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Journal of Autoimmunity May 2024In polymyalgia rheumatica (PMR), glucocorticoids (GCs) relieve pain and stiffness, but fatigue may persist. We aimed to explore the effect of disease, GCs and PMR...
OBJECTIVE
In polymyalgia rheumatica (PMR), glucocorticoids (GCs) relieve pain and stiffness, but fatigue may persist. We aimed to explore the effect of disease, GCs and PMR symptoms in the metabolite signatures of peripheral blood from patients with PMR or the related disease, giant cell arteritis (GCA).
METHODS
Nuclear magnetic resonance spectroscopy was performed on serum from 40 patients with untreated PMR, 84 with new-onset confirmed GCA, and 53 with suspected GCA who later were clinically confirmed non-GCA, and 39 age-matched controls. Further samples from PMR patients were taken one and six months into glucocorticoid therapy to explore relationship of metabolites to persistent fatigue. 100 metabolites were identified using Chenomx and statistical analysis performed in SIMCA-P to examine the relationship between metabolic profiles and, disease, GC treatment or symptoms.
RESULTS
The metabolite signature of patients with PMR and GCA differed from that of age-matched non-inflammatory controls (R > 0.7). There was a smaller separation between patients with clinically confirmed GCA and those with suspected GCA who later were clinically confirmed non-GCA (R = 0.135). In PMR, metabolite signatures were further altered with glucocorticoid treatment (R = 0.42) but did not return to that seen in controls. Metabolites correlated with CRP, pain, stiffness, and fatigue (R ≥ 0.39). CRP, pain, and stiffness declined with treatment and were associated with 3-hydroxybutyrate and acetoacetate, but fatigue did not. Metabolites differentiated patients with high and low fatigue both before and after treatment (R > 0.9). Low serum glutamine was predictive of high fatigue at both time points (0.79-fold change).
CONCLUSION
PMR and GCA alter the metabolite signature. In PMR, this is further altered by glucocorticoid therapy. Treatment-induced metabolite changes were linked to measures of inflammation (CRP, pain and stiffness), but not to fatigue. Furthermore, metabolite signatures distinguished patients with high or low fatigue.
PubMed: 38797046
DOI: 10.1016/j.jaut.2024.103260 -
The Oncologist May 2024Patients with radioiodine-refractory (RAIR) differentiated thyroid carcinoma (DTC; RAIR-DTC) have a poor prognosis. The aim of this study was to provide new insights and...
OBJECTIVE
Patients with radioiodine-refractory (RAIR) differentiated thyroid carcinoma (DTC; RAIR-DTC) have a poor prognosis. The aim of this study was to provide new insights and possibilities for the diagnosis and treatment of RAIR-DTC.
METHODS
The metabolomics of 24 RAIR-DTC and 18 non-radioiodine-refractory (NonRAIR) DTC patients samples were analyzed by liquid chromatograph-mass spectrometry. Cellular radioiodine uptake was detected with γ counter. Sodium iodide symporter (NIS) expression and thyroid stimulating hormone receptor (TSHR) were measured by Western blot analysis. CCK8 and colony formation assays were used to measure cellular proliferation. Scratch and transwell assays were performed to assess cell migration and invasion. Annexin V/PI staining was used to detect cell apoptosis. Cell growth in vivo was evaluated by a tumor xenograft model. The acetoacetate (AcAc) level was measured by ELISA. Pathological changes, Ki67, NIS, and TSHR expression were investigated by immunohistochemistry.
RESULTS
The metabolite profiles of RAIR could be distinguished from those of NonRAIR, with AcAc significantly lower in RAIR. The significantly different metabolic pathway was ketone body metabolism. AcAc increased NIS and TSHR expression and improved radioiodine uptake. AcAc inhibited cell proliferation, migration, and invasion, and as well promoted cell apoptosis. Ketogenic diet (KD) elevated AcAc levels and significantly suppressed tumor growth, as well as improved NIS and TSHR expression.
