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Journal of Nuclear Medicine : Official... Jul 2021Over the past decade, there has been a growing recognition of the links between intracellular metabolism and immune cell activation, that is, immunometabolism, and its...
Over the past decade, there has been a growing recognition of the links between intracellular metabolism and immune cell activation, that is, immunometabolism, and its consequences in atherogenesis. However, most immunometabolic investigations have been conducted in cultured cells through pharmacologic or genetic manipulations of selected immunologic or metabolic pathways, limiting their extrapolation to the complex microenvironment of plaques. In vivo metabolic imaging is ideally situated to address this gap and to determine the clinical implications of immunometabolic alterations for diagnosis and management of patients. Indeed, F-FDG has been widely used in clinical studies with promising results for risk stratification of atherosclerosis and monitoring the response to therapeutic interventions, though the biologic basis of its uptake in plaques has been evolving. Herein, we describe recent advances in understanding of immunometabolism of atherosclerosis with an emphasis on macrophages, and we review promising metabolic imaging approaches using F-FDG and other PET radiotracers.
Topics: Fluorodeoxyglucose F18; Humans; Plaque, Atherosclerotic
PubMed: 33963045
DOI: 10.2967/jnumed.120.245407 -
Seminars in Radiation Oncology Jan 2019Dysregulated glucose and redox metabolism are near universal features of cancers. They therefore represent potential selectively toxic metabolic targets. This review... (Review)
Review
Dysregulated glucose and redox metabolism are near universal features of cancers. They therefore represent potential selectively toxic metabolic targets. This review outlines the preclinical and clinical data for targeting glucose and hydroperoxide metabolism in cancer, with a focus on drug strategies that have the most available evidence. In particular, inhibition of glycolysis using 2-deoxyglucose, and inhibition of redox metabolism using the glutathione pathway inhibitor buthionine sulfoximine and the thioredoxin pathway inhibitor auranofin, have shown promise in preclinical studies to increase sensitivity to chemotherapy and radiation by increasing intracellular oxidative stress. Combined inhibition of glycolysis, glutathione, and thioredoxin pathways sensitizes highly glycolytic, radioresistant cancer models in vitro and in vivo. Although the preclinical data support this approach, clinical data are limited to exploratory trials using a single drug in combination with either chemotherapy or radiation. Open research questions include optimizing drug strategies for targeting glycolysis and redox metabolism, determining the appropriate timing for administering this therapy with concurrent chemotherapy and radiation, and identifying biomarkers to determine the cancers that would benefit most from this approach. Given the quality of preclinical evidence, dual targeting of glycolysis and redox metabolism in combination with chemotherapy and radiation should be further evaluated in clinical trials.
Topics: Animals; Auranofin; Buthionine Sulfoximine; Deoxyglucose; Glucose; Glycolysis; Humans; Hydrogen Peroxide; Neoplasms; Oxidation-Reduction; Oxidative Stress; Radiation-Sensitizing Agents
PubMed: 30573182
DOI: 10.1016/j.semradonc.2018.10.007 -
Pediatric Radiology Feb 2022Accurate staging and re-staging of cancer in children is crucial for patient management. Currently, children with a newly diagnosed cancer must undergo a series of... (Review)
Review
Accurate staging and re-staging of cancer in children is crucial for patient management. Currently, children with a newly diagnosed cancer must undergo a series of imaging tests, which are stressful, time-consuming, partially redundant, expensive, and can require repetitive anesthesia. New approaches for pediatric cancer staging can evaluate the primary tumor and metastases in a single session. However, traditional one-stop imaging tests, such as CT and positron emission tomography (PET)/CT, are associated with considerable radiation exposure. This is particularly concerning for children because they are more sensitive to ionizing radiation than adults and they live long enough to experience secondary cancers later in life. In this review article we discuss child-tailored imaging tests for tumor detection and therapy response assessment - tests that can be obtained with substantially reduced radiation exposure compared to traditional CT and PET/CT scans. This includes diffusion-weighted imaging (DWI)/MRI and integrated [F-18]2-fluoro-2-deoxyglucose (F-FDG) PET/MRI scans. While several investigators have compared the value of DWI/MRI and F-FDG PET/MRI for staging pediatric cancer, the value of these novel imaging technologies for cancer therapy monitoring has received surprisingly little attention. In this article, we share our experiences and review existing literature on this subject.
Topics: Adult; Child; Diffusion Magnetic Resonance Imaging; Fluorodeoxyglucose F18; Humans; Magnetic Resonance Imaging; Neoplasm Staging; Neoplasms; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Radiopharmaceuticals; Whole Body Imaging
PubMed: 33929564
DOI: 10.1007/s00247-021-05076-x -
Scientific Reports Jun 2023Glioblastoma, a malignant tumor, has no curative treatment. Recently, mitochondria have been considered a potential target for treating glioblastoma. Previously, we...
