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1.
Neuropeptides ; 76: 101932, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31227312

RESUMO

Inflammation is an important factor in the pathology of epilepsy with the hallmarks of resident microglia activation and infiltration of circulating monocytes in the damaged area. In the case of recovery and tissue repair, some monocytes change to macrophages (mo-MΦ) to enhance tissue repair. 2-deoxyglucose (2DG) is an analog of glucose capable of protecting the brain, and progranulin is a neurotrophic factor produced mainly by microglia and has an inflammation modulator effect. This study attempted to evaluate if one of the neuroprotective mechanisms of 2-DG is comprised of increasing monocyte-derived macrophages (mo-MΦ) and progranulin production. Status epilepticus (SE) was induced by i.c.v. injection of kainic acid (KA).2DG (125/mg/kg/day) was administered intraperitoneally. Four days later, animals were sacrificed. Their brain sections were then stained with Cresyl violet and Fluoro-Jade B to count the number of necrotic and degenerating neurons in CA3 and Hilus of dentate gyrus of the hippocampus. Lastly, immunohistochemistry was used to detect CD11b + monocyte, macrophage cells, and Progranulin level was evaluated by Western blotting. The histological analysis showed that 2DG can reduce the number of necrotic and degenerating neurons in CA3 and Hilar areas. Following KA administration, a great number of cD11b+ cells with monocyte morphology were observed in the hippocampus. 2DG not only reduced cD11b+ monocyte cells but was able to convert them to cells with the morphology of macrophages (mo-MΦ). 2DG also caused a significant increase in progranulin level in the hippocampus. Because macrophages and microglia are the most important sources of progranulin, it appears that 2DG caused the derivation of monocytes to macrophages and these cells produced progranulin with a subsequent anti-inflammation effect. In summary, it was concluded that 2DG is neuroprotective and probably one of its neuroprotective mechanisms is by modulating monocyte-derived macrophages by progranulin production.


Assuntos
Desoxiglucose/administração & dosagem , Epilepsia do Lobo Temporal/patologia , Epilepsia do Lobo Temporal/prevenção & controle , Hipocampo/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Progranulinas/metabolismo , Animais , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/induzido quimicamente , Hipocampo/patologia , Ácido Caínico/administração & dosagem , Macrófagos/patologia , Masculino , Neurônios/patologia , Ratos Wistar
2.
Clin Nucl Med ; 44(5): 386-393, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30888989

RESUMO

PURPOSE: Insulin resistance is a key feature of the metabolic syndrome and type 2 diabetes, in which noninvasive assessment is not currently allowed by any methodology. We previously validated an iodinated tracer of glucose transport (6DIG) and a new methodology for the in vivo quantification of cardiac insulin resistance in rodents. The aim of this study was to investigate the safety, biodistribution, and radiation dosimetry of this method using I-6DIG in 5 healthy and 6 diabetic volunteers. METHODS: The collection of adverse effects (AEs) and medical supervision of vital parameters and biological variables allowed the safety evaluation. Biodistribution was studied by sequentially acquiring whole-body images at 1, 2, 4, 8, and 24 hours postinjection. The total number of disintegrations in each organ normalized to the injected activity was calculated as the area under the time-activity curves. Dosimetry calculations were performed using OLINDA/EXM. RESULTS: No major adverse events were observed. The average dose corresponding to the 2 injections of I-6DIG used in the protocol was 182.1 ± 7.5 MBq. A fast blood clearance of I-6DIG was observed. The main route of elimination was urinary, with greater than 50% of urine activity over 24 hours. No blood or urine metabolite was detected. I-6DIG accumulation mostly occurred in elimination organs such as kidneys and liver. Mean radiation dosimetry calculations indicated an effective whole-body absorbed dose of 3.35 ± 0.57 mSv for the whole procedure. CONCLUSIONS: I-6DIG was well tolerated in human with a dosimetry profile comparable to that of other commonly used iodinated tracers, thereby allowing further clinical development of the tracer.


