-
Molecular Nutrition & Food Research Sep 2023Vitamin D is vital to cardiovascular health. This study examines the association between plasma 25-hydroxyvitamin D (25[OH]D) and the progression of carotid intima-media...
SCOPE
Vitamin D is vital to cardiovascular health. This study examines the association between plasma 25-hydroxyvitamin D (25[OH]D) and the progression of carotid intima-media thickness (cIMT) and identifies the potential mediating biomarkers of gut microbiota and metabolites in adults.
METHODS AND RESULTS
This 9-year prospective study includes 2975 subjects with plasma 25(OH)D at baseline and determined cIMT every 3 years. Higher circulating 25(OH)D is associated with decreased odds of higher (≥median) 9-year cIMT changes at the common carotid artery (hΔCCA-cIMT) (p-trend < 0.001). Multivariable-adjusted OR (95%CI) of hΔCCA-cIMT for tertiles 2 and 3 (vs. 1) of 25(OH)D is 0.87 (0.73-1.04) and 0.68 (0.57-0.82). Gut microbiome and metabolome analysis identify 18 biomarkers significantly associated with both 25(OH)D and hΔCCA-cIMT, including three microbial genera, seven fecal metabolites, eight serum metabolites, and pathway of synthesis and degradation of ketone bodies. Mediation/path analyses show the scores generated from the overlapped differential gut microbiota, fecal and serum metabolites, and serum acetoacetic acid alone could mediate the beneficial association between 25(OH)D and hΔCCA-cIMT by 10.8%, 23.1%, 59.2%, and 62.0% (all p < 0.05), respectively.
CONCLUSIONS
These findings show a beneficial association between plasma 25(OH)D and the CCA-cIMT progression. The identified multi-omics biomarkers provide novel mechanistic insights for the epidemiological association.
Topics: Humans; Adult; Carotid Intima-Media Thickness; Gastrointestinal Microbiome; Prospective Studies; Vitamin D; Calcifediol; Biomarkers; Risk Factors
PubMed: 37377073
DOI: 10.1002/mnfr.202300017 -
Metabolites Nov 2021Renal cell carcinoma (RCC) is the most common form of kidney malignancy. RCC is more common among men with a 2/1 male/female incidence ratio worldwide. Given the...
Renal cell carcinoma (RCC) is the most common form of kidney malignancy. RCC is more common among men with a 2/1 male/female incidence ratio worldwide. Given the underlying epidemiological differences in the RCC incidence between males and females, we explored the gender specific H NMR serum metabolic profiles of RCC patients and their matched controls. A number of differential metabolites were shared by male and female RCC patients. These RCC specific changes included lower lactate, threonine, histidine, and choline levels together with increased levels of pyruvate, -acetylated glycoproteins, beta-hydroxybutyrate, acetoacetate, and lysine. Additionally, serum lactate/pyruvate ratio was a strong predictor of RCC status regardless of gender. Although only moderate changes in metabolic profiles were observed between control males and females there were substantial gender related differences among RCC patients. Gender specific metabolic features associated with RCC status were identified suggesting that different metabolic panels could be leveraged for a more precise diagnostic.
PubMed: 34822425
DOI: 10.3390/metabo11110767 -
Oncogene Jul 2023The International Agency for Research on Cancer determined that obesity is the primary preventable cause of breast cancer. The nuclear receptor peroxisome proliferator...
The International Agency for Research on Cancer determined that obesity is the primary preventable cause of breast cancer. The nuclear receptor peroxisome proliferator activated receptor γ (PPARγ) binds inflammatory mediators in obesity and its expression is reduced in human breast cancer. We created a new model to better understand how the obese microenvironment alters nuclear receptor function in breast cancer. The obesity related cancer phenotype was PPARγ dependent; deletion of PPARγ in mammary epithelium which is a tumor suppressor in lean mice unexpectedly increased tumor latency, reduced the luminal progenitor (LP) tumor cell fraction, and increased autophagic and senescent cells. Loss of PPARγ expression in mammary epithelium of obese mice increased expression of 2-aminoadipate semialdehyde synthase (AASS) which regulates lysine catabolism to acetoacetate. PPARγ-associated co-repressors and activators regulated AASS expression via a canonical response element. AASS expression was significantly reduced in human breast cancer, and AASS overexpression or acetoacetate treatment inhibited proliferation and induced autophagy and senescence in human breast cancer cell lines. Genetic or pharmacologic HDAC inhibition promoted autophagy and senescence in mammary tumor cells in vitro and in vivo. We concluded that lysine metabolism is a novel metabolic tumor suppressor pathway in breast cancer.