Glioblastoma, a malignant tumor, has no curative treatment. Recently, mitochondria have been considered a potential target for treating glioblastoma. Previously, we reported that agents initiating mitochondrial dysfunction were effective under glucose-starved conditions. Therefore, this study aimed to develop a mitochondria-targeted treatment to achieve normal glucose conditions. This study used U87MG (U87), U373, and patient-derived stem-like cells as well as chloramphenicol (CAP) and 2-deoxy-D-glucose (2-DG). We investigated whether CAP and 2-DG inhibited the growth of cells under normal and high glucose concentrations. In U87 cells, 2-DG and long-term CAP administration were more effective under normal glucose than high-glucose conditions. In addition, combined CAP and 2-DG treatment was significantly effective under normal glucose concentration in both normal oxygen and hypoxic conditions; this was validated in U373 and patient-derived stem-like cells. 2-DG and CAP acted by influencing iron dynamics; however, deferoxamine inhibited the efficacy of these agents. Thus, ferroptosis could be the underlying mechanism through which 2-DG and CAP act. In conclusion, combined treatment of CAP and 2-DG drastically inhibits cell growth of glioblastoma cell lines even under normal glucose conditions; therefore, this treatment could be effective for glioblastoma patients.
Topics: Humans; Glioblastoma; Ferroptosis; Chloramphenicol; Glucose; Deoxyglucose
PubMed: 37380755
DOI: 10.1038/s41598-023-37483-5 -
Diabetes/metabolism Research and Reviews Jan 2023Approximately 30% of the global population is affected by obesity. Traditional non-surgical measures for weight loss have limited efficacy and tolerability. Therefore,... (Review)
Review
BACKGROUND
Approximately 30% of the global population is affected by obesity. Traditional non-surgical measures for weight loss have limited efficacy and tolerability. Therefore, there is a need for novel, effective therapies. Brown adipose tissue (BAT) has been implicated in physiological energy expenditure, indicating that it could be targeted to achieve weight loss in humans. The use of F-fluorodeoxyglucose ( F-FDG) positron emission tomography-computed tomography-(PET-CT) imaging has enabled the discovery of functionally active BAT in the supraclavicular, subclavian, and thoracic spine regions of human adults. This review aims to discuss the reasons behind the renewed interest in BAT, assess whether it is metabolically important in humans, and evaluate its feasibility as a therapeutic target for treating obesity.
SOURCES OF MATERIAL
PubMed Central, Europe PMC, Medline.
FINDINGS
In vivo studies have shown that BAT activity is regulated by thyroid hormones and the sympathetic nervous system. Furthermore, BAT uniquely contains uncoupling protein 1 (UCP1) that is largely responsible for non-shivering thermogenesis. Cold exposure can increase BAT recruitment through the browning of white adipose tissue (WAT); however, this technique has practical limitations that may preclude its use. Currently available medicines for humans, such as the β3-adrenergic receptor agonist mirabegron or the farnesoid X receptor agonist obeticholic acid, have generated excitement, although adverse effects are a concern. Capsinoids represent a tolerable alternative, which require further investigation.
CONCLUSIONS
The use of currently available BAT-activating agents alone is unlikely to achieve significant weight loss in humans. A combination of BAT activation with physical exercise and modern, successful dietary strategies represents a more realistic option.
Topics: Adult; Humans; Adipose Tissue, Brown; Positron Emission Tomography Computed Tomography; Body Weight; Obesity; Fluorodeoxyglucose F18; Weight Loss; Adipose Tissue, White
PubMed: 36398906
DOI: 10.1002/dmrr.3594 -
The Journal of Thoracic and... Mar 2020
Topics: Disasters; Fluorodeoxyglucose F18; Humans; Lung Diseases, Interstitial; Lung Neoplasms
PubMed: 31619331
DOI: 10.1016/j.jtcvs.2019.08.124 -
Seminars in Nuclear Medicine Mar 2022Nuclear medicine procedures are generally avoided during pregnancy out of concern for the radiation dose to the fetus. However, for clinical reasons,... (Review)
Review
Nuclear medicine procedures are generally avoided during pregnancy out of concern for the radiation dose to the fetus. However, for clinical reasons, radiopharmaceuticals must occasionally be administered to pregnant women. The procedures most likely to be performed voluntarily during pregnancy are lung scans to diagnose pulmonary embolism and F-fluoro-2-deoxyglucose (F-FDG) scans for the staging of cancers. This article focuses on the challenges of fetal dose calculation after administering radiopharmaceuticals to pregnant women. In particular, estimation of the fetal dose is hampered by the lack of fetal biokinetic data of good quality and is subject to the variability associated with methodological choices in dose calculations, such as the use of various anthropomorphic phantoms and modeling of the maternal bladder. Despite these sources of uncertainty, the fetal dose can be reasonably calculated within a range that is able to inform clinical decisions. Current dose estimates suggest that clinically justified nuclear medicine procedures should be performed even during pregnancy because the clinical benefits for the mother and the fetus outweigh the small and purely hypothetical radiation risk to the fetus. In addition, the fetal radiation dose should be minimized without compromising image quality, such as by encouraging bladder voiding and by using positron emission tomography (PET)/magnetic resonance imaging (MRI) devices or high-sensitivity PET scanners that generate images of good quality with a lower injected activity.
