjects, while a negative association was observed with the levels of creatine, phosphorylcholine and acetic acid. On the other hand, glucose was positively associated with the progression of NAFLD among the female subjects, while levels of threonine were negatively related. Fluctuations in ketone bodies acetoacetate and acetone were also observed among the female subjects probing a significant reduction in the circulatory levels of the former in NAFLD cases. A complex glycine response to hepatic steatosis of the female subjects deserves further investigation.
CONCLUSION
Results of this study aspire to address the paucity of data on sex differences regarding NAFLD pathogenesis. Targeted circulatory metabolome measurements could be used as diagnostic markers for the distinct stages of NAFLD in each sex and eventually aid in the development of novel sex-related therapeutic options.
Topics: Humans; Female; Male; Non-alcoholic Fatty Liver Disease; Metabolomics; Obesity; Metabolome
PubMed: 37854184
DOI: 10.3389/fendo.2023.1230457 -
Osteoarthritis and Cartilage Open Sep 2022Inflammatory responses are associated with changes in tissue metabolism. Prior studies find altered metabolomic profiles in both the synovial fluid (SF) and serum of...
OBJECTIVE
Inflammatory responses are associated with changes in tissue metabolism. Prior studies find altered metabolomic profiles in both the synovial fluid (SF) and serum of osteoarthritis subjects. Our study determined the metabolomic profile of synovial tissue (ST) and SF of individuals with osteoarthritis (OA) and its association with synovial inflammation.
DESIGN
37 OA ST samples were collected during joint replacement, 21 also had SF. ST samples were fixed in formalin for histological analysis, cultured (explants) for cytokine analysis by enzyme-linked immunosorbent assay, or snap-frozen for metabolomic analysis. ST samples were categorized by Krenn synovitis score and picrosirius red. CD68 and vimentin expression was assessed by immunohistochemistry and semi-quantified using Image J. Proton-nuclear magnetic resonance (H NMR) was used to acquire a spectrum from ST and SF samples. Chenomx NMR suite 8.5 was used for metabolite identification and quantification. Metaboanalyst 5.0, SPSS v26, and R (v4.1.2) were used for statistical analysis.
RESULTS
42 and 29 metabolites were detected in the ST and SF respectively by H NMR. Only 3 metabolites, lactate, dimethylamine, and creatine positively correlated between SF and ST. ST concentrations of several metabolites (lactate, alanine, fumarate, glutamine, glycine, leucine, lysine, methionine, trimethylamine -oxide, tryptophan and valine) were associated with synovitis score, mostly to the lining score. IL-6, acetoacetate, and tyrosine in SF predicted high Krenn synovitis scores in ST.
CONCLUSION
Metabolomic profiling of ST identified metabolic changes associated with inflammation. Further studies are needed to determine whether metabolomic profiling of synovial tissue can identify new therapeutic targets in osteoarthritis.
PubMed: 36474936
DOI: 10.1016/j.ocarto.2022.100295 -
Reviews in Endocrine & Metabolic... Dec 2019Gut microbiota (GM) is a key contributor to host metabolism and physiology. Data generated on comparing diseased and healthy subjects have reported changes in the GM... (Review)
Review
Gut microbiota (GM) is a key contributor to host metabolism and physiology. Data generated on comparing diseased and healthy subjects have reported changes in the GM profile between both health states, suggesting certain bacterial composition could be involved in pathogenesis. Moreover, studies reported that reshaping of GM could contribute actively to disease recovery. Interestingly, ketogenic diets (KD) have emerged recently as new economic dietotherapeutic strategy to combat a myriad of diseases (refractory epilepsy, obesity, cancer, neurodegenerative diseases…). KD, understood in a broad sense, refers to whatever dietetic approximation, which causes physiological ketosis. Therefore, high fat-low carbs diets, fasting periods or caloric restriction constitute different strategies to produce an increase of main ketones bodies, acetoacetate and β-hydroxybutyrate, in blood. Involved biological mechanisms in ketotherapeutic effects are still to be unravelled. However, it has been pointed out that GM remodelling by KD, from now on "keto microbiota", may play a crucial role in patient response to KD treatment. In fact, germ-free animals were resistant to ketotherapeutic effects; reinforcing keto microbiota may be a powerful contributor to host disease recovery. In this review, we will comment the influence of gut microbiota on host, as well as, therapeutic potential of ketogenic diets and keto microbiota to restore health status. Current progress and limitations will be argued too. In spite of few studies have defined applicability and mechanisms of KD, in the light of results, keto microbiota might be a new useful therapeutic agent.