Topics: Mice; Humans; Animals; Female; Breast Neoplasms; PPAR gamma; Lysine; Acetoacetates; Obesity; Tumor Microenvironment
PubMed: 37393340
DOI: 10.1038/s41388-023-02766-8 -
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 -
Journal of Materials Chemistry. B Apr 2022Emulsion hydrogels are structurally composite materials combining the advantages of emulsions and hydrogels with the ability to accommodate hydrophobic and hydrophilic...
Emulsion hydrogels are structurally composite materials combining the advantages of emulsions and hydrogels with the ability to accommodate hydrophobic and hydrophilic components in one system. It is a promising strategy for the excellent encapsulation and delivery of many bioactive ingredients. In this work, the thyme oil-loaded zwitterionic emulsion hydrogels are constructed by the cellulose acetoacetate-horseradish peroxidase-hydrogen peroxide-initiated (CAA-HRP-HO-initiated) ternary enzyme-mediated polymerization of the thyme oil-in-water (O/W) emulsions stabilized by cellulose acetoacetate (CAA). CAA is the key component in the system, acting as the emulsifier and the polymerization mediator simultaneously. The formed zwitterionic poly(sulfobetaine methacrylate) (PSBMA) hydrogel network provides emulsion hydrogels with good hydration capacity and potential anti-fouling performance. The thyme oil-loaded zwitterionic emulsion hydrogels exhibit interconnected, uniform, and adjustable porous structures with tunable mechanical properties, antifouling performance, good biocompatibility, and excellent antibacterial activity against and . These results all demonstrate that the ternary enzyme-mediated polymerization of zwitterionic monomers in the continuous phase of O/W emulsion templates is a facile and efficient strategy to encapsulate hydrophobic bioactive ingredients.
Topics: Anti-Bacterial Agents; Emulsions; Escherichia coli; Hydrogels; Hydrogen Peroxide; Plant Oils; Staphylococcus aureus; Thymol; Thymus Plant
PubMed: 35098955
DOI: 10.1039/d1tb02853g -
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 -
Metabolites Jun 2023Opposing evidence exists for the source of the hydrogen ions (H) during ketoacidosis. Organic and computational chemistry using dissociation constants and alpha...
Opposing evidence exists for the source of the hydrogen ions (H) during ketoacidosis. Organic and computational chemistry using dissociation constants and alpha equations for all pertinent ionizable metabolites were used to (1) document the atomic changes in the chemical reactions of ketogenesis and ketolysis and (2) identify the sources and quantify added fractional (~) H exchange (~He). All computations were performed for pH conditions spanning from 6.0 to 7.6. Summation of the ~He for given pH conditions for all substrates and products of each reaction of ketogenesis and ketolysis resulted in net reaction and pathway ~He coefficients, where negative revealed ~H release and positive revealed ~H uptake. Results revealed that for the liver (pH = 7.0), the net ~He for the reactions of ketogenesis ending in each of acetoacetate (AcAc), β-hydroxybutyrate (β-HB), and acetone were -0.9990, 0.0026, and 0.0000, respectively. During ketogenesis, ~H release was only evident for HMG CoA production, which is caused by hydrolysis and not ~H dissociation. Nevertheless, there is a net ~H release during ketogenesis, though this diminishes with greater proportionality of acetone production. For reactions of ketolysis in muscle (pH = 7.1) and brain (pH = 7.2), net ~H coefficients for β-HB and AcAc oxidation were -0.9649 and 0.0363 (muscle), and -0.9719 and 0.0291 (brain), respectively. The larger ~H release values for β-HB oxidation result from covalent ~H release during the oxidation-reduction. For combined ketogenesis and ketolysis, which would be the metabolic condition in vivo, the net ~H coefficient depends once again on the proportionality of the final ketone body product. For ketone body production in the liver, transference to blood, and oxidation in the brain and muscle for a ratio of 0.6:0.2:0.2 for β-HB:AcAc:acetone, the net ~He coefficients for liver ketogenesis, blood transfer, brain ketolysis, and net total (ketosis) equate to -0.1983, -0.0003, -0.2872, and -0.4858, respectively. The traditional theory of ketone bodies being metabolic acids causing systemic acidosis is incorrect. Summation of ketogenesis and ketolysis yield H coefficients that differ depending on the proportionality of ketone body production, though, in general, there is a small net H release during ketosis. Products formed during ketogenesis (HMG-CoA, acetoacetate, β-hydroxybutyrate) are created as negatively charged bases, not acids, and the final ketone body, acetone, does not have pH-dependent ionizable groups. Proton release or uptake during ketogenesis and ketolysis are predominantly caused by covalent modification, not acid dissociation/association. Ketosis (ketogenesis and ketolysis) results in a net fractional H release. The extent of this release is dependent on the final proportionality between acetoacetate, β-hydroxybutyrate, and acetone.