Topics: Female; Fetus; Fluorodeoxyglucose F18; Humans; Positron-Emission Tomography; Pregnancy; Radiation Dosage; Radiopharmaceuticals
PubMed: 35067360
DOI: 10.1053/j.semnuclmed.2021.12.007 -
Journal of the American College of... Sep 2019
Topics: Fluorodeoxyglucose F18; Humans; Plaque, Atherosclerotic; Positron-Emission Tomography
PubMed: 31466621
DOI: 10.1016/j.jacc.2019.07.009 -
Proceedings of the National Academy of... Aug 2021The amino acid and oligopeptide transporter Solute carrier family 15 member A4 (SLC15A4), which resides in lysosomes and is preferentially expressed in immune cells,...
The amino acid and oligopeptide transporter Solute carrier family 15 member A4 (SLC15A4), which resides in lysosomes and is preferentially expressed in immune cells, plays critical roles in the pathogenesis of lupus and colitis in murine models. Toll-like receptor (TLR)7/9- and nucleotide-binding oligomerization domain-containing protein 1 (NOD1)-mediated inflammatory responses require SLC15A4 function for regulating the mechanistic target of rapamycin complex 1 (mTORC1) or transporting L-Ala-γ-D-Glu-meso-diaminopimelic acid, IL-12: interleukin-12 (Tri-DAP), respectively. Here, we further investigated the mechanism of how SLC15A4 directs inflammatory responses. Proximity-dependent biotin identification revealed glycolysis as highly enriched gene ontology terms. Fluxome analyses in macrophages indicated that SLC15A4 loss causes insufficient biotransformation of pyruvate to the tricarboxylic acid cycle, while increasing glutaminolysis to the cycle. Furthermore, SLC15A4 was required for M1-prone metabolic change and inflammatory IL-12 cytokine productions after TLR9 stimulation. SLC15A4 could be in close proximity to AMP-activated protein kinase (AMPK) and mTOR, and SLC15A4 deficiency impaired TLR-mediated AMPK activation. Interestingly, SLC15A4-intact but not SLC15A4-deficient macrophages became resistant to fluctuations in environmental nutrient levels by limiting the use of the glutamine source; thus, SLC15A4 was critical for macrophage's respiratory homeostasis. Our findings reveal a mechanism of metabolic regulation in which an amino acid transporter acts as a gatekeeper that protects immune cells' ability to acquire an M1-prone metabolic phenotype in inflammatory tissues by mitigating metabolic stress.
Topics: 4-Chloro-7-nitrobenzofurazan; Animals; Cell Differentiation; Cell Line; Dendritic Cells; Deoxyglucose; Energy Metabolism; Gene Expression Regulation; Gene Silencing; Humans; Macrophages; Membrane Transport Proteins; Mice; Mice, Knockout; Nerve Tissue Proteins; Oligodeoxyribonucleotides
PubMed: 34385317
DOI: 10.1073/pnas.2100295118 -
Biomedicine & Pharmacotherapy =... Dec 2022Chronic exposure to high glucose inside the human body helps in the progression of cancer by activating various signaling pathways including PI3K, Akt, mTOR, Ras, Raf,... (Review)
Review
Chronic exposure to high glucose inside the human body helps in the progression of cancer by activating various signaling pathways including PI3K, Akt, mTOR, Ras, Raf, MAPK, and PKC. Hyperglycemia induces ROS and AGE production and decreases the functional activities of the cellular antioxidant system. By downregulating the prolyl hydroxylase, it stabilizes HIF-α leading to EMT-induced cancer progression and inhibition of apoptosis. High glucose level increases inflammation by creating a pro-inflammatory environment through the production of certain pro-inflammatory mediators (cytokines, chemokines, leukotrienes), and by influencing the recruitment of immune cells, leukocytes in the inflamed region. High glucose impairs the immune response and dysregulates ROS formation through the alteration in ETC and glutaminolysis which makes hyperglycemic patients more susceptible to viral infection. 2-DG is a modified form of D-glucose, that shows anticancer, anti-inflammatory, and anti-viral effects. It enters the cells through GLUT transporters and is converted into 2-deoxy-D-glucose-6-phosphate with the help of hexokinase. It inhibits the glycolysis, the TCA cycle, and the pentose phosphate pathway leading to ATP depletion. By downregulating glucose uptake and energy (ATP) production it halts various pathways responsible for cancer progression. It promotes the formation of anti-inflammatory mediators, and macrophage polarization, and also modulates immune function, which decreases inflammation. 2-DG inhibits PI3K/Akt/mTOR and upregulates the AMPK pathway, causing activation of the SIRT-4 gene that reduces lipogenesis, glucose uptake, nucleotide formation, and alters viral replication thus reducing the chances of infection.
Topics: Humans; Glucose; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; TOR Serine-Threonine Kinases; Cell Proliferation; Glycolysis; Neoplasms; Deoxyglucose; Inflammation; Adenosine Triphosphate; Virus Diseases
PubMed: 36228369
DOI: 10.1016/j.biopha.2022.113801