Topics: Animals; Diet, Ketogenic; Dysbiosis; Gastrointestinal Microbiome; Humans; Ketosis
PubMed: 31720986
DOI: 10.1007/s11154-019-09518-8 -
Frontiers in Psychiatry 2021Alcohol use disorder (AUD) is a chronic, relapsing brain disorder, characterized by compulsive alcohol seeking and disrupted brain function. In individuals with AUD,... (Review)
Review
Alcohol use disorder (AUD) is a chronic, relapsing brain disorder, characterized by compulsive alcohol seeking and disrupted brain function. In individuals with AUD, abstinence from alcohol often precipitates withdrawal symptoms than can be life threatening. Here, we review evidence for nutritional ketosis as a potential means to reduce withdrawal and alcohol craving. We also review the underlying mechanisms of action of ketosis. Several findings suggest that during alcohol intoxication there is a shift from glucose to acetate metabolism that is enhanced in individuals with AUD. During withdrawal, there is a decline in acetate levels that can result in an energy deficit and could contribute to neurotoxicity. A ketogenic diet or ingestion of a ketone ester elevates ketone bodies (acetoacetate, β-hydroxybutyrate and acetone) in plasma and brain, resulting in nutritional ketosis. These effects have been shown to reduce alcohol withdrawal symptoms, alcohol craving, and alcohol consumption in both preclinical and clinical studies. Thus, nutritional ketosis may represent a unique treatment option for AUD: namely, a nutritional intervention that could be used alone or to augment the effects of medications.
PubMed: 34916977
DOI: 10.3389/fpsyt.2021.781668 -
The Journal of Clinical Endocrinology... Sep 2020Ketone bodies - 3-hydroxybutyrate (3-OHB), acetoacetate, and acetone - are ancient, evolutionarily preserved, small fuel substrates, which uniquely can substitute and... (Review)
Review
Ketone bodies - 3-hydroxybutyrate (3-OHB), acetoacetate, and acetone - are ancient, evolutionarily preserved, small fuel substrates, which uniquely can substitute and alternate with glucose under conditions of fuel and food deficiency. Once canonized as a noxious, toxic pathogen leading to ketoacidosis in patients with diabetes, it is now becoming increasingly clear that 3-OHB possesses a large number of beneficial, life-preserving effects in the fields of clinical science and medicine. 3-OHB, the most prominent ketone body, binds to specific hydroxyl-carboxylic acid receptors and inhibits histone deacetylase enzymes, free fatty acid receptors, and the NOD-like receptor protein 3 inflammasome, tentatively inhibiting lipolysis, inflammation, oxidative stress, cancer growth, angiogenesis, and atherosclerosis, and perhaps contributing to the increased longevity associated with exercise and caloric restriction. Clinically ketone bodies/ketogenic diets have for a long time been used to reduce the incidence of seizures in epilepsy and may have a role in the treatment of other neurological diseases such as dementia. 3-OHB also acts to preserve muscle protein during systemic inflammation and is an important component of the metabolic defense against insulin-induced hypoglycemia. Most recently, a number of studies have reported that 3-OHB dramatically increases myocardial blood flow and cardiac output in control subjects and patients with heart failure. At the moment, scientific interest in ketone bodies, in particular 3-OHB, is in a hectic transit and, hopefully, future, much needed, controlled clinical studies will reveal and determine to which extent the diverse biological manifestations of 3-OHB should be introduced medically.