CONCLUSION
Significant metabolic differences were observed between RAIR and NonRAIR, and ketone body metabolism might play an important role in RAIR-DTC. AcAc improved cellular iodine uptake and had antitumor effects for thyroid carcinoma. KD might be a new therapeutic strategy for RAIR-DTC.
PubMed: 38760956
DOI: 10.1093/oncolo/oyae075 -
Frontiers in Endocrinology 2024This feasibility study aimed to investigate the use of exhaled breath analysis to capture and quantify relative changes of metabolites during resolution of acute...
PURPOSE
This feasibility study aimed to investigate the use of exhaled breath analysis to capture and quantify relative changes of metabolites during resolution of acute diabetic ketoacidosis under insulin and rehydration therapy.
METHODS
Breath analysis was conducted on 30 patients of which 5 with DKA. They inflated Nalophan bags, and their metabolic content was subsequently interrogated by secondary electrospray ionization high-resolution mass spectrometry (SESI-HRMS).
RESULTS
SESI-HRMS analysis showed that acetone, pyruvate, and acetoacetate, which are well known to be altered in DKA, were readily detectable in breath of participants with DKA. In addition, a total of 665 mass spectral features were found to significantly correlate with base excess and prompt metabolic trajectories toward an in-control state as they progress toward homeostasis.
CONCLUSION
This study provides proof-of-principle for using exhaled breath analysis in a real ICU setting for DKA monitoring. This non-invasive new technology provides new insights and a more comprehensive overview of the effect of insulin and rehydration during DKA treatment.
Topics: Humans; Diabetic Ketoacidosis; Breath Tests; Male; Female; Adult; Middle Aged; Insulin; Feasibility Studies; Fluid Therapy; Aged; Biomarkers; Spectrometry, Mass, Electrospray Ionization
PubMed: 38752172
DOI: 10.3389/fendo.2024.1360989 -
Frontiers in Neuroscience 2024HIV can invade the central nervous system (CNS) early during infection, invading perivascular macrophages and microglia, which, in turn, release viral particles and...
BACKGROUND
HIV can invade the central nervous system (CNS) early during infection, invading perivascular macrophages and microglia, which, in turn, release viral particles and immune mediators that dysregulate all brain cell types. Consequently, children living with HIV often present with neurodevelopmental delays.
METHODS
In this study, we used proton nuclear magnetic resonance (H-NMR) spectroscopy to analyze the neurometabolic profile of HIV infection using cerebrospinal fluid samples obtained from 17 HIV+ and 50 HIV- South African children.
RESULTS
Nine metabolites, including glucose, lactate, glutamine, 1,2-propanediol, acetone, 3-hydroxybutyrate, acetoacetate, 2-hydroxybutyrate, and myo-inositol, showed significant differences when comparing children infected with HIV and those uninfected. These metabolites may be associated with activation of the innate immune response and disruption of neuroenergetics pathways.
CONCLUSION
These results elucidate the neurometabolic state of children infected with HIV, including upregulation of glycolysis, dysregulation of ketone body metabolism, and elevated reactive oxygen species production. Furthermore, we hypothesize that neuroinflammation alters astrocyte-neuron communication, lowering neuronal activity in children infected with HIV, which may contribute to the neurodevelopmental delay often observed in this population.
PubMed: 38745940
DOI: 10.3389/fnins.2024.1270041 -
BMC Chemistry May 2024The pursuit of advanced multifunctional compounds has gained significant momentum in recent scientific endeavours. This study is dedicated to elucidating the synthesis,...
