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Microbes and Infection 2023Viral infection treatment is a difficult task due to its complex structure and metabolism. Additionally, viruses can alter the metabolism of host cells, mutate, and...
Viral infection treatment is a difficult task due to its complex structure and metabolism. Additionally, viruses can alter the metabolism of host cells, mutate, and readily adjust to harsh environments. Coronavirus stimulates glycolysis, weakens mitochondrial activity, and impairs infected cells. In this study, we investigated the efficacy of 2-DG in inhibiting coronavirus-induced metabolic processes and antiviral host defense systems, which have not been explored so far. 2-Deoxy-d-glucose (2-DG), a molecule restricting substrate availability, has recently gained attention as a potential antiviral drug. The results revealed that 229E human coronavirus promoted glycolysis, producing a significant increase in the concentration of fluorescent 2-NBDG, a glucose analog, particularly in the infected host cells. The addition of 2-DG decreased its viral replication and suppressed infection-induced cell death and cytopathic effects, thereby improving the antiviral host defense response. It was also observed that administration of low doses of 2-DG inhibited glucose uptake, indicating that 2-DG consumption in virus-infected host cells was mediated by high-affinity glucose transporters, whose levels were amplified upon coronavirus infection. Our findings indicated that 2-DG could be a potential drug to improve the host defense system in coronavirus-infected cells.
Topics: Humans; Deoxyglucose; Virulence; Glycolysis; Glucose; Coronavirus; Antiviral Agents
PubMed: 37178787
DOI: 10.1016/j.micinf.2023.105150 -
European Journal of Cardio-thoracic... Feb 2024In the last decades, 4 different scores for the prediction of mortality following surgery for type A acute aortic dissection (TAAD) were proposed. We aimed to validate...
OBJECTIVES
In the last decades, 4 different scores for the prediction of mortality following surgery for type A acute aortic dissection (TAAD) were proposed. We aimed to validate these scores in a large external multicentre cohort.
METHODS
We retrospectively analysed patients who underwent surgery for TAAD between 2000 and 2020. Patients were enrolled from 10 centres from 2 European countries. Outcomes were the early (30-day and/or in-hospital) and 1-year mortality. Discrimination, calibration and observed/expected (O/E) ratio were evaluated.
RESULTS
A total of 1895 patients (31.7% females, mean age 63.72 ± 12.8 years) were included in the study. Thirty-day mortality and in-hospital mortality were 21.7% (n = 412) and 22.5% (n = 427) respectively. The German Registry of Acute Aortic Dissection Type A (GERAADA) score shows to have the best discrimination [area under the curve (AUC) 0.671 and 0.672] in predicting as well the early and the 1-year mortality, followed by the International Registry of Acute Aortic Dissection (IRAD) model 1 (AUC 0.658 and 0.672), the Centofanti (AUC 0.645 and 0.66) and the UK aortic score (AUC 0.549 and 0.563). According to Hosmer-Lemeshow and Brier tests, the IRAD model I and GERAADA, respectively, were well calibrated for the early mortality, while the GERAADA and Centofanti for the 1-year mortality. The O/E analysis showed a marked underestimation for patients labelled as low-risk for UK aortic score and IRAD model I for both outcomes.
CONCLUSIONS
The GERAADA score showed the best performance in comparison with other scores. However, none of them achieved together a fair discrimination and a good calibration for predicting either the early or the 1-year mortality.
Topics: Humans; Female; Middle Aged; Aged; Male; Retrospective Studies; Aortic Dissection; Hospital Mortality; Europe; Registries; Risk Factors; Treatment Outcome; Azides; Deoxyglucose
PubMed: 38212996
DOI: 10.1093/ejcts/ezae005 -
Clinical Chemistry Nov 2014
Topics: Deoxyglucose; Diabetes Mellitus; Diabetic Retinopathy; Female; Humans; Hyperglycemia; Male; Renal Insufficiency, Chronic
PubMed: 25217368
DOI: 10.1373/clinchem.2014.231720 -
Feedback amplification of senolysis using caspase-3-cleavable peptide-doxorubicin conjugate and 2DG.Journal of Controlled Release :... Jun 2022Therapy-induced senescence (TIS), a common outcome of current cancer therapy, is a known cause of late recurrence and metastasis and thus its eradication is crucial for...
