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Nihon Hoshasen Gijutsu Gakkai Zasshi 2023
Topics: Positron-Emission Tomography; Fluorodeoxyglucose F18
PubMed: 36682784
DOI: 10.6009/jjrt.2023-2144 -
Nutrients Nov 2018Calorie restriction (CR) can prolong the human lifespan, but enforcing long-term CR is difficult. Therefore, a compound that reproduces the effect of CR without CR is... (Review)
Review
Calorie restriction (CR) can prolong the human lifespan, but enforcing long-term CR is difficult. Therefore, a compound that reproduces the effect of CR without CR is needed. In this review, we summarize the current knowledge on compounds with CR mimetic (CRM) effects. More than 10 compounds have been listed as CRMs, some of which are conventionally categorized as upstream-type CRMs showing glycolytic inhibition, while the others are categorized as downstream-type CRMs that regulate or genetically modulate intracellular signaling proteins. Among these, we focus on upstream-type CRMs and propose their classification as compounds with energy metabolism inhibition effects, particularly glucose metabolism modulation effects. The upstream-type CRMs reviewed include chitosan, acarbose, sodium-glucose cotransporter 2 inhibitors, and hexose analogs such as 2-deoxy-d-glucose, d-glucosamine, and d-allulose, which show antiaging and longevity effects. Finally, we discuss the molecular definition of upstream-type CRMs.
Topics: Acarbose; Aging; Animals; Blood Glucose; Caloric Restriction; Chitosan; Deoxyglucose; Glucosamine; Glycolysis; Hexoses; Humans; Longevity; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 30469486
DOI: 10.3390/nu10121821 -
Journal of Diabetes and Its... Mar 20191,5 Anhydroglucitol (1,5 AG) is reported to be a more sensitive marker of glucose variability and short-term glycemic control (1-2 weeks) in patients with type1 and...
OBJECTIVE
1,5 Anhydroglucitol (1,5 AG) is reported to be a more sensitive marker of glucose variability and short-term glycemic control (1-2 weeks) in patients with type1 and type 2 diabetes. However, the role of 1,5 AG in gestational diabetes mellitus (GDM) is not clear. We estimated the serum levels of 1,5 AG in pregnant women with and without GDM.
METHODS
We recruited 220 pregnant women, 145 without and 75 with GDM visiting antenatal clinics in Tamil Nadu in South India. Oral glucose tolerance tests (OGTTs) were carried out using 82.5 g oral glucose (equivalent to 75 g of anhydrous glucose) and GDM was diagnosed based on the International Association of Diabetes and Pregnancy Study Group criteria. Serum 1,5 AG levels were measured using an enzymatic, colorimetric assay kit (Glycomark®, New York, NY). Receiver operating characteristic (ROC) curves were used to identify 1,5 AG cut-off points to identify GDM.
RESULTS
The mean levels of the 1,5 AG were significantly lower in women with GDM (11.8 ± 5.7 μg/mL, p < 0.001) compared to women without GDM (16.2 ± 6.2 μg/mL). In multiple logistic regression analysis, 1.5 AG showed a significant association with GDM (odds ratio [OR]: 0.876, 95% confidence interval [CI]: 0.812-0.944, p < 0.001) after adjusting for potential confounders. 1,5 AG had a C statistic of 0.693 compared to Fructosamine (0.671) and HbA1c (0.581) for identifying GDM. A 1,5 AG cut-off of 13.21 μg/mL had a C statistic of 0.6936 (95% CI: 0.6107-0.7583, p < 0.001), sensitivity of 67.6%, and specificity of 65.3% to identify GDM.
CONCLUSION
1,5AG levels are lower in pregnant women with GDM compared to individuals without GDM.
