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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 -
Journal of Magnetic Resonance Imaging :... May 2024Emerging evidence suggests that fasting could play a key role in cancer treatment. Its metabolic effects on gliomas require further investigation.
BACKGROUND
Emerging evidence suggests that fasting could play a key role in cancer treatment. Its metabolic effects on gliomas require further investigation.
PURPOSE
To design a multi-voxel H/P MR-spectroscopic imaging (MRSI) protocol for noninvasive metabolic monitoring of cerebral, fasting-induced changes on an individual patient/tumor level, and to assess its technical reliability/reproducibility.
STUDY TYPE
Prospective.
POPULATION
MRS phantom. Twenty-two patients (mean age = 61, 6 female) with suspected WHO grade II-IV glioma examined before and after 72-hour-fasting prior to biopsy/resection.
FIELD STRENGTH/SEQUENCE
3-T, H decoupled 3D P MRSI, 2D H sLASER MRSI at an echo time of 144 msec, 2D H MRSI (as water reference), T1-weighted, T1-weighted contrast-enhanced, T2-weighted, and FLAIR. sLASER and PRESS sequences were used for phantom measurements.
ASSESSMENT
Phantom measurements and spectral simulations were performed with various echo-times for protocol optimization. In vivo spectral analyses were conducted using LCModel and AMARES, obtaining quality/fitting parameters (linewidth, signal-to-noise-ratio, and uncertainty measures of fitting) and metabolite intensities. The volume of glioma sub-regions was calculated and correlated with MRS findings. Ex-vivo spectra of necrotic tumor tissues were obtained using high-resolution magic-angle spinning (HR-MAS) technique.
STATISTICAL TESTS
Wilcoxon signed-rank test, Bland-Altman plots, and coefficient of variation were used for repeatability analysis of quality/fitting parameters and metabolite concentrations. Spearman ρ correlation for the concentration of ketone bodies with volumes of glioma sub-regions was determined. A P-value <0.05 was considered statistically significant.
RESULTS
H and P repeatability measures were highly consistent between the two sessions. β-hydroxybutyrate and acetoacetate were detectable (fitting-uncertainty <50%) in glioma sub-regions of all patients who completed the 72-hour-fasting cycle. β-hydroxybutyrate accumulation was significantly correlated with the necrotic/non-enhancing tumor core volume (ρ = 0.81) and validated using ex-vivo H HR-MAS.
DATA CONCLUSION
We propose a comprehensive MRS protocol that may be used for monitoring cerebral, fasting-induced changes in patients with glioma.
EVIDENCE LEVEL
1 TECHNICAL EFFICACY: Stage 4.
PubMed: 38722043
DOI: 10.1002/jmri.29422 -
American Journal of Physiology. Cell... Jun 2024Ketone bodies (acetoacetate and β-hydroxybutyrate) are oxidized in skeletal muscle mainly during fasting as an alternative source of energy to glucose. Previous studies...
Ketone bodies (acetoacetate and β-hydroxybutyrate) are oxidized in skeletal muscle mainly during fasting as an alternative source of energy to glucose. Previous studies suggest that there is a negative relationship between increased muscle ketolysis and muscle glucose metabolism in mice with obesity and/or type 2 diabetes. Therefore, we investigated the connection between increased ketone body exposure and muscle glucose metabolism by measuring the effect of a 3-h exposure to ketone bodies on glucose uptake in differentiated L6 myotubes. We showed that exposure to acetoacetate at a typical concentration (0.2 mM) resulted in increased basal glucose uptake in L6 myotubes, which was dependent on increased membrane glucose transporter type 4 (GLUT4) translocation. Basal and insulin-stimulated glucose uptake was also increased with a concentration of acetoacetate reflective of diabetic ketoacidosis or a ketogenic diet (1 mM). We found that β-hydroxybutyrate had a variable effect on basal glucose uptake: a racemic mixture of the two β-hydroxybutyrate enantiomers (d and l) appeared to decrease basal glucose uptake, while 3 mM d-β-hydroxybutyrate alone increased basal glucose uptake. However, the effects of the ketone bodies individually were not observed when acetoacetate was present in combination with β-hydroxybutyrate. These results provide insight that will help elucidate the effect of ketone bodies in the context of specific metabolic diseases and nutritional states (e.g., type 2 diabetes and ketogenic diets). A limited number of studies investigate the effect of ketone bodies at concentrations reflective of both typical fasting and ketoacidosis. We tested a mix of physiologically relevant concentrations of ketone bodies, which allowed us to highlight the differential effects of d- and l-β-hydroxybutyrate and acetoacetate on skeletal muscle cell glucose uptake. Our findings will assist in better understanding the mechanisms that contribute to muscle insulin resistance and provide guidance on recommendations regarding ketogenic diets.
