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Nutrients Oct 2023In glucose-deprived conditions, ketone bodies are produced by the liver mitochondria, through the catabolism of fatty acids, and are used peripherally, as an alternative... (Review)
Review
In glucose-deprived conditions, ketone bodies are produced by the liver mitochondria, through the catabolism of fatty acids, and are used peripherally, as an alternative energy source. Ketones are produced in the body under normal conditions, including during pregnancy and the neonatal period, when following a ketogenic diet (KD), fasting, or exercising. Additionally, ketone synthesis is also augmented under pathological conditions, including cases of diabetic ketoacidosis (DKA), alcoholism, and several metabolic disorders. Nonetheless, diet is the main regulator of total body ketone concentrations. The KDs are mimicking the fasting state, altering the default metabolism towards the use of ketones as the primary fuel source. Recently, KD has gained recognition as a medical nutrition therapy for a plethora of metabolic conditions, including obesity and diabetes mellitus (DM). The present review aims to discuss the role of ketones, KDs, ketonemia, and ketonuria in DM, presenting all the available new evidence in a comprehensive manner.
Topics: Female; Pregnancy; Infant, Newborn; Humans; Ketone Bodies; Ketones; Diabetic Ketoacidosis; Ketosis; Glucose; Diet, Ketogenic; Metabolic Diseases; Diabetes Mellitus
PubMed: 37892458
DOI: 10.3390/nu15204383 -
Frontiers in Physiology 2023Ketones are alternative energy substrates for the heart and kidney but no studies have investigated their metabolism simultaneously in both organs in humans. The present...
Ketones are alternative energy substrates for the heart and kidney but no studies have investigated their metabolism simultaneously in both organs in humans. The present double tracer positron emission tomography (PET) study evaluated the organ distribution and basal kinetic rates of the radiolabeled ketone, C-acetoacetate (C-AcAc), in the heart and kidney compared to C-acetate (C-Ac), which is a well-validated metabolic radiotracer. Both tracers were highly metabolized by the left ventricle and the renal cortex. In the heart, kinetic rates were similar for both tracers. But in the renal cortex, uptake of C-Ac was higher compared to C-AcAc, while the reverse was observed for the clearance. Interestingly, infusion of C-AcAc led to a significantly delayed release of radioactivity in the renal medulla and pelvis, a phenomenon not observed with C-Ac. This suggests an equilibrium of C-AcAc with the other ketone, C-D-beta-hydroxybutyrate, and a different clearance profile. Overall, this suggests that in the kidney, the absorption and metabolism of C-AcAc is different compared to C-Ac. This dual tracer PET protocol provides the opportunity to explore the relative importance of ketone metabolism in cardiac and renal diseases, and to improve our mechanistic understanding of new metabolic interventions targeting these two organs.
PubMed: 37869718
DOI: 10.3389/fphys.2023.1280191 -
MethodsX Dec 2023Camphor is synthesized from the Sumatran camphor plant () in previous experiments. It can be synthesized with thiosemicarbazide, ethy-2‑chloro acetoacetate, and sodium...
Camphor is synthesized from the Sumatran camphor plant () in previous experiments. It can be synthesized with thiosemicarbazide, ethy-2‑chloro acetoacetate, and sodium acetate (catalyze) to form camphor derivate with thiazole ring structure. Hydrazine and phenylhydrazine were both used to make the thiazole ring variations. All the compounds were purified by recrystallization method and characterized by TLC, FTIR, UV-vis, and LC-MS Camphor thiazole (Product 1), camphor thiazole hydrazine (Product 2), and camphor thiazole phenylhydrazine (Product 3) were successfully synthesized with%yields of 73.24 %; 77.36 %; and 72.91 % respectively. Furthermore, their antioxidant activity was measured using the DPPH free radical method. Product 2 had the strongest antioxidant activity with IC value of 6.93 ppm. The antidiabetic activity was measured using the α-glucosidase enzyme. This indicated that product 1 had the best inhibitory activity against the α-glucosidase enzyme with IC values of 869.06 ppm.•We developed an alternative method to utilize camphor extracted from the plant to be used as an alternative medicinal ingredient related to antioxidants and antidiabetes.•All products were successfully synthesized and have the potential to be used as antioxidants with an IC value of 6.93 ppm for Product 2 and as antidiabetics by means of an α-glucosidase inhibitor with an IC value of 869.06 ppm for Product 1.
PubMed: 37867914
DOI: 10.1016/j.mex.2023.102429 -
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 -
Scientific Reports Oct 2023In this study, a Co-MOF was synthesized via a co-precipitation procedure and then used as support for stabilizing Ag ions and producing Co-MOF@AgO nanocomposite by...
