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Journal of the American Society of... Jul 2016Autosomal dominant polycystic kidney disease (ADPKD) is an important cause of ESRD for which there exists no approved therapy in the United States. Defective glucose...
Autosomal dominant polycystic kidney disease (ADPKD) is an important cause of ESRD for which there exists no approved therapy in the United States. Defective glucose metabolism has been identified as a feature of ADPKD, and inhibition of glycolysis using glucose analogs ameliorates aggressive PKD in preclinical models. Here, we investigated the effects of chronic treatment with low doses of the glucose analog 2-deoxy-d-glucose (2DG) on ADPKD progression in orthologous and slowly progressive murine models created by inducible inactivation of the Pkd1 gene postnatally. As previously reported, early inactivation (postnatal days 11 and 12) of Pkd1 resulted in PKD developing within weeks, whereas late inactivation (postnatal days 25-28) resulted in PKD developing in months. Irrespective of the timing of Pkd1 gene inactivation, cystic kidneys showed enhanced uptake of (13)C-glucose and conversion to (13)C-lactate. Administration of 2DG restored normal renal levels of the phosphorylated forms of AMP-activated protein kinase and its target acetyl-CoA carboxylase. Furthermore, 2DG greatly retarded disease progression in both model systems, reducing the increase in total kidney volume and cystic index and markedly reducing CD45-positive cell infiltration. Notably, chronic administration of low doses (100 mg/kg 5 days per week) of 2DG did not result in any obvious sign of toxicity as assessed by analysis of brain and heart histology as well as behavioral tests. Our data provide proof of principle support for the use of 2DG as a therapeutic strategy in ADPKD.
Topics: Animals; Deoxyglucose; Disease Models, Animal; Disease Progression; Female; Male; Mice; Polycystic Kidney, Autosomal Dominant
PubMed: 26534924
DOI: 10.1681/ASN.2015030231 -
Nuclear Medicine Communications Jun 2021The most prevalent primary malignancy of the liver is hepatocellular carcinoma (HCC); its poor prognosis is mainly related to intrahepatic recurrence and extrahepatic...
The most prevalent primary malignancy of the liver is hepatocellular carcinoma (HCC); its poor prognosis is mainly related to intrahepatic recurrence and extrahepatic metastases. However, survival from HCC has improved due to better control of the primary tumor, the development of newer treatment modalities, including liver transplant, together with advances in imaging techniques. Therefore, the significance of patient management as corresponds with distant metastases has increased; since the proper evaluation and detection of extrahepatic metastases is crucial to optimize potential therapy for patients. Conventional imaging like CT, MRI play crucial rule in patient's diagnosis and qualifying for a certain type of therapy. More recently, a molecular imaging tool with radiolabeled deoxyglucose and fluorocholine has proved its promising value as a complementary tool to conventional studies. In this review, the frequent sites of metastases and HCC spread are discussed as well as the imaging findings as seen by both conventional imaging techniques and by molecular imaging tools, namely 18F-Choline PET/CT, and FDG PET. The implications of guiding treatment planning have also been discussed.
Topics: Aged; Carcinoma, Hepatocellular; Fluorodeoxyglucose F18; Humans; Liver Neoplasms; Middle Aged; Positron Emission Tomography Computed Tomography
PubMed: 33625188
DOI: 10.1097/MNM.0000000000001380 -
PET Clinics Apr 20212-[18F]-fluoro-2-deoxyglucose (FDG) is the most commonly used radiotracer and provides valuable information about glucose metabolism. With the advent of newer... (Review)
Review
2-[18F]-fluoro-2-deoxyglucose (FDG) is the most commonly used radiotracer and provides valuable information about glucose metabolism. With the advent of newer receptor-based tracers in the management of hormonally active malignancies, the focus has been shifted from FDG. These tracers might be more specific than FDG because they target specific hormone receptors. But because FDG is widely available, this review discusses what information still can be harnessed from this workhorse of molecular imaging. The personalized implementation of FDG imaging in undifferentiated malignancies will help in characterization of tumor and may aid in patient management.
Topics: Fluorodeoxyglucose F18; Glucose; Humans; Neoplasms
PubMed: 33648663
DOI: 10.1016/j.cpet.2020.12.007 -
Biochemical and Biophysical Research... Mar 2015Dicarbonyl stress is the abnormal accumulation of dicarbonyl metabolites leading to increased protein and DNA modification contributing to cell and tissue dysfunction in... (Review)
Review
Dicarbonyl stress is the abnormal accumulation of dicarbonyl metabolites leading to increased protein and DNA modification contributing to cell and tissue dysfunction in ageing and disease. Enzymes metabolising dicarbonyls, glyoxalase 1 and aldoketo reductases, provide an efficient and stress-response enzyme defence against dicarbonyl stress. Dicarbonyl stress is produced by increased formation and/or decreased metabolism of dicarbonyl metabolites, and by exposure to exogenous dicarbonyls. It contributes to ageing, disease and activity of cytototoxic chemotherapeutic agents.