The pursuit of advanced multifunctional compounds has gained significant momentum in recent scientific endeavours. This study is dedicated to elucidating the synthesis, rigorous characterization, and multifaceted applications-encompassing anti-corrosion, antimicrobial, and antioxidant properties-of Diethyl 4-(5-bromo-1H-indol-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate. The 1,4-dihydropyridine derivative was meticulously synthesized through a strategic reaction of ethyl acetoacetate, ammonium acetate, and 5-bromoindole-3-carboxaldehydein the ethanol medium at 60 C. Subsequent spectral validations were conducted using sophisticated techniques, namely FTIR, NMR, and Mass spectrometry, resulting in data that perfectly resonated with the hypothesized chemical structure of the compound. Its anti-corrosive potential was assessed on mild steel subjected to an aggressive acidic environment, employing comprehensive methodologies like gravimetric analysis, Tafel polarization, and EIS. Concurrently, its antimicrobial prowess was ascertained against a spectrum of bacterial and fungal pathogens viz., Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas, Candida albicansandAspergillusniger, leveraging the disc diffusion method and using Gentamicin as a reference standard.The empirical results illustrated a substantial decrement in corrosion rates with ascending concentrations of the organic compound, achieving an apex of anti-corrosive efficacy at 81.89% for a concentration of 2 × 10 M. Furthermore, the compound outperformed Gentamicin in antimicrobial screenings, manifesting superior efficacy against all tested pathogens. The antioxidant potential, quantified using the DPPH free radical scavenging assay against ascorbic acid as a benchmark, was found to have an IC value of 113.964 ± 0.076 µg/ml.This comprehensive investigation accentuates the paramount potential of the synthesized dihydropyridine derivative in diverse domains-from industrial applications as a corrosion inhibitor to therapeutic avenues given its pronounced antimicrobial and antioxidant capabilities. The compelling results obtained pave the way for expansive research and development initiatives cantered around this multifaceted compound.
PubMed: 38730412
DOI: 10.1186/s13065-024-01123-4 -
Frontiers in Nutrition 2024The consumption of cheese and fish has been linked to the onset of depression. However, the connection between consuming cheese, consuming fish, experiencing depression,...
BACKGROUND
The consumption of cheese and fish has been linked to the onset of depression. However, the connection between consuming cheese, consuming fish, experiencing depression, and the pathways that mediate this relationship remains unclear. The purpose of this research was to investigate the potential association between the consumption of cheese and fish and the occurrence of depression. Moreover, it is important to identify any metabolites that might be involved and understand their respective roles and functions.
METHODS
A two-step, two-sample Mendelian randomization (MR) study was conducted using genome-wide association study (GWAS) data on cheese, non-oily fish, and oily fish consumption and depression, along with 12 alternate mediators. The study included a total of 451,486 participants in the cheese consumption group, 460,880 in the non-oily fish consumption group, 460,443 in the oily fish consumption group, and 322,580 with a diagnosis of depression. The single nucleotide polymorphism (SNP) estimates were pooled using inverse-variance weighted, weighted median, MR-Egger, simple mode, and weighted mode.
RESULTS
The data we collected suggested that consuming more cheese correlated with a lower likelihood of experiencing depression (OR: 0.95; 95% CI: 0.92 to 0.98). Neither non-oily fish nor oily fish consumption was directly linked to depression onset ( = 0.08, = 0.78, respectively). Although there was a direct causal relationship with depression, the mediating relationship of triglycerides (TG), total cholesterol in large HDL, cholesterol to total lipids ratio in large HDL, free cholesterol to total lipids ratio in large HDL, glycine, and phospholipids to total lipids ratio in very large HDL of cheese intake on depression risk were - 0.002 (95% CI: -0.023 - 0.020), -0.002 (95% CI: -0.049 - 0.045), -0.001 (95% CI: -0.033 - 0.031), -0.001 (95% CI: -0.018 - 0.015), 0.001 (95% CI: -0.035 - 0.037), and - 0.001 (95% CI: -0.024 - 0.021), respectively. The mediating relationship of uridine, free cholesterol to total lipids ratio in large HDL, total cholesterol in large HDL, acetoacetate, and 3-hydroxybutyrate (3-HB) between non-oily fish consumption and depression risk were 0.016 (95% CI: -0.008 - 0.040), 0.011 (95% CI: -1.269 - 1.290), 0.010 (95% CI: -1.316 - 1.335), 0.011 (95% CI: -0.089 - 0.110), and 0.008 (95% CI: -0.051 - 0.068), respectively. The mediation effect of uridine and free cholesterol to total lipids ratio in large HDL between intake of oily fish and the risk of depression was found to be 0.006 (95% CI: -0.015 - 0.028) and - 0.002 (95% CI: -0.020 - 0.017), respectively. The correlation between eating cheese and experiencing depression persisted even when adjusting for other variables like Indian snacks, mango consumption, sushi consumption, and unsalted peanuts using multivariable MR.