Topics: 3-Hydroxybutyric Acid; Animals; Cardiovascular System; Central Nervous System; Diabetes Mellitus; Exercise; Fasting; Humans; Inflammation; Ketone Bodies; Longevity; Metabolic Networks and Pathways; Metabolic Syndrome
PubMed: 32525972
DOI: 10.1210/clinem/dgaa370 -
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 -
Frontiers in Physiology 2020Key tissues are dysfunctional in obesity, diabetes, cardiovascular disease, fatty liver and other metabolic diseases. Focus has centered on individual organs as though... (Review)
Review
Key tissues are dysfunctional in obesity, diabetes, cardiovascular disease, fatty liver and other metabolic diseases. Focus has centered on individual organs as though each was isolated. Attention has been paid to insulin resistance as the key relevant pathosis, particularly insulin receptor signaling. However, many tissues play important roles in synergistically regulating metabolic homeostasis and should be considered part of a network. Our approach identifies redox as an acute regulator of the greater metabolic network. Redox reactions involve the transfer of electrons between two molecules and in this work refer to commonly shared molecules, reflective of energy state, that can readily lose electrons to increase or gain electrons to decrease the oxidation state of molecules including NAD(P), NAD(P)H, and thiols. Metabolism alters such redox molecules to impact metabolic function in many tissues, thus, responding to anabolic and catabolic stimuli appropriately and synergistically. It is also important to consider environmental factors that have arisen or increased in recent decades as putative modifiers of redox and reactive oxygen species (ROS) and thus metabolic state. ROS are highly reactive, controlled by the thiol redox state and influence the function of thousands of proteins. Lactate (L) and pyruvate (P) in cells are present in a ratio of about 10 reflective of the cytosolic NADH to NAD ratio. Equilibrium is maintained in cells because lactate dehydrogenase is highly expressed and near equilibrium. The major source of circulating lactate and pyruvate is muscle, although other tissues also contribute. Acetoacetate (A) is produced primarily by liver mitochondria where β-hydroxybutyrate dehydrogenase is highly expressed, and maintains a ratio of β-hydroxybutyrate (β) to A of about 2, reflective of the mitochondrial NADH to NAD ratio. All four metabolites as well as the thiols, cysteine and glutathione, are transported into and out of cells, due to high expression of relevant transporters. Our model supports regulation of all collaborating metabolic organs through changes in circulating redox metabolites, regardless of whether change was initiated exogenously or by a single organ. Validation of these predictions suggests novel ways to understand function by monitoring and impacting redox state.
PubMed: 33178037
DOI: 10.3389/fphys.2020.567796 -
Saudi Journal of Biological Sciences Jan 2021A new series of coumarin-yl-chalcone derivatives () had been designed and synthesized through different reactions such as aromatic addition, cyclization and...
A new series of coumarin-yl-chalcone derivatives () had been designed and synthesized through different reactions such as aromatic addition, cyclization and Claisen-Schmidt reactions in good yields (54-78%). 5-acetyl-4-(2-hydroxyphenyl) -6-methyl-3, 4-dihydropyrimidin-2(1H) -one has been synthesized by multi-component one pot reaction of salicylaldehyde, methyl acetoacetate and urea, which was further reacted with malonic acid employing ZnCl catalyst to yield 5-acetyl-4-(4-hydroxy-2-oxo-2-chromen-8-yl) -6-methyl-3, 4-dihydropyrimidin-2(1) -one The title compounds ( were synthesised by reacting 5-acetyl-4-(4-hydroxy-2-oxo-2-chromen-8-yl) -6-methyl-3, 4-dihydropyrimidin-2(1)-one () with different aromatic aldehydes in the presence of potassium hydroxide. studies, a preliminary screening method for predicting the anti-cancer activity was performed for the synthesized compounds ( against Src, Alb tyrosine kinase and homology model protein (PDB ID: 4csv). The derivatives and showed moderate binding energies. The cytotoxic activity was evaluated for the compounds and by using human cancer cell-line morphology and MTT assay against three human cell-lines A549 (Lung), Jurkat (Leukemia) and MCF-7 (Breast). The results indicate that the derivatives and display significant anti-cancer activity, however it was found to be less cytotoxic when compared to the standard used i.e. Imatinib.