In this study, a Co-MOF was synthesized via a co-precipitation procedure and then used as support for stabilizing Ag ions and producing Co-MOF@AgO nanocomposite by microwave irradiation. The characterization of synthesized Co-MOF@AgO nanocomposite was performed by using different techniques such as field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray (EDX) analyses, X-ray diffraction (XRD), Thermogravimetric analysis (TGA), Brunauer-Emmett-Teller (BET) and Fourier-transform infrared (FT-IR). The prepared Co-MOF@AgO nanocomposite was applied as a heterogeneous nano-catalyst in the synthesis of pyrazolopyranopyrimidines in water at 50 °C via the one-pot multicomponent reaction of ethyl acetoacetate, hydrazine hydrate, aromatic aldehydes and barbituric acid derivatives. Through this straightforward and effective protocol, different tricyclic fused pyrazolopyranopyrimidines were synthesized at high yields, and short reaction times, through an uncomplicated work-up process with no by-product. The Co-MOF@AgO nanocomposite has been effectively recycled for four consecutive cycles without appreciable loss in its activity. Cost-effectiveness, no need for column chromatography, mild conditions, catalyst recyclability, and eco-friendly nature make it a promising candidate compared to other methods.
PubMed: 37840041
DOI: 10.1038/s41598-023-44667-6 -
Acta Crystallographica. Section E,... Oct 2023The title com-pound, CHFNO, a highly functionalized tetra-hydro-pyridine, was synthesized by a one-pot multi-com-ponent reaction of 4-fluoro-aniline, ethyl aceto-acetate...
Synthesis, crystal structure, Hirshfeld surface analysis, DFT and NBO study of ethyl 1-(4-fluoro-phen-yl)-4-[(4-fluoro-phen-yl)amino]-2,6-diphenyl-1,2,5,6-tetra-hydro-pyridine-3-carboxyl-ate.
The title com-pound, CHFNO, a highly functionalized tetra-hydro-pyridine, was synthesized by a one-pot multi-com-ponent reaction of 4-fluoro-aniline, ethyl aceto-acetate and benzaldehyde at room temperature using sodium lauryl sulfate as a catalyst. The com-pound crystallizes with two mol-ecules in the asymmetric unit. The tetra-hydro-pyridine ring adopts a distorted boat conformation in both mol-ecules and the dihedral angles between the planes of the fluoro-substituted rings are 77.1 (6) and 77.3 (6)°. The amino group and carbonyl O atom are involved in an intra-molecular N-H⋯O hydrogen bond, thereby generating an (6) ring motif. In the crystal, mol-ecules are linked by C-H⋯F hydrogen bonds forming a three-dimensional network and C-H⋯π inter-actions. A Hirshfeld surface analysis of the crystal structure indicates that the most important contributions to the crystal packing are from H⋯H (47.9%), C⋯H/H⋯C (30.7%) and F⋯H/H⋯F (12.4%) contacts. The optimized structure calculated using density functional theory (DFT) at the B3LYP/6-311+G(2d,p) level is compared with the experimentally determined molecular structure in the solid state. The HOMO-LUMO behaviour was used to determine the energy gap and the Natural Bond Orbital (NBO) analysis was done to study donor-acceptor interconnections.
PubMed: 37817948
DOI: 10.1107/S205698902300748X -
Revista Medica Del Instituto Mexicano... Sep 2023Succinyl-CoA:3 oxoacid CoA transferase deficiency (SCOTD) is a rare autosomal recessive disease, characterized by altered utilization of ketone bodies, with acute...
BACKGROUND
Succinyl-CoA:3 oxoacid CoA transferase deficiency (SCOTD) is a rare autosomal recessive disease, characterized by altered utilization of ketone bodies, with acute episodes of ketoacidosis.
CLINICAL CASE
It is presented the case of a patient with SCOTD, with a first atypical episode accompanied by hyperglycemia, with 4 subsequent episodes with classic manifestations of the disease, presenting with a biochemical pattern of permanent ketonuria with marked elevation of ketone bodies (acetoacetate, 3 beta-hydroxybutyrate) in the study of urinary organic acids by gas chromatography and mass spectrometry, together with the clinical picture granting the diagnosis. It was started a maintenance therapy with a characteristic feeding plan; it was shown an adequate response to treatment, and the absence of permanent ketosis was surmised.
CONCLUSION
Being a rare disease, the categorization of these patients as diabetic ketoacidosis is frequent. The clinical and biochemical characteristics with ketosis or persistent ketonuria should be analyzed very carefully, especially in patients presenting with hyperglycemia, which is an atypical manifestation of the disease, in order to make an early diagnosis and treatment, positively impacting the prognosis of patients.