Topics: Adult; Biomarkers; Blood Glucose; Deoxyglucose; Diabetes, Gestational; Female; Glucose Tolerance Test; Glycated Hemoglobin; Humans; India; Odds Ratio; Pregnancy; ROC Curve
PubMed: 30594413
DOI: 10.1016/j.jdiacomp.2018.11.010 -
International Journal of Molecular... Feb 2017Molecular pathological pathways leading to multi-organ failure in critical illness are progressively being unravelled. However, attempts to modulate these pathways have... (Review)
Review
Molecular pathological pathways leading to multi-organ failure in critical illness are progressively being unravelled. However, attempts to modulate these pathways have not yet improved the clinical outcome. Therefore, new targetable mechanisms should be investigated. We hypothesize that increased dicarbonyl stress is such a mechanism. Dicarbonyl stress is the accumulation of dicarbonyl metabolites (i.e., methylglyoxal, glyoxal, and 3-deoxyglucosone) that damages intracellular proteins, modifies extracellular matrix proteins, and alters plasma proteins. Increased dicarbonyl stress has been shown to impair the renal, cardiovascular, and central nervous system function, and possibly also the hepatic and respiratory function. In addition to hyperglycaemia, hypoxia and inflammation can cause increased dicarbonyl stress, and these conditions are prevalent in critical illness. Hypoxia and inflammation have been shown to drive the rapid intracellular accumulation of reactive dicarbonyls, i.e., through reduced glyoxalase-1 activity, which is the key enzyme in the dicarbonyl detoxification enzyme system. In critical illness, hypoxia and inflammation, with or without hyperglycaemia, could thus increase dicarbonyl stress in a way that might contribute to multi-organ failure. Thus, we hypothesize that increased dicarbonyl stress in critical illness, such as sepsis and major trauma, contributes to the development of multi-organ failure. This mechanism has the potential for new therapeutic intervention in critical care.
Topics: Biomarkers; Comorbidity; Critical Care; Critical Illness; Deoxyglucose; Glyoxal; Humans; Hypoxia; Inflammation; Multiple Organ Failure; Pyruvaldehyde; Stress, Physiological
PubMed: 28178202
DOI: 10.3390/ijms18020346 -
Pharmacology Research & Perspectives Feb 2024Our previous work has shown a synergistic tumoricidal efficacy of combining the hexokinase (HK) inhibitor 2-deoxyglucose (2-DG) and the autophagy inhibitor chloroquine...
Our previous work has shown a synergistic tumoricidal efficacy of combining the hexokinase (HK) inhibitor 2-deoxyglucose (2-DG) and the autophagy inhibitor chloroquine (CQ) through intraperitoneal injections on HK2-addicted prostate cancers in animal models. The pharmacokinetic (PK) behaviors of these oral drugs after simultaneous oral administration have not been reported. We developed high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) analytical methods for 2-DG and the clinically favored drug hydroxychloroquine (HCQ) for sera samples. Using a jugular vein-cannulated male rat model with serial blood collection before and after a single gavage dose of each drug alone or in combination, we examined their PK metrics for drug-drug interactions. The data demonstrated a rapid and complete separation of 2-DG from common monosaccharides by HPLC-MS-MS multi-reaction monitoring. Application of the HPLC-MS-MS 2-DG and HCQ methods to sera samples of nine rats showed a peak time (T ) for 2-DG of 0.5 h after 2-DG alone or with HCQ and identical post-peak half-life of approximately 1 h. With a seemingly bi-modal time course for HCQ, the T for HCQ alone (1.2 h) was faster than that for the combination (2 h; p = .017). After combination dosing, the peak concentration (C ) and area under the curve (AUC ) of 2-DG were decreased by 53.8% (p = .0004) and 53.7% (p = .0001), whereas AUC for HCQ was decreased by 30.8% (p = .0279) from the respective single dosing. Without changing the mean residence time (MRT ) of each drug, the combination affected the apparent volume of distribution (V ) and clearance (CL) of 2-DG, and CL for HCQ without affecting its V . We observed significant negative PK interactions, probably at the intestinal absorption level, between 2-DG and HCQ taken simultaneously by mouth. Future optimization efforts are warranted for their combination regimen for clinical translation.
Topics: Male; Rats; Animals; Hydroxychloroquine; Chromatography, High Pressure Liquid; Liquid Chromatography-Mass Spectrometry; Administration, Oral; Deoxyglucose
PubMed: 38294142
DOI: 10.1002/prp2.1173 -
Journal of the American Heart... May 2023Background Cardiac metabolic abnormalities are present in heart failure. Few studies have followed metabolic changes accompanying diastolic and systolic heart failure in...