CONCLUSION
The consumption of cheese and fish influenced the likelihood of experiencing depression, and this may be mediated by certain metabolites in the body. Our study provided a new perspective on the clinical treatment of depression.
PubMed: 38694223
DOI: 10.3389/fnut.2024.1322254 -
Heliyon Apr 2024In this study, a biodegradable and eco-friendly biocatalyst (eggshell/FeO) was synthesized utilizing eggshell impregnated with FeO nanoparticles. The characterization of...
In this study, a biodegradable and eco-friendly biocatalyst (eggshell/FeO) was synthesized utilizing eggshell impregnated with FeO nanoparticles. The characterization of prepared catalyst was carried out by Fourier transform infrared radiation (FT-IR), scanning electron microscopy (SEM), X-ray Diffraction (XRD), energy-dispersive X-ray (EDX), thermal gravimetric analysis-differential thermogravimetry (TGA-DTG), vibrating sample magnometer (VSM), and atomic force microscopy (AFM). The eggshell/FeO biocatalyst was served in multi-component reactions (MCRs) for the synthesis of 2-amino thiophene derivatives from variety aromatic aldehydes, malononitrile, ethyl acetoacetate, and sulfur (S8). To achieve optimal reaction conditions, a thorough examination was conducted on key factors, such as the solvent type, reaction time and temperature, and the ratio of eggshell to FeO. The findings suggest that high yield product can be obtained at microwave temperature (MW) in EtOH solvent within 10 min. Additionally, the eggshell/FeO biocatalyst exhibited high catalytic activity, which was sustained over the five cycles, without any significant decline in its performance.
PubMed: 38681630
DOI: 10.1016/j.heliyon.2024.e29674 -
Molecules (Basel, Switzerland) Mar 2024Ursodeoxycholic acid (UDCA) and acetoacetate are natural compounds present in the human intestine and blood, respectively. A number of studies highlighted that besides...
Ursodeoxycholic acid (UDCA) and acetoacetate are natural compounds present in the human intestine and blood, respectively. A number of studies highlighted that besides their well-known primary biological roles, both compounds possess the ability to influence a variety of cellular processes involved in the etiology of various diseases. These reasons suggested the potential of acetoacetate-UDCA hybrids as possible therapeutic agents and prompted us to develop a synthetic strategy to selectively derivatize the hydroxyl groups of the bile acid with acetoacetyl moieties. 3α-acetoacetoxy UDCA was obtained (60% isolated yield) via the regioselective transesterification of methyl acetoacetate with UDCA promoted by the lipase B (CAL-B). 3α,7β-bis-acetoacetoxy UDCA was obtained instead by thermal condensation of methyl acetoacetate and UDCA (80% isolated yield). This bis-adduct was finally converted to the 7β-acetoacetoxy UDCA (82% isolated yield) via CAL-B catalyzed regioselective alcoholysis of the ester group on the 3α position. In order to demonstrate the value of the above new hybrids as UDCA-based scaffolds, 3α-acetoacetoxy UDCA was subjected to multicomponent Biginelli reaction with benzaldehyde and urea to obtain the corresponding 4-phenyl-3,4-dihydropyrimidin-2-()-one derivative in 65% isolated yield.