Therapy-induced senescence (TIS), a common outcome of current cancer therapy, is a known cause of late recurrence and metastasis and thus its eradication is crucial for therapy success. In this study, we introduced a conceptually novel strategy combining radiation-induced apoptosis-targeted chemotherapy (RIATC) with an effective glycolysis inhibitor, 2-deoxy-d-glucose (2DG) to target TIS. RIATC releases cytotoxic payload by amplification, continually increasing TIS, and this can be targeted by 2DG that stimulates an intrinsic apoptotic pathway in senescent cells, the senolysis; the senolytic 2DG also sensitizes cancer cells to chemo/radiation treatment. Anti-tumor efficacy of RIATC was investigated in numerous tumor models, and various cancer types were screened for TIS. Furthermore, in vitro evaluations of molecular markers of senescence, such as senescence-associated β-galactosidase (SA-β-Gal) assay, were performed to confirm that TIS was induced by RIATC therapy in MCF-7 cells. The combination therapy with 2DG proved to be effective in MCF-7 tumor-bearing mice that demonstrated feedback amplification of senolysis and successful inhibition of tumor growth. Our findings suggest that RIATC, when given together with 2DG, can overcome therapy-induced senescence and this combination is a promising strategy that enhances the therapeutic benefit of anti-cancer cytotoxic therapy.
Topics: Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Deoxyglucose; Doxorubicin; Humans; MCF-7 Cells; Mice; Peptides
PubMed: 35452763
DOI: 10.1016/j.jconrel.2022.04.012 -
Biochimica Et Biophysica Acta. General... Sep 2023Glycolytic inhibitor 2-deoxy-d-glucose (2-DG) binds to hexokinase in a non-competitive manner and phosphoglucose isomerase in a competitive manner, blocking the initial...
Multitranscript analysis reveals an effect of 2-deoxy-d-glucose on gene expression linked to unfolded protein response and integrated stress response in primary human monocytes and monocyte-derived macrophages.
BACKGROUND
Glycolytic inhibitor 2-deoxy-d-glucose (2-DG) binds to hexokinase in a non-competitive manner and phosphoglucose isomerase in a competitive manner, blocking the initial steps of the glycolytic pathway. Although 2-DG stimulates endoplasmic reticulum (ER) stress, activating the unfolded protein response to restore protein homeostasis, it is unclear which ER stress-related genes are modulated in response to 2-DG treatment in human primary cells. Here, we aimed to determine whether the treatment of monocytes and monocyte-derived macrophages (MDMs) with 2-DG leads to a transcriptional profile specific to ER stress.
METHODS
We performed bioinformatics analysis to identify differentially expressed genes (DEGs) in previously reported RNA-seq datasets of 2-DG treated cells. RT-qPCR was performed to verify the sequencing data on cultured MDMs.
RESULTS
A total of 95 common DEGs were found by transcriptional analysis of monocytes and MDMs treated with 2-DG. Among these, 74 were up-regulated and 21 were down-regulated. Multitranscript analysis showed that DEGs are linked to integrated stress response (GRP78/BiP, PERK, ATF4, CHOP, GADD34, IRE1α, XBP1, SESN2, ASNS, PHGDH), hexosamine biosynthetic pathway (GFAT1, GNA1, PGM3, UAP1), and mannose metabolism (GMPPA and GMPPB).
CONCLUSIONS
Results reveal that 2-DG triggers a gene expression program that might be involved in restoring protein homeostasis in primary cells.
GENERAL SIGNIFICANCE
2-DG is known to inhibit glycolysis and induce ER stress; however, its effect on gene expression in primary cells is not well understood. This work shows that 2-DG is a stress inducer shifting the metabolic state of monocytes and macrophages.
Topics: Humans; Glucose; Monocytes; Endoribonucleases; Protein Serine-Threonine Kinases; Unfolded Protein Response; Macrophages; Endoplasmic Reticulum Chaperone BiP; Deoxyglucose; Gene Expression; Sestrins
PubMed: 37290716
DOI: 10.1016/j.bbagen.2023.130397 -
Endocrinology Aug 2022The ventromedial hypothalamic (VMH) nucleus is a well-established hub for energy and glucose homeostasis. In particular, VMH neurons are thought to be important for...