Topics: Humans; Coenzyme A-Transferases; Ketone Bodies; Ketosis; 3-Hydroxybutyric Acid; Hyperglycemia
PubMed: 37773183
DOI: 10.5281/zenodo.8316483 -
Journal of Atherosclerosis and... Dec 2023Ketone bodies, consisting of beta-hydroxybutyrate, acetoacetate, and acetone, are metabolic byproducts known as energy substrates during fasting. Recent advancements... (Review)
Review
Ketone bodies, consisting of beta-hydroxybutyrate, acetoacetate, and acetone, are metabolic byproducts known as energy substrates during fasting. Recent advancements have shed light on the multifaceted effects of ketone body metabolism, which led to increased interest in therapeutic interventions aimed at elevating ketone body levels. However, excessive elevation of ketone body concentration can lead to ketoacidosis, which may have fatal consequences. Therefore, in this review, we aimed to focus on the latest insights on ketone body metabolism, particularly emphasizing its association with mitochondria as the primary site of interaction. Given the distinct separation between ketone body synthesis and breakdown pathways, we provide an overview of each metabolic pathway. Additionally, we discuss the relevance of ketone bodies to conditions such as nonalcoholic fatty liver disease or nonalcoholic steatohepatitis and cardiovascular diseases. Moreover, we explore the utilization of ketone body metabolism, including dietary interventions, in the context of aging, where mitochondrial dysfunction plays a crucial role. Through this review, we aim to present a comprehensive understanding of ketone body metabolism and its intricate relationship with mitochondrial function, spanning the potential implications in various health conditions and the aging process.
Topics: Humans; Cardiovascular Diseases; Ketone Bodies; 3-Hydroxybutyric Acid; Acetone; Non-alcoholic Fatty Liver Disease; Mitochondria
PubMed: 37766574
DOI: 10.5551/jat.RV22011 -
Biomedicines Sep 2023The ketone bodies, sodium and lithium salts of acetoacetate (AcAc) and sodium 3-hydroxybutyrate (3-HB; commonly called beta-hydroxybutyrate) have been found to inhibit...
The ketone bodies, sodium and lithium salts of acetoacetate (AcAc) and sodium 3-hydroxybutyrate (3-HB; commonly called beta-hydroxybutyrate) have been found to inhibit the proliferation of cancer cells. Previous studies have suggested that lithium itself may be an inhibiting agent but may be additive or synergistic with the effect of AcAc. We previously found that sodium acetoacetate (NaAcAc) inhibits the growth of human colon cancer cell line SW480. We report here similar results for several other cancer cell lines including ovarian, cervical and breast cancers. We found that NaAcAc does not kill cancer cells but rather blocks their proliferation. Similar inhibition of growth was seen in the effect of lithium ion alone (as LiCl). The effect of LiAcAc appears to be due to the combined effects of acetoacetate and the lithium ion. The ketone bodies, when given together with chemotherapeutic agents, rapamycin, methotrexate and the new peptide anti-cancer agent, PNC-27, substantially lowers their IC values for cancer cell, killing suggesting that ketone bodies and ketogenic diets may be powerful adjunct agents in treating human cancers.
PubMed: 37760956
DOI: 10.3390/biomedicines11092515 -
Antioxidants (Basel, Switzerland) Sep 2023In the pursuit of longevity and healthspan, we are challenged with first overcoming chronic diseases of ageing: cardiovascular disease, hypertension, cancer, dementias,...
In the pursuit of longevity and healthspan, we are challenged with first overcoming chronic diseases of ageing: cardiovascular disease, hypertension, cancer, dementias, type 2 diabetes mellitus. These are hyperinsulinaemia diseases presented in different tissue types. Hyperinsulinaemia reduces endogenous antioxidants, via increased consumption and reduced synthesis. Hyperinsulinaemia enforces glucose fuelling, consuming 4 NAD to produce 2 acetyl moieties; beta-oxidation, ketolysis and acetoacetate consume 2, 1 and 0, respectively. This decreases sirtuin, PARPs and oxidative management capacity, leaving reactive oxygen species to diffuse to the cytosol, upregulating aerobic glycolysis, NF-kB and cell division signalling. Also, oxidising cardiolipin, reducing oxidative phosphorylation (OXPHOS) and apoptosis ability; driving a tumourigenic phenotype. Over time, increasing senescent/pathological cell populations occurs, increasing morbidity and mortality. Beta-hydroxybutyrate, an antioxidant, metabolite and signalling molecule, increases synthesis of antioxidants via preserving NAD availability and enhancing OXPHOS capacity. Fasting and ketogenic diets increase ketogenesis concurrently decreasing insulin secretion and demand; hyperinsulinaemia inhibits ketogenesis. Lifestyles that maintain lower insulin levels decrease antioxidant catabolism, additionally increasing their synthesis, improving oxidative stress management and mitochondrial function and, subsequently, producing healthier cells. This supports tissue and organ health, leading to a better healthspan, the first challenge that must be overcome in the pursuit of youthful longevity.
PubMed: 37760052
DOI: 10.3390/antiox12091749