Topics: Aging; Aldehydes; Cardiovascular Diseases; Deoxyglucose; Diabetes Mellitus; Glyoxal; Humans; Inflammation; Kidney Diseases; Models, Biological; Oxidative Stress; Pyruvaldehyde; Stress, Physiological
PubMed: 25666945
DOI: 10.1016/j.bbrc.2015.01.140 -
Current Protein & Peptide Science 2020Glycation refers to the covalent binding of sugar molecules to macromolecules, such as DNA, proteins, and lipids in a non-enzymatic reaction, resulting in the formation... (Review)
Review
Glycation refers to the covalent binding of sugar molecules to macromolecules, such as DNA, proteins, and lipids in a non-enzymatic reaction, resulting in the formation of irreversibly bound products known as advanced glycation end products (AGEs). AGEs are synthesized in high amounts both in pathological conditions, such as diabetes and under physiological conditions resulting in aging. The body's anti-glycation defense mechanisms play a critical role in removing glycated products. However, if this defense system fails, AGEs start accumulating, which results in pathological conditions. Studies have been shown that increased accumulation of AGEs acts as key mediators in multiple diseases, such as diabetes, obesity, arthritis, cancer, atherosclerosis, decreased skin elasticity, male erectile dysfunction, pulmonary fibrosis, aging, and Alzheimer's disease. Furthermore, glycation of nucleotides, proteins, and phospholipids by α-oxoaldehyde metabolites, such as glyoxal (GO) and methylglyoxal (MGO), causes potential damage to the genome, proteome, and lipidome. Glyoxalase-1 (GLO-1) acts as a part of the anti-glycation defense system by carrying out detoxification of GO and MGO. It has been demonstrated that GLO-1 protects dicarbonyl modifications of the proteome and lipidome, thereby impeding the cell signaling and affecting age-related diseases. Its relationship with detoxification and anti-glycation defense is well established. Glycation of proteins by MGO and GO results in protein misfolding, thereby affecting their structure and function. These findings provide evidence for the rationale that the functional modulation of the GLO pathway could be used as a potential therapeutic target. In the present review, we summarized the newly emerged literature on the GLO pathway, including enzymes regulating the process. In addition, we described small bioactive molecules with the potential to modulate the GLO pathway, thereby providing a basis for the development of new treatment strategies against age-related complications.
Topics: Aging; Deoxyglucose; Diabetes Mellitus; Gene Expression Regulation; Glycation End Products, Advanced; Glyoxal; Humans; Isoenzymes; Lactoylglutathione Lyase; Metabolic Diseases; Neurodegenerative Diseases; Oxidative Stress; Protein Carbonylation; Pyruvaldehyde; Reactive Oxygen Species; Schiff Bases; Signal Transduction
PubMed: 32368974
DOI: 10.2174/1389203721666200505101734 -
Acta Diabetologica Mar 2018Our previous studies demonstrated that serum 1,5-anhydroglucitol (1,5-AG) levels increased slightly rather than declined after an acute glucose load. Therefore, the...
AIMS
Our previous studies demonstrated that serum 1,5-anhydroglucitol (1,5-AG) levels increased slightly rather than declined after an acute glucose load. Therefore, the current study aims at exploring the transport and metabolic characteristics of 1,5-AG, as well as the effect of glucose on 1,5-AG transport.
METHODS
K and V were determined to measure the affinity of glucose oxidase (GOD) and hexokinase (HK) for 1,5-AG and glucose. HepG2, C2C12, and primary mouse hepatocytes were incubated for 2 h with 1,5-AG at concentrations of 0, 80, and 160 μg/mL. Then, intracellular and extracellular concentrations of 1,5-AG were measured before and after washing with PBS to evaluate the transport and metabolic rates of 1,5-AG. In addition, the influence of an acute glucose load on the transport of 1,5-AG was studied.
RESULTS
The affinity of GOD and HK for 1,5-AG is 5 and 42.5% of that for glucose, respectively. Moreover, there is no de novo synthesis of 1,5-AG, and its metabolic rate is < 3%. After a 2 h incubation with additional 1,5-AG, the intracellular levels of 1,5-AG were 50-80% of extracellular levels. Moreover, intracellular 1,5-AG concentrations decreased rapidly and reached zero following the removal of 1,5-AG from the external medium. In addition, an acute glucose load can affect the dynamic balance of 1,5-AG, causing the intracellular 1,5-AG levels to decline significantly and the extracellular levels to increase slightly in HepG2 cells.