The ventromedial hypothalamic (VMH) nucleus is a well-established hub for energy and glucose homeostasis. In particular, VMH neurons are thought to be important for initiating the counterregulatory response to hypoglycemia, and ex vivo electrophysiology and immunohistochemistry data indicate a clear role for VMH neurons in sensing glucose concentration. However, the temporal response of VMH neurons to physiologically relevant changes in glucose availability in vivo has been hampered by a lack of available tools for measuring neuronal activity over time. Since the majority of neurons within the VMH are glutamatergic and can be targeted using the vesicular glutamate transporter Vglut2, we expressed cre-dependent GCaMP7s in Vglut2 cre mice and examined the response profile of VMH to intraperitoneal injections of glucose, insulin, and 2-deoxyglucose (2DG). We show that reduced available glucose via insulin-induced hypoglycemia and 2DG-induced glucoprivation, but not hyperglycemia induced by glucose injection, inhibits VMH Vglut2 neuronal population activity in vivo. Surprisingly, this inhibition was maintained for at least 45 minutes despite prolonged hypoglycemia and initiation of a counterregulatory response. Thus, although VMH stimulation, via pharmacological, electrical, or optogenetic approaches, is sufficient to drive a counterregulatory response, our data suggest VMH Vglut2 neurons are not the main drivers required to do so, since VMH Vglut2 neuronal population activity remains suppressed during hypoglycemia and glucoprivation.
Topics: Animals; Blood Glucose; Deoxyglucose; Glucose; Hypoglycemia; Insulin; Male; Mice; Neurons; Photometry; Rats; Rats, Sprague-Dawley; Ventromedial Hypothalamic Nucleus
PubMed: 35788848
DOI: 10.1210/endocr/bqac095 -
Ultrasound in Medicine & Biology Jun 2018Inhibition of the increased aerobic glycolysis in cancer cells is a promising methodology for various malignant tumor therapies but is limited by systemic toxicity, at...
Inhibition of the increased aerobic glycolysis in cancer cells is a promising methodology for various malignant tumor therapies but is limited by systemic toxicity, at least in part. Recent studies suggest that dual restriction of glycolysis and mitochondrial function may overcome this issue. Sonodynamic therapy (SDT), a prospective therapeutic modality for cancers, has been reported to induce mitochondria-dependent cell damage. Here, we investigated the combined effect of SDT and 2-deoxyglucose (2DG), an anti-glycolytic agent, on breast cancer both in vitro and in vivo. In vitro, we found that, compared with a single treatment, SDT + 2DG co-treatment significantly decreased cell viability and increased cell apoptosis. Moreover, the generation of reactive oxygen species was enhanced and mitochondrial membrane potential (MMP) was reduced after SDT + 2DG co-treatment. Furthermore, the oxidative phosphorylation was also restrained after SDT + 2DG co-treatment, further to cause the blockage of ATP provision. In vivo, SDT + 2DG markedly reduced tumor volume and weight, consistent with the in vitro findings. Furthermore, toxicology tests concurrently indicated that the dosages of sinoporphyrin sodium and 2DG were comparatively tolerable. Generally, these results indicated that SDT + 2DG combination therapy may be an available, promising therapy for highly metastatic breast cancer.
Topics: Animals; Antimetabolites; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Deoxyglucose; Female; Glycolysis; Humans; Mice; Mice, Inbred BALB C; Ultrasonic Therapy
PubMed: 29555321
DOI: 10.1016/j.ultrasmedbio.2018.01.020 -
Molecular Imaging and Biology Aug 2021This study evaluated the use of molecular imaging of fluorescent glucose analog 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG) as a...
PURPOSE
This study evaluated the use of molecular imaging of fluorescent glucose analog 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG) as a discriminatory marker for intraoperative tumor border identification in a murine glioma model.
PROCEDURES
2-NBDG was assessed in GL261 and U251 orthotopic tumor-bearing mice. Intraoperative fluorescence of topical and intravenous 2-NBDG in normal and tumor regions was assessed with an operating microscope, handheld confocal laser scanning endomicroscope (CLE), and benchtop confocal laser scanning microscope (LSM). Additionally, 2-NBDG fluorescence in tumors was compared with 5-aminolevulinic acid-induced protoporphyrin IX fluorescence.
RESULTS
Intravenously administered 2-NBDG was detectable in brain tumor and absent in contralateral normal brain parenchyma on wide-field operating microscope imaging. Intraoperative and benchtop CLE showed preferential 2-NBDG accumulation in the cytoplasm of glioma cells (mean [SD] tumor-to-background ratio of 2.76 [0.43]). Topically administered 2-NBDG did not create sufficient tumor-background contrast for wide-field operating microscope imaging or under benchtop LSM (mean [SD] tumor-to-background ratio 1.42 [0.72]). However, topical 2-NBDG did create sufficient contrast to evaluate cellular tissue architecture and differentiate tumor cells from normal brain parenchyma. Protoporphyrin IX imaging resulted in a more specific delineation of gross tumor margins than intravenous or topical 2-NBDG and a significantly higher tumor-to-normal-brain fluorescence intensity ratio.