Background Cardiac metabolic abnormalities are present in heart failure. Few studies have followed metabolic changes accompanying diastolic and systolic heart failure in the same model. We examined metabolic changes during the development of diastolic and severe systolic dysfunction in spontaneously hypertensive rats (SHR). Methods and Results We serially measured myocardial glucose uptake rates with dynamic 2-[F] fluoro-2-deoxy-d-glucose positron emission tomography in vivo in 9-, 12-, and 18-month-old SHR and Wistar Kyoto rats. Cardiac magnetic resonance imaging determined systolic function (ejection fraction) and diastolic function (isovolumetric relaxation time) and left ventricular mass in the same rats. Cardiac metabolomics was performed at 12 and 18 months in separate rats. At 12 months, SHR hearts, compared with Wistar Kyoto hearts, demonstrated increased isovolumetric relaxation time and slightly reduced ejection fraction indicating diastolic and mild systolic dysfunction, respectively, and higher (versus 9-month-old SHR decreasing) 2-[F] fluoro-2-deoxy-d-glucose uptake rates (Ki). At 18 months, only few SHR hearts maintained similar abnormalities as 12-month-old SHR, while most exhibited severe systolic dysfunction, worsening diastolic function, and markedly reduced 2-[F] fluoro-2-deoxy-d-glucose uptake rates. Left ventricular mass normalized to body weight was elevated in SHR, more pronounced with severe systolic dysfunction. Cardiac metabolite changes differed between SHR hearts at 12 and 18 months, indicating progressive defects in fatty acid, glucose, branched chain amino acid, and ketone body metabolism. Conclusions Diastolic and severe systolic dysfunction in SHR are associated with decreasing cardiac glucose uptake, and progressive abnormalities in metabolite profiles. Whether and which metabolic changes trigger progressive heart failure needs to be established.
Topics: Rats; Animals; Rats, Inbred SHR; Hypertension; Tomography, X-Ray Computed; Heart Failure; Rats, Inbred WKY; Glucose; Deoxyglucose; Blood Pressure
PubMed: 37183873
DOI: 10.1161/JAHA.122.026950 -
Biomolecules Apr 2022Hydrogen sulfide (HS) and inorganic polysulfides are important signaling molecules; however, little is known about their role in adipose tissue. We examined the effect...
Hydrogen sulfide (HS) and inorganic polysulfides are important signaling molecules; however, little is known about their role in adipose tissue. We examined the effect of HS and polysulfides on insulin sensitivity of the adipose tissue in rats. Plasma glucose, insulin, non-esterified fatty acids, and glycerol were measured after administration of HS and the polysulfide donors, NaS and NaS, respectively. In addition, the effect of NaS and NaS on insulin-induced glucose uptake and inhibition of lipolysis was studied in adipose tissue explants ex vivo. NaS and NaS administered in vivo at a single dose of 100 μmol/kg had no effect on plasma glucose and insulin concentrations. In addition, NaS and NaS did not modify the effect of insulin on plasma glucose, fatty acids, and glycerol concentrations. NaS and NaShad no effect on the antilipolytic effect of insulin in adipose tissue explants ex vivo. The effect of insulin on 2-deoxyglucose uptake by adipose tissue was impaired in obese rats which was accompanied by lower insulin-induced tyrosine phosphorylation of IRS-1 and Akt. NaS, but not NaS, improved insulin signaling and increased insulin-stimulated 2-deoxyglucose uptake by adipose tissue of obese rats. The results suggest that polysulfides may normalize insulin sensitivity, at least in the adipose tissue, in obesity/metabolic syndrome.
Topics: Adipose Tissue; Animals; Blood Glucose; Deoxyglucose; Glycerol; Hydrogen Sulfide; Insulin; Insulin Resistance; Obesity; Rats; Sulfides
PubMed: 35625574
DOI: 10.3390/biom12050646 -
British Journal of Cancer Apr 2020Dysregulation of the metabolome is a hallmark of primary brain malignancies. In this work we examined whether metabolic reprogramming through a multi-targeting approach...