CONCLUSIONS
Unlike glucose, 1,5-AG is hard to be metabolized in vivo, and its transport is influenced by an acute glucose load in hepatocytes.
Topics: Animals; Biological Transport; Cells, Cultured; Deoxyglucose; Glucose; Glucose Oxidase; Hep G2 Cells; Hepatocytes; Hexokinase; Humans; Intracellular Fluid; Male; Mice; Mice, Inbred C57BL
PubMed: 29318370
DOI: 10.1007/s00592-017-1093-8 -
BioMed Research International 2020Our previous research suggests that 3-deoxyglucosone (3DG), formed in the caramelization course and Maillard reactions in food, is an independent factor for the...
Our previous research suggests that 3-deoxyglucosone (3DG), formed in the caramelization course and Maillard reactions in food, is an independent factor for the development of prediabetes. Since the relationship between type 2 diabetes (T2D) and intestinal microbiota is moving from correlation to causality, we investigated the alterations in the composition and function of the intestinal microbiota in 3DG-induced prediabetic rats. Rats were given 50 mg/kg 3DG by intragastric administration for two weeks. Microbial profiling in faeces samples was determined through the 16S rRNA gene sequence. The glucagon-like peptide 2 (GLP-2) and lipopolysaccharide (LPS) levels in plasma and intestinal tissues were measured by ELISA and Limulus test, respectively. 3DG treatment did not significantly change the richness and evenness but affected the composition of intestinal microbiota. At the phylum level, 3DG treatment increased the abundance of nondominant bacteria but did not cause the change of the dominant bacteria. Meanwhile, the abundance of the family and genus and the family and order and its attachment to the class were overrepresented in the 3DG group. The bacteria of genus, genus, and family and its attachment to order were apparently more abundant in the control group. In addition, 45 KEGG pathways were altered after two-week intragastric administration of 3DG. Among these KEGG pathways, 13 KEGG pathways were involved in host metabolic function related to amino acid metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins, and metabolism of terpenoids and polyketides. Moreover, the increased LPS levels and the decreased GLP-2 concentration in plasma and intestinal tissues were observed in 3DG-treated rats, together with the impaired fasting glucose and oral glucose tolerance. The alterations in composition and function of the intestinal microbiota were observed in 3DG-treated rats, which provides a possible mechanism linking exogenous 3DG intake to the development of prediabetes.
Topics: Administration, Oral; Animals; Deoxyglucose; Gastrointestinal Microbiome; Glucagon-Like Peptide 2; Glucose Tolerance Test; Lipopolysaccharides; Male; Prediabetic State; RNA, Ribosomal, 16S; Rats, Sprague-Dawley
PubMed: 32908918
DOI: 10.1155/2020/8406846 -
Journal of Immunology (Baltimore, Md. :... Aug 2020Metabolic reprogramming plays a central role in T cell activation and differentiation, and the inhibition of key metabolic pathways in activated T cells represents a...
Metabolic reprogramming plays a central role in T cell activation and differentiation, and the inhibition of key metabolic pathways in activated T cells represents a logical approach for the development of new therapeutic agents for treating autoimmune diseases. The widely prescribed antidiabetic drug metformin and the glycolytic inhibitor 2-deoxyglucose (2-DG) have been used to study the inhibition of oxidative phosphorylation and glycolysis, respectively, in murine immune cells. Published studies have demonstrated that combination treatment with metformin and 2-DG was efficacious in dampening mouse T cell activation-induced effector processes, relative to treatments with either metformin or 2-DG alone. In this study, we report that metformin + 2-DG treatment more potently suppressed IFN-γ production and cell proliferation in activated primary human CD4 T cells than either metformin or 2-DG treatment alone. The effects of metformin + 2-DG on human T cells were accompanied by significant remodeling of activation-induced metabolic transcriptional programs, in part because of suppression of key transcriptional regulators MYC and HIF-1A. Accordingly, metformin + 2-DG treatment significantly suppressed MYC-dependent metabolic genes and processes, but this effect was found to be independent of mTORC1 signaling. These findings reveal significant insights into the effects of metabolic inhibition by metformin + 2-DG treatment on primary human T cells and provide a basis for future work aimed at developing new combination therapy regimens that target multiple pathways within the metabolic networks of activated human T cells.
Topics: Animals; CD4-Positive T-Lymphocytes; Cell Proliferation; Cells, Cultured; Deoxyglucose; Glycolysis; Humans; Mechanistic Target of Rapamycin Complex 1; Metabolic Networks and Pathways; Metformin; Mice; Oxidative Phosphorylation; Signal Transduction
PubMed: 32641388
DOI: 10.4049/jimmunol.2000137 -
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 -
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