CONCLUSION
After intravenous administration, 2-NBDG selectively accumulated in the experimental brain tumors and provided bright contrast under wide-field fluorescence imaging with a clinical-grade operating microscope. Topical 2-NBDG was able to create a sufficient contrast to differentiate tumor from normal brain cells on the basis of visualization of cellular architecture with CLE. 5-Aminolevulinic acid demonstrated superior specificity in outlining tumor margins and significantly higher tumor background contrast. Given the nontoxicity of 2-NBDG, its use as a topical molecular marker for noninvasive in vivo intraoperative microscopy is encouraging and warrants further clinical evaluation.
Topics: 4-Chloro-7-nitrobenzofurazan; Aminolevulinic Acid; Animals; Apoptosis; Brain; Brain Neoplasms; Cell Proliferation; Deoxyglucose; Female; Fluorescence; Glioma; Glucose; Humans; Mice; Mice, Inbred C57BL; Molecular Imaging; Monitoring, Intraoperative; Protoporphyrins; Surgery, Computer-Assisted; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 33544308
DOI: 10.1007/s11307-021-01579-z -
International Journal of Radiation... May 2020A study is presented of the irradiation of cancerous cervical cell line HeLa loaded with a platinum salt, betamethasone and deoxyglucose. The presence of the platinum...
A study is presented of the irradiation of cancerous cervical cell line HeLa loaded with a platinum salt, betamethasone and deoxyglucose. The presence of the platinum increases the free-radical concentration and augments the cell death rate, whereas betamethasone or deoxyglucose induces radiosensitization by the alteration of metabolic pathways. Two by two combinations of these chemicals are made to investigate the possible benefit when two radiosensitizers are present. A model is proposed to understand the results of the presence of two modifying agents on the dose effects. The cells were incubated for 6 h in the presence of the following molecules: dichloro terpyridine platinum, concentration = 350 μM, betamethasone and deoxyglucose with concentrations of = 0.2 μM and = 6 mM, respectively. The cells were subsequently irradiated by carbon C ion 290 MeV/amu up to a dose of 2.5 Gy, under atmospheric conditions. The presence of the platinum salt or bethamethasone augments the cell death rate. The combination of betamethasone with the platinum salt also increases the cell death rate, but less than for the platinum salt alone. The explanation is that any radiosensitizer also behaves as a scavenger of free radicals. This dual behavior should be considered in any optimization of the design of radiosensitizers when different ionizing particles are used.
Topics: Betamethasone; Deoxyglucose; HeLa Cells; Humans; Hydroxyl Radical; Linear Energy Transfer; Models, Theoretical; Platinum Compounds; Proton Therapy; Radiation-Sensitizing Agents
PubMed: 31976790
DOI: 10.1080/09553002.2020.1721594 -
Nuclear Medicine Communications Jan 2022Bone and lung are the common sites of metastasis in pediatric round cell tumors and its presence indicates poor outcomes. Staging workup for these malignancies thus...
BACKGROUND AND HYPOTHESIS
Bone and lung are the common sites of metastasis in pediatric round cell tumors and its presence indicates poor outcomes. Staging workup for these malignancies thus includes bone marrow biopsy (BMB) along with evaluation of thorax, and tissue analysis for N MYCN status in neuroblastoma. BMB is an invasive procedure requiring general anesthesia with known disadvantages.With an aim of avoiding an invasive BMB a study was taken up to evaluate efficacy of FDG PET CT in detecting marrow involvement in neuroblastoma and rhabdomyosarcoma at staging.
MATERIALS AND METHOD
Prospective observational study evaluated 83 newly diagnosed treatment naïve patients of neuroblastoma (n = 43) and rhabdomyosarcoma (n = 42) who underwent conventional imaging of PETCT with CECT of local region along with a CT thorax and BMB (both iliac crest) done within 1 week. Findings of FDG PETCT were compared with bone marrow histology and accuracy parameters were calculated.
RESULT
The overall sensitivity, specificity, accuracy, positive-predictive value (PPV), negative-predictive value (NPV) of FDG PETCT for detection of marrow disease was 100%, 86.1%, 89.4%. 68.9% and 100%, respectively. Subset analysis showed sensitivity, specificity, PPV and NPV of 100%, 66%, 71.4% and 100%, respectively, for neuroblastoma, with rhabdomyosarcoma patients having few events NPV of 100% accuracy of 97.6%.
CONCLUSION
FDG PETCT with sensitivity and NPV of 100% can be considered as a first stop imaging and biopsy can be avoided in patients with a negative scan.
Topics: Fluorodeoxyglucose F18
PubMed: 34618718
DOI: 10.1097/MNM.0000000000001491