PubMed: 33424321
DOI: 10.1016/j.sjbs.2020.10.020 -
Dalton Transactions (Cambridge, England... May 2023Asymmetrically substituted porphyrins possessing ethyl acetoacetate or acetylacetone (EAA or acac) with six bromine atoms at β-positions were synthesized and then...
Asymmetrically substituted porphyrins possessing ethyl acetoacetate or acetylacetone (EAA or acac) with six bromine atoms at β-positions were synthesized and then characterized by various spectroscopic techniques, such as UV-Vis, fluorescence and NMR, and also by CV, DFT, MALDI-TOF-MS and elemental analysis. The mechanistic pathway followed the nucleophilic substitution reaction (nucleophile: EAA and acac) with MTPP(NO)Br (M = 2H, Cu(II), and Ni(II)), and the resultant β-heptasubstituted porphyrins exhibited keto-enol tautomerism, as supported by H NMR spectroscopy. The six bulky bromo and EAA/acac groups made the macrocyclic ring highly electron deficient and nonplanar such that the quantum yield and fluorescence intensity for HTPP[EAA]Br and HTPP[acac]Br were severely reduced in contrast to those values for HTPP. The poor electron density and nonplanarity over the porphyrin ring shifted the first oxidation potential from 11 to 521 mV anodically for MTPP[X]Br [M = 2H, Cu(II), and Ni(II); X = EAA or acac] as compared to corresponding MTPPs. Notably, density functional theory proved the nonplanarity of the synthesized porphyrins as Δ24 spans from ±0.546 to ± 0.559 Å while Δ stretches from ±0.973 to ±1.162 Å. The third-order nonlinear optical measurements were performed using the femtosecond pulsed laser -scan technique at 800 nm and 1 kHz repetition rate to acquire insights into nonlinear absorption and nonlinear refraction of the porphyrins. The three-photon absorption coefficients () are in the range of 2.2 × 10-2.8 × 10 cm W and the nonlinear refractive index values were in the range of 3.7 × 10-5.1 × 10 cm W. The higher-order nonlinear absorption exhibited by porphyrins helps improve resolution at depth for various photonic and optoelectronic applications.
PubMed: 37005971
DOI: 10.1039/d3dt00005b -
The FEBS Journal May 2023Exploring mechanisms responsible for brown adipose tissue's (BAT) high metabolic activity is crucial to exploit its energy-dissipating ability for therapeutic purposes....
Exploring mechanisms responsible for brown adipose tissue's (BAT) high metabolic activity is crucial to exploit its energy-dissipating ability for therapeutic purposes. Basigin (Bsg), a multifunctional highly glycosylated transmembrane protein, was recently proposed as one of the 98 critical markers allowing to distinguish 'white' and 'brown' adipocytes, yet its function in thermogenic brown adipocytes is unknown. Here, we report that Bsg is negatively associated with obesity in mice. By contrast, Bsg expression increased in the mature adipocyte fraction of BAT upon cold acclimation. Additionally, Bsg levels were highly induced during brown adipocyte maturation in vitro and were further increased upon β-adrenergic stimulation in a HIF-1α-dependent manner. siRNA-mediated Bsg gene silencing in cultured brown adipocytes did not impact adipogenesis nor mitochondrial function. However, a significant decrease in mitochondrial respiration, lipolysis and Ucp1 transcription was observed in adipocytes lacking Bsg, when activated by norepinephrine. Furthermore, using gas chromatography/mass spectrometry-time-of-flight analysis to assess the composition of cellular metabolites, we demonstrate that brown adipocytes lacking Bsg have lower levels of intracellular lactate and acetoacetate. Bsg was additionally required to regulate intracellular AcAc and tricarboxylic acid cycle intermediate levels in NE-stimulated adipocytes. Our study highlights the critical role of Bsg in active brown adipocytes, possibly by controlling cellular metabolism.
Topics: Mice; Animals; Adipocytes, Brown; Adipose Tissue, Brown; Basigin; Lipolysis; Obesity; Thermogenesis; Uncoupling Protein 1
PubMed: 36595342
DOI: 10.1111/febs.16716