Assuntos
Desoxiglucose/análogos & derivados , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Compostos Radiofarmacêuticos/farmacocinética , Adulto , Desoxiglucose/administração & dosagem , Desoxiglucose/efeitos adversos , Desoxiglucose/farmacocinética , Feminino , Humanos , Masculino , Doses de Radiação , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/efeitos adversos , Eliminação Renal , Distribuição Tecidual
4.
Diabetologia ; 62(4): 676-686, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30627753

RESUMO

AIMS/HYPOTHESIS: This study evaluates whether the non-selective ß-blocker, carvedilol, can be used to prevent counterregulatory failure and the development of impaired awareness of hypoglycaemia (IAH) in recurrently hypoglycaemic rats. METHODS: Sprague Dawley rats were implanted with vascular catheters and intracranial guide cannulas targeting the ventromedial hypothalamus (VMH). These animals underwent either three bouts of insulin-induced hypoglycaemia or received three saline injections (control group) over 3 days. A subgroup of recurrently hypoglycaemic animals was treated with carvedilol. The next day, the animals underwent a hypoglycaemic clamp with microdialysis without carvedilol treatment to evaluate changes in central lactate and hormone levels. To assess whether carvedilol prevented IAH, we treated rats that had received repeated 2-deoxyglucose (2DG) injections to impair their awareness of hypoglycaemia with carvedilol and measured food intake in response to insulin-induced hypoglycaemia as a surrogate marker for hypoglycaemia awareness. RESULTS: Compared with the control group, recurrently hypoglycaemic rats had a ~1.7-fold increase in VMH lactate and this was associated with a 75% reduction in the sympathoadrenal response to hypoglycaemia. Treatment with carvedilol restored VMH lactate levels and improved the adrenaline (epinephrine) responses. In 2DG-treated rats compared with control animals receiving saline, food intake was reduced in response to hypoglycaemia and increased with carvedilol treatment. CONCLUSIONS/INTERPRETATION: We conclude that carvedilol may be a useful therapy to prevent counterregulatory failure and improve IAH.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Carvedilol/uso terapêutico , Hiperglicemia/tratamento farmacológico , Hipoglicemia/tratamento farmacológico , Hipoglicemia/prevenção & controle , Animais , Glicemia , Peso Corporal , Cateterismo , Desoxiglucose/administração & dosagem , Modelos Animais de Doenças , Técnica Clamp de Glucose , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Ácido Láctico/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Recidiva , Fatores de Tempo , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos
5.
Benef Microbes ; 10(3): 293-300, 2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-30638397

RESUMO

Various lactobacilli have been suggested to exert beneficial effects in humans. In this study, we examined the effects of intraduodenal (ID) administration of heat-killed Lactobacillus delbrueckii LAB4 (LAB4) on activities of efferent sympathetic nerves innervating the liver and pancreas. Consequently, it was observed that ID administration of LAB4 significantly reduced either the efferent hepatic sympathetic nerve activity (hepatic-SNA) or pancreatic sympathetic nerve activity (pancreatic-SNA) in urethane-anaesthetised rats. Moreover, the effect of acute and chronic administration of LAB4 (1×109 cells/ml) on hyperglycaemia induced by intracranial injection of 2-deoxy-D-glucose (2DG) were examined in conscious rats. We found that LAB4 significantly inhibited 2DG-induced hyperglycaemia. These findings suggest that ID administration of heat-killed LAB4 might lower plasma glucose level via changes in the autonomic nervous system in rats.


Assuntos
Vias Autônomas/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Lactobacillus delbrueckii/fisiologia , Fígado/inervação , Pâncreas/inervação , Probióticos/farmacologia , Animais , Desoxiglucose/administração & dosagem , Desoxiglucose/toxicidade , Modelos Animais de Doenças , Hiperglicemia/induzido quimicamente , Hiperglicemia/tratamento farmacológico , Masculino , Probióticos/administração & dosagem , Ratos Wistar
6.
Bioorg Med Chem Lett ; 28(21): 3446-3453, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30268701

RESUMO

A new series of (2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols as dual inhibitors of sodium glucose co-transporter proteins (SGLTs) were disclosed. Two methods were developed to efficiently synthesize C5-fluoro-lactones 3 and 4, which are key intermediates to the C5-fluoro-hexose based C-aryl glucosides. Compound 2b demonstrated potent hSGLT1 and hSGLT2 inhibition (IC50 = 43 nM for SGLT1 and IC50 = 9 nM for SGLT2). It showed robust inhibition of blood glucose excursion in oral glucose tolerance test (OGTT) in Sprague Dawley (SD) rats and exerted pronounced antihyperglycemic effects in db/db mice and high-fat diet-fed ZDF rats when dosed orally at 10 mg/kg.