Topics: Acetoacetates; Animals; 3-Hydroxybutyric Acid; Glucose; Insulin; Muscle Fibers, Skeletal; Cell Line; Muscle, Skeletal; Glucose Transporter Type 4; Rats; Ketone Bodies; Mice
PubMed: 38708524
DOI: 10.1152/ajpcell.00718.2023 -
Diabetes, Obesity & Metabolism May 2024To examine the effects of the thiazolidinedione (TZD) pioglitazone on reducing ketone bodies in non-obese patients with T2DM treated with the sodium-glucose...
AIM
To examine the effects of the thiazolidinedione (TZD) pioglitazone on reducing ketone bodies in non-obese patients with T2DM treated with the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin.
METHODS
Crossover trials with two periods, each treatment period lasting 4 weeks, with a 4-week washout period, were conducted. Participants were randomly assigned in a 1:1 ratio to receive pioglitazone combined with canagliflozin (PIOG + CANA group) versus canagliflozin monotherapy (CANA group). The primary outcome was change (Δ) in β-hydroxybutyric acid (β-HBA) before and after the CANA or PIOG + CANA treatments. The secondary outcomes were Δchanges in serum acetoacetate and acetone, the rate of conversion into urinary ketones, and Δchanges in factors related to SGLT2 inhibitor-induced ketone body production including non-esterified fatty acids (NEFAs), glucagon, glucagon to insulin ratio, and noradrenaline (NA). Analyses were performed in accordance with the intention-to-treat principle.
RESULTS
Twenty-five patients with a mean age of 49 ± 7.97 years and a body mass index of 25.35 ± 2.22 kg/m were included. One patient discontinued the study during the washout period. Analyses revealed a significant increase in the levels of serum ketone bodies and an elevation in the rate of conversion into urinary ketones after both interventions. However, differernces in levels of ketone bodies (except for acetoacetate) in the PIOG + CANA group were significantly smaller than in the CANA group (219.84 ± 80.21 μmol/L vs. 317.69 ± 83.07 μmol/L, p < 0.001 in β-HBA; 8.98 ± 4.17 μmol/L vs. 12.29 ± 5.27 μmol/L, p = 0.018 in acetone). NEFA, glucagon, glucagon to insulin ratio, and NA were also significantly increased after both CANA and PIOG + CANA treatments; while only NEFAs demonstrated a significant difference between the two groups. Correlation analyses revealed a significant association between the difference in Δchanges in serum NEFA levels with the differences in Δchanges in ketones of β-HBA and acetoacetate.
CONCLUSION
Supplementation of pioglitazone could alleviate canagliflozin-induced ketone bodies. This benefit may be closely associated with decreased substrate NEFAs rather than other factors including glucagon, fasting insulin and NA.
PubMed: 38699792
DOI: 10.1111/dom.15641 -
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 -
Bioorganic Chemistry Jun 2024Environment-benign, multicomponent synthetic methodologies are vital in modern pharmaceutical research and facilitates multi-targeted drug development via synergistic...
Pyrano[2,3-c]pyrazole fused spirooxindole-linked 1,2,3-triazoles as antioxidant agents: Exploring their utility in the development of antidiabetic drugs via inhibition of α-amylase and DPP4 activity.
Environment-benign, multicomponent synthetic methodologies are vital in modern pharmaceutical research and facilitates multi-targeted drug development via synergistic approach. Herein, we reported green and efficient synthesis of pyrano[2,3-c]pyrazole fused spirooxindole linked 1,2,3-triazoles using a tea waste supported copper catalyst (TWCu). The synthetic approach involves a one-pot, five-component reaction using N-propargylated isatin, hydrazine hydrate, ethyl acetoacetate, malononitrile/ethyl cyanoacetate and aryl azides as model substrates. Mechanistically, the reaction was found to proceed via in situ pyrazolone formation followed by Knoevenagel condensation, azide alkyne cycloaddition and Michael's addition reactions. The molecules were developed using structure-based drug design. The primary goal is to identifying anti-oxidant molecules with potential ability to modulate α-amylase and DPP4 (dipeptidyl-peptidase 4) activity. The anti-oxidant analysis, as determined via DPPH, suggested that the synthesized compounds, A6 and A10 possessed excellent anti-oxidant potential compared to butylated hydroxytoluene (BHT). In contrast, compounds A3, A5, A8, A9, A13, A15, and A18 were found to possess comparable anti-oxidant potential. Among these, A3 and A13 possessed potential α-amylase inhibitory activity compared to the acarbose, and A3 further emerged as dual inhibitors of both DPP4 and α-amylase with anti-oxidant potential. The relationship of functionalities on their anti-oxidant and enzymatic inhibition was explored in context to their SAR that was further corroborated using in silico techniques and enzyme kinetics.
Topics: Pyrazoles; Antioxidants; Triazoles; Hypoglycemic Agents; Structure-Activity Relationship; alpha-Amylases; Dipeptidyl Peptidase 4; Molecular Structure; Humans; Dose-Response Relationship, Drug; Dipeptidyl-Peptidase IV Inhibitors; Molecular Docking Simulation; Picrates; Spiro Compounds; Oxindoles; Benzopyrans; Nitriles
PubMed: 38657527
DOI: 10.1016/j.bioorg.2024.107363