Topics: Humans; Ursodeoxycholic Acid; Acetoacetates; Bile Acids and Salts
PubMed: 38542941
DOI: 10.3390/molecules29061305 -
Canadian Liver Journal Feb 2024Hepatorenal tyrosinemia type 1 (HT-1) is a rare autosomal recessive disease that results from a deficiency of fumaryl acetoacetate hydrolase (FAH), a critical enzyme in... (Review)
Review
Hepatorenal tyrosinemia type 1 (HT-1) is a rare autosomal recessive disease that results from a deficiency of fumaryl acetoacetate hydrolase (FAH), a critical enzyme in the catabolic pathway for tyrosine. This leads to the accumulation of toxic metabolites such as fumaryl and maleylacetoacetate, which can damage the liver, kidneys, and nervous system. The discovery of 2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione (NTBC or nitisinone) has significantly improved the management of HT-1, particularly when initiated before the onset of symptoms. Therefore, newborn screening for HT-1 is essential for timely diagnosis and prompt treatment. The analysis of succinyl acetone (SA) in dried blood spots of newborns followed by quantification of SA in blood or urine for high-risk neonates has excellent sensitivity and specificity for the diagnosis of HT-1. NTBC combined with dietary therapy, if initiated early, can provide liver transplant (LT) free survival and reduce the risk of hepatocellular carcinoma (HCC). Patients failing medical treatment (eg, due to non-adherence), and who develop acute liver failure (ALF), have HCC or evidence of histologically proven dysplastic liver nodule(s), or experience poor quality of life secondary to severe dietary restrictions are currently indicated for LT. Children with HT-1 require frequent monitoring of liver and renal function to assess disease progression and treatment compliance. They are also at risk of long-term neurocognitive impairment, which highlights the need for neurocognitive assessment and therapy.
PubMed: 38505790
DOI: 10.3138/canlivj-2023-0018 -
Frontiers in Endocrinology 2024Alzheimer's disease (AD) is increasing in prevalence, but effective treatments for its cognitive impairment remain severely limited. This study investigates the impact...
BACKGROUND
Alzheimer's disease (AD) is increasing in prevalence, but effective treatments for its cognitive impairment remain severely limited. This study investigates the impact of ketone body production through dietary manipulation on memory in persons with mild cognitive impairment due to early AD and explores potential mechanisms of action.
METHODS
We conducted a 12-week, parallel-group, controlled feasibility trial of a ketogenic diet, the modified Atkins diet (MAD), compared to a control diet in patients with cognitive impairments attributed to AD. We administered neuropsychological assessments, including memory tests, and collected blood samples at baseline and after 12 weeks of intervention. We performed untargeted lipidomic and targeted metabolomic analyses on plasma samples to detect changes over time.
RESULTS
A total of 839 individuals were screened to yield 38 randomized participants, with 20 assigned to receive MAD and 18 assigned to receive a control diet. Due to attrition, only 13 in the MAD arm and nine in the control arm were assessed for the primary endpoint, with two participants meeting ketosis levels used to define MAD adherence criteria. The average change from baseline in the Memory Composite Score was 1.37 (95% CI: -0.87, 4.90) points higher in the MAD group compared to the control group. The effect size of the intervention on baseline MAD change was moderate (Cohen's = 0.57, 95% CI: -0.67, 1.33). In the 15 participants (nine MAD, six control) assessed for lipidomic and metabolomic-lipidomics and metabolomics, 13 metabolites and 10 lipids showed significant changes from baseline to 12 weeks, including triacylglycerols (TAGs, 50:5, 52:5, and 52:6), sphingomyelins (SM, 44:3, 46:0, 46:3, and 48:1), acetoacetate, fatty acylcarnitines, glycerol-3-phosphate, and hydroxy fatty acids.
CONCLUSIONS
Attrition was greatest between baseline and week 6. All participants retained at week 6 completed the study. Despite low rates of adherence by criteria defined , lipidomic and metabolomic analyses indicate significant changes from baseline in circulating lipids and metabolites between MAD and control participants at 12-week postrandomization, and MAD participants showed greater, albeit nonsignificant, improvement in memory.
Topics: Humans; Aged; Alzheimer Disease; Diet, High-Protein Low-Carbohydrate; Feasibility Studies; Cognitive Dysfunction; Fatty Acids
PubMed: 38505743
DOI: 10.3389/fendo.2024.1182519