Assuntos
Desoxiglucose/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Desoxiglucose/administração & dosagem , Desoxiglucose/análogos & derivados , Desoxiglucose/síntese química , Desenho de Fármacos , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Macaca fascicularis , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos Sprague-Dawley , Ratos Zucker , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/síntese química , Inibidores do Transportador 2 de Sódio-Glicose/química , Relação Estrutura-Atividade
7.
Front Immunol ; 9: 1973, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30233578

RESUMO

The K/BxN mouse is a spontaneous model of arthritis driven by T cell receptor transgenic CD4+ T cells from the KRN strain that are activated by glucose-6-phosphate isomerase (GPI) peptides presented by the H-2g7 allele from the NOD strain. It is a model of autoimmune seropositive arthritis because the production of anti-GPI IgG is necessary and sufficient for joint pathology. The production of high levels of anti-GPI IgG requires on the expansion of CD4+ follicular helper T (Tfh) cells. The metabolic requirements of this expansion have never been characterized. Based on the therapeutic effects of the combination of metformin and 2-deoxyglucose (2DG) in lupus models that normalized the expansion of effector CD4+ T cells. We showed that the CD4+ T cells and to a lesser extent, the B cells from K/BxN mice are more metabolically active than the KRN controls. Accordingly, preventive inhibition of glycolysis with 2DG significantly reduced joint inflammation and the activation of both adaptive and innate immune cells, as well as the production of pathogenic autoantibodies. However, contrary to the lupus-prone mice, the addition of metformin had little beneficial effect, suggesting that glycolysis is the major driver of immune activation in this model. We propose that K/BxN mice are another model in which autoreactive Tfh cells are highly glycolytic and that their function can be limited by inhibiting glucose metabolism.


Assuntos
Artrite Reumatoide/metabolismo , Desoxiglucose/administração & dosagem , Glicólise/fisiologia , Articulações/imunologia , Animais , Artrite Reumatoide/imunologia , Autoanticorpos/metabolismo , Linfócitos T CD4-Positivos/imunologia , Modelos Animais de Doenças , Progressão da Doença , Centro Germinativo/imunologia , Glucose-6-Fosfato Isomerase/imunologia , Humanos , Metformina/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/genética
8.
Int J Mol Sci ; 19(8)2018 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-30127309

RESUMO

Cancer metabolism is characterized by extensive glucose consumption through aerobic glycolysis. No effective therapy exploiting this cancer trait has emerged so far, in part, due to the substantial side effects of the investigated drugs. In this study, we examined the side effects of a combination of isocaloric ketogenic diet (KD) with the glycolysis inhibitor 2-deoxyglucose (2-DG). Two groups of eight athymic nude mice were either fed a standard diet (SD) or a caloric unrestricted KD with a ratio of 4 g fat to 1 g protein/carbohydrate. 2-DG was investigated in commonly employed doses of 0.5 to 4 g/kg and up to 8 g/kg. Ketosis was achieved under KD (ketone bodies: SD 0.5 ± 0.14 mmol/L, KD 1.38 ± 0.28 mmol/L, p < 0.01). The intraperitoneal application of 4 g/kg of 2-DG caused a significant increase in blood glucose, which was not prevented by KD. Sedation after the 2-DG treatment was observed and a behavioral test of spontaneous motion showed that KD reduced the sedation by 2-DG (p < 0.001). A 2-DG dose escalation to 8 g/kg was lethal for 50% of the mice in the SD and for 0% of the mice in the KD group (p < 0.01). A long-term combination of KD and an oral 1 or 2 g 2-DG/kg was well-tolerated. In conclusion, KD reduces the sedative effects of 2-DG and dramatically increases the maximum tolerated dose of 2-DG. A continued combination of KD and anti-glycolytic therapy is feasible. This is, to our knowledge, the first demonstration of increased tolerance to glycolysis inhibition by KD.


Assuntos
Antimetabólitos/efeitos adversos , Desoxiglucose/efeitos adversos , Dieta Cetogênica/métodos , Animais , Antimetabólitos/administração & dosagem , Glicemia/metabolismo , Desoxiglucose/administração & dosagem , Feminino , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Corpos Cetônicos/metabolismo , Cetose/etiologia , Cetose/metabolismo , Camundongos Nus , Neoplasias/metabolismo
9.
Sci Rep ; 8(1): 10723, 2018 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-30013070

RESUMO

Regular exercise elicits advantageous metabolic adaptations in skeletal muscle, such as improved insulin sensitivity. However, the underpinning molecular mechanisms and the effect of diet on muscle exercise training benefits are unclear. We therefore characterized the skeletal muscle proteome following exercise training (ET) in mice fed chow or high-fat diet (HFD). ET increased exercise performance, lowered body-weight, decreased fat mass and improved muscle insulin action in chow- and HFD-fed mice. At the molecular level, ET regulated 170 muscle proteins in chow-fed mice, but only 29 proteins in HFD-fed mice. HFD per se altered 56 proteins, most of which were regulated in a similar direction by ET. To identify proteins that might have particular health-related bearing on skeletal muscle metabolism, we filtered for differentially regulated proteins in response to ET and HFD. This yielded 15 proteins, including the major urinary protein 1 (MUP1), which was the protein most decreased after HFD, but increased with ET. The ET-induced Mup1 expression was absent in mouse muscle lacking functional AMPK. MUP1 also potentiated insulin-stimulated GLUT4 translocation in cultured muscle cells. Collectively, we provide a resource of ET-regulated proteins in insulin-sensitive and insulin-resistant skeletal muscle. The identification of MUP1 as a diet-, ET- and AMPK-regulated skeletal muscle protein that improves insulin sensitivity in muscle cells demonstrates the usefulness of these data.


Assuntos
Resistência à Insulina/fisiologia , Redes e Vias Metabólicas/fisiologia , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Condicionamento Físico Animal/fisiologia , Adenilato Quinase/genética , Adenilato Quinase/metabolismo , Animais , Comportamento Animal/fisiologia , Peso Corporal , Linhagem Celular , Desoxiglucose/administração & dosagem , Desoxiglucose/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Feminino , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Humanos , Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mioblastos , Proteínas/metabolismo , Proteômica/métodos , Comportamento Sedentário
10.
Magn Reson Med ; 80(2): 488-495, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29569739

RESUMO

PURPOSE: Glucose uptake and metabolism can be measured by chemical exchange-sensitive spin-lock (CESL) MRI with an administration of glucose or its analogs. This study investigates the sensitivity, the spatiotemporal characteristics, and the signal source of glucoCESL with a 9L rat brain tumor model. METHODS: Dynamic CESL MRI with intravenous injection of D-glucose, 2-deoxy-D-glucose (2DG), and L-glucose were measured and compared with gadolinium-based dynamic contrast-enhanced (DCE) MRI. RESULTS: The CESL signals with an injection of glucose or analogs have faster and larger changes in tumors than normal brain tissue. In tumors, the CESL signal with 2DG injection has larger and slower peak response than that with D-glucose due to the accumulation of 2DG and 2DG-6-phosphate in the intracellular compartment, whereas L-glucose, which cannot be transported intracellularly by glucose transporters, only induces a small change. The initial glucoCESL maps (< 4 minutes) are qualitatively similar to DCE maps, whereas later maps (> 4 minutes) show more widespread responses. The rise times of D-glucose-CESL and 2DG-CESL signals in the tumor are slower than that of DCE. Our data suggest that the initial CESL contrast primarily reflects a passive increase of glucose content in the extracellular space of tumors due to a higher vascular permeability, whereas the later period may have a significant contribution from the uptake/metabolism of glucose in the intracellular compartment. CONCLUSIONS: Our results demonstrate that glucoCESL MRI has both extracellular and intracellular contributions, and can be a useful tool for measurements of both vascular permeability and glucose uptake in tumors.


Assuntos
Neoplasias Encefálicas , Encéfalo , Desoxiglucose/farmacocinética , Glucose/farmacocinética , Imagem por Ressonância Magnética/métodos , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Química Encefálica , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Desoxiglucose/administração & dosagem , Desoxiglucose/análise , Glucose/administração & dosagem , Glucose/análise , Interpretação de Imagem Assistida por Computador , Masculino , Ratos , Ratos Endogâmicos F344
11.
Ultrasound Med Biol ; 44(6): 1233-1243, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29555321

RESUMO

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.


Assuntos
Neoplasias da Mama/terapia , Desoxiglucose/administração & dosagem , Terapia por Ultrassom/métodos , Animais , Antimetabólitos/administração & dosagem , Apoptose , Linhagem Celular Tumoral , Feminino , Glicólise/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C
12.
Int J Nanomedicine ; 12: 5701-5715, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28848348

RESUMO

A combination administration of chemical agents was highlighted to treat tumors. Recently, tumor cell has been found to be different from normal cell in metabolic manner. Most of cancer cells prefer aerobic glycolysis to mitochondrial oxidative phosphorylation (OXPHOS) to satisfy energy and biomass synthesis requirement to survive, grow and proliferate, which provides novel and potential therapeutic targets for chemotherapy. Here, 2-deoxy-d-glucose (2-DG), a potent inhibitor of glucose metabolism, was used to inhibit glycolysis of tumor cells; α-tocopheryl succinate (α-TOS), a water-insoluble vitamin E derivative, was chosen to suppress OXPHOS. Our data demonstrated that the combination treatment of 2-DG and α-TOS could significantly promote the anti-tumor efficiency in vitro compared with administration of the single drug. In order to maximize therapeutic activity and minimize negative side effects, a co-delivery nanocarrier targeting folate receptor (FR) was developed to encapsulate 2-DG and α-TOS simultaneously based on our previous work. Transmission electron microscope, dynamic light scattering method and UV-visible spectrophotometers were used to investigate morphology, size distribution and loading efficiency of the α-TOS-2-DG-loaded and FR-targeted nanoparticles (TDF NPs). The TDF NPs were found to possess a layer-by-layer shape, and the dynamic size was <100 nm. The final encapsulation efficiencies of α-TOS and 2-DG in TDF NPs were 94.3%±1.3% and 61.7%±7.7% with respect to drug-loading capacities of 8.9%±0.8% and 13.2%±2.6%, respectively. Almost no α-TOS release was found within 80 h, and release of 2-DG was sustained and slow within 72 h. The results of FR binding assay and fluorescence biodistribution revealed that TDF NPs could target FR highly expressed on tumor cell in vitro and in vivo. Further, in vivo anti-tumor experiments showed that TDF NPs had an improved biological function with less toxicity. Thus, our work indicates that the co-delivery TDF NPs have a great potential in tumor therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxiglucose/administração & dosagem , Portadores de Fármacos/administração & dosagem , Receptores de Folato com Âncoras de GPI/metabolismo , alfa-Tocoferol/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/química , Linhagem Celular Tumoral , Desoxiglucose/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Difusão Dinâmica da Luz , Humanos , Camundongos Nus , Microscopia Eletrônica de Transmissão , Terapia de Alvo Molecular/métodos , Nanopartículas/administração & dosagem , Nanopartículas/química , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto , alfa-Tocoferol/farmacocinética , alfa-Tocoferol/farmacologia
13.
Int J Pharm ; 532(1): 149-156, 2017 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-28844900

RESUMO

Cancer cells increase their metabolism to produce the energy and biomolecules necessary for growth and proliferation. Thus, energy metabolism pathways may serve as targets for anti-cancer therapy. NCL-240 is a second generation anti-cancer drug belonging to the PITenins class of PI3K-Akt inhibitors. Our analysis suggested that NCL-240 caused disruptions in mitochondrial oxidative phosphorylation and up-regulated glycolysis, as evidenced by the loss of NMR peaks for the amino acid products derived from the TCA cycle along with presence of only lactate peaks and the loss of glucose peaks. NCL-240 was combined with 2-deoxy-d-glucose (2-DG) in early proof-of-concept studies on multiple cell lines. 2-DG enhanced cell death response to NCL-240 administration, with cytotoxicity results similar to those under hypoglycemic conditions. In further studies, NCL-240 encapsulated in phosphatidylcholine/cholesterol liposomes was combined with freely dissolved 2-DG. Cell cycle analysis of sensitive and resistant strains of A2780 cells treated with combinations of NCL-240/2-DG pointed to a G0/G1 phase arrest for 80-90% of the total, indicating an inability to grow and divide. Cytotoxicity studies with in vitro cancer cell monolayer models confirmed the results of cell cycle analysis. Significant improvements in cytotoxicity with combination treatments over control and individual treatments were seen in multiple cell lines. NCI/ADR-RES cancer cell spheroids further demonstrated the effectiveness of a NCL-240/2-DG combination.


Assuntos
Antineoplásicos/administração & dosagem , Clorofenóis/administração & dosagem , Desoxiglucose/administração & dosagem , Metabolismo Energético/efeitos dos fármacos , Neoplasias/metabolismo , Triazóis/administração & dosagem , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Interações Medicamentosas , Humanos , Lipossomos , Neoplasias/tratamento farmacológico
14.
Mol Med Rep ; 16(3): 2976-2984, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28656301

RESUMO

ß­cell dysfunction is the primary cause of type 2 diabetes mellitus (T2DM). 1,2­dicarbonyl compounds, such as 3­deoxyglucosone (3DG) have been reported to increase the risk of T2DM. Abnormal elevation of plasma 3DG may impair ß­cell function and thereby, it is linked to T2DM. Previous findings suggest that exogenous 3DG may serve an important role in the development of pre­diabetes. In the present study, the authors examine whether exogenous 3DG induces impaired glucose regulation in mice by decreasing ß­cell function involving of accumulation of plasma 3DG. At two weeks following administration of 3DG, fasting blood glucose (FBG) levels, oral glucose tolerance (by a glucose meter) and plasma levels of 3DG (by HPLC) and insulin (by radioimmunoassay) were measured. Glucose­stimulated insulin secretion in cultured pancreas islets and INS­1 cells was measured by radioimmunoassay. Western blotting was used to examine the expression of the key molecules of the insulin­PI3K signaling pathway. 3DG treatment increased FBG and fasting blood insulin levels, reduced oral glucose tolerance in conjunction with decreased ∆Ins30­0/∆G30­0. In 3DG­treated mice, an increase in the plasma 3DG level was observed, which was most likely the mechanism for decreased ß­cell function. This idea was further supported by these results that non­cytotoxic 3DG concentration obviously decreased glucose­stimulated insulin secretion in cultured pancreas islets and INS­1 cells exposure to high glucose (25.5 mM). 3DG decreased the expression of GLUT2 and phosphorylation of IRS­1, PI3K­p85 and Akt in high glucose­induced INS­1 cells. To the best of the authors' knowledge, the present study is the first to demonstrate that exogenous 3DG induced normal mice to develop IGR, resulting from ß­cell dysfunction. Exogenous 3DG administration increased plasma 3DG levels, which participates in inducing ß­cell dysfunction, at least in part, through impairing IRS­1/PI3K/GLUT2 signaling.


Assuntos
Desoxiglucose/análogos & derivados , Glucose/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Animais , Glicemia/metabolismo , Linhagem Celular , Desoxiglucose/administração & dosagem , Desoxiglucose/sangue , Desoxiglucose/farmacologia , Jejum/sangue , Teste de Tolerância a Glucose , Insulina/sangue , Células Secretoras de Insulina/efeitos dos fármacos , Masculino , Camundongos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
15.
Oncotarget ; 8(19): 30978-30991, 2017 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-28415682

RESUMO

Recent studies showed that 2-deoxy-D-glucose (2-DG), a glucose analog with dual activity of inhibiting glycolysis and N-linked glycosylation, can be selectively taken up by cancer cells and be used as a potential chemo- and radio-sensitizer. Meanwhile, 2-DG can kill cancer cells under normoxia. However, its efficacy is limited by the high-dose induced systemic toxicity. Here, we showed that low-dose 2-DG could be used as a single agent to kill acute lymphoblastic leukemia (ALL) cells, and as a GC sensitizer to overcome GC resistance under normoxia. Addition of exogenous mannose, a sugar essential for N-linked glycosylation, rescued 2-DG-treated ALL cells, indicating that inhibition of N-linked glycosylation and induction of endoplasmic reticulum stress is the main mechanism for 2-DG to induce cell death and reverse GC resistance in ALL cells. These data provides new insight into the molecular mechanisms involved in GC resistance. More important, it indicates that 2-DG might be the promising drug for designing novel high efficiency and low toxic protocol for ALL patients.


Assuntos
Antineoplásicos/farmacologia , Desoxiglucose/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glucocorticoides/farmacologia , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desoxiglucose/administração & dosagem , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Glicosilação/efeitos dos fármacos , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras
16.
Int J Radiat Biol ; 93(6): 590-599, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28291374

RESUMO

PURPOSE: Two-deoxy-D-glucose (2DG) causes cytotoxicity in the cancer cells by disrupting the thiol metabolism, and MLN4924 inactivates the SCF E3 ligase and so causes the accumulation of its substrates which trigger apoptosis and hence might enhance the efficiency of radiotherapy and overcame on the radioresistance of the cancer cells. MATERIALS AND METHODS: SKBR3 and MCF-7 breast cancer cells were treated with 500 µM 2DG and/or MLN4924 (30, 100, 200 and 300 nM), and in combination in the presence and absence of 1, 1.5 and 2 Gy gamma irradiation. The effects of the treatments - 2DG, MLN4924, irradiation alone and combined - on MCF-7 and SKBR3 cell lines were evaluated by MTT assay, TUNEL assay, cell death detection, Q-PCR for caspase-3 and Bcl-2 expression analysis, and finally clonogenic survival assay. RESULTS: The treatments enhanced the further radio cytotoxicity via inducing the apoptosis cell signaling gene, caspase-3. The 2DG and MLN4924 treatments could act as a radiosensitizer, especially on the SKBR3 cells, and further sensitized the cells with a sensitivity enhancement ratio (SER) of 1.