BACKGROUND
Dysregulation of the metabolome is a hallmark of primary brain malignancies. In this work we examined whether metabolic reprogramming through a multi-targeting approach causes enhanced anti-cancer activity in glioblastoma.
METHODS
Preclinical testing of a combined treatment with ONC201/TIC10 and 2-Deoxyglucose was performed in established and primary-cultured glioblastoma cells. Extracellular flux analysis was used to determine real-time effects on OXPHOS and glycolysis. Respiratory chain complexes were analysed by western blotting. Biological effects on tumour formation were tested on the chorioallantoic membrane (CAM).
RESULTS
ONC201/TIC10 impairs mitochondrial respiration accompanied by an increase of glycolysis. When combined with 2-Deoxyglucose, ONC201/TIC10 induces a state of energy depletion as outlined by a significant decrease in ATP levels and a hypo-phosphorylative state. As a result, synergistic anti-proliferative and anti-migratory effects were observed among a broad panel of different glioblastoma cells. In addition, this combinatorial approach significantly impaired tumour formation on the CAM.
CONCLUSION
Treatment with ONC201/TIC10 and 2-Deoxyglucose results in a dual metabolic reprogramming of glioblastoma cells resulting in a synergistic anti-neoplastic activity. Given, that both agents penetrate the blood-brain barrier and have been used in clinical trials with a good safety profile warrants further clinical evaluation of this therapeutic strategy.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Chick Embryo; Deoxyglucose; Energy Metabolism; Glioblastoma; Glycolysis; Humans; Imidazoles; Oxidative Phosphorylation; Pyridines; Pyrimidines
PubMed: 32115576
DOI: 10.1038/s41416-020-0759-0 -
Journal of Nuclear Medicine : Official... Aug 2021
Topics: Fluorodeoxyglucose F18; Humans; Inflammation; Middle Aged; Positron-Emission Tomography
PubMed: 33893189
DOI: 10.2967/jnumed.121.262446 -
PLoS Genetics Jul 2020Yeast and fast-growing human tumor cells share metabolic similarities in that both cells use fermentation of glucose for energy and both are highly sensitive to the...
Yeast and fast-growing human tumor cells share metabolic similarities in that both cells use fermentation of glucose for energy and both are highly sensitive to the glucose analog 2-deoxyglucose. Spontaneous mutations in S. cerevisiae that conferred resistance to 2-deoxyglucose were identified by whole genome sequencing. Missense alleles of the HXK2, REG1, GLC7 and SNF1 genes were shown to confer significant resistance to 2-deoxyglucose and all had the potential to alter the activity and or target selection of the Snf1 kinase signaling pathway. All three missense alleles in HXK2 resulted in significantly reduced catalytic activity. Addition of 2DG promotes endocytosis of the glucose transporter Hxt3. All but one of the 2DG-resistant strains reduced the 2DG-mediated hexose transporter endocytosis by increasing plasma membrane occupancy of the Hxt3 protein. Increased expression of the DOG (deoxyglucose) phosphatases has been associated with resistance to 2-deoxyglucose. Expression of both the DOG1 and DOG2 mRNA was elevated after treatment with 2-deoxyglucose but induction of these genes is not associated with 2DG-resistance. RNAseq analysis of the transcriptional response to 2DG showed large scale, genome-wide changes in mRNA abundance that were greatly reduced in the 2DG resistant strains. These findings suggest the common adaptive response to 2DG is to limit the magnitude of the response. Genetic studies of 2DG resistance using the dominant SNF1-G53R allele in cells that are genetically compromised in both the endocytosis and DOG pathways suggest that at least one more mechanism for conferring resistance to this glucose analog remains to be discovered.
Topics: Deoxyglucose; Endocytosis; Energy Metabolism; Gene Expression Regulation, Fungal; Glucose; Glucose Transport Proteins, Facilitative; Hexokinase; Humans; Mutation; Phosphoric Monoester Hydrolases; Protein Phosphatase 1; Protein Serine-Threonine Kinases; RNA, Messenger; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction; Whole Genome Sequencing
PubMed: 32673313
DOI: 10.1371/journal.pgen.1008484