PubMed: 37512510
DOI: 10.3390/metabo13070803 -
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 Molecular Neuroscience 2023A growing body of evidence supports the beneficial effects of the ketone bodies (KBs), acetoacetate and β-hydroxybutyrate (BHB), on diverse physiological processes and... (Review)
Review
A growing body of evidence supports the beneficial effects of the ketone bodies (KBs), acetoacetate and β-hydroxybutyrate (BHB), on diverse physiological processes and diseases. Hence, KBs have been suggested as therapeutic tools for neurodegenerative diseases. KBs are an alternative fuel during fasting and starvation as they can be converted to Ac-CoA to produce ATP. A ketogenic diet (KD), enriched in fats and low in carbohydrates, induces KB production in the liver and favors their use in the brain. BHB is the most abundant KB in the circulation; in addition to its role as energy fuel, it exerts many actions that impact the set of proteins in the cell and tissue. BHB can covalently bind to proteins in lysine residues as a new post-translational modification (PTM) named β-hydroxybutyrylation (Kbhb). Kbhb has been identified in many proteins where Kbhb sites can be critical for binding to other proteins or cofactors. Kbhb is mostly found in proteins involved in chromatin structure, DNA repair, regulation of spliceosome, transcription, and oxidative phosphorylation. Histones are the most studied family of proteins with this PTM, and H3K9bhb is the best studied histone mark. Their target genes are mainly related to cell metabolism, chromatin remodeling and the control of circadian rhythms. The role of Kbhb on physiological processes is poorly known, but it might link KB metabolism to cell signaling and genome regulation. BHB also impacts the proteome by influencing proteostasis. This KB can modulate the Unfolded Protein Response (UPR) and autophagy, two processes involved in the maintenance of protein homeostasis through the clearance of accumulated unfolded and damaged proteins. BHB can support proteostasis and regulate the UPR to promote metabolism adaptation in the liver and prevent cell damage in the brain. Also, BHB stimulates autophagy aiding to the degradation of accumulated proteins. Protein aggregation is common to proteinopathies like Alzheimer's (AD) and Parkinson's (PD) diseases, where the KD and BHB treatment have shown favorable effects. In the present review, the current literature supporting the effects of KBs on proteome conformation and proteostasis is discussed, as well as its possible impact on AD and PD.
PubMed: 37575967
DOI: 10.3389/fnmol.2023.1214092 -
Angewandte Chemie (International Ed. in... Sep 2023Devising energy-efficient strategies for the depolymerization of plastics and the recovery of their structural components in high yield and purity is key to a circular...
Devising energy-efficient strategies for the depolymerization of plastics and the recovery of their structural components in high yield and purity is key to a circular plastics economy. Here, we report a case study in which we demonstrate that vinylogous urethane (VU) vitrimers synthesized from bis-polyethylene glycol acetoacetates (aPEG) and tris(2-aminoethyl)amine can be degraded by water at moderate temperature with almost quantitative recovery (≈98 %) of aPEG. The rate of depolymerization can be controlled by the temperature, amount of water, molecular weight of aPEG, and composition of the starting material. These last two parameters also allow one to tailor the mechanical properties of the final materials, and this was used to access soft, tough, and brittle vitrimers, respectively. The straightforward preparation and depolymerization of the aPEG-based VU vitrimers are interesting elements for the design of polymer materials with enhanced closed-loop recycling characteristics.
PubMed: 37439363
DOI: 10.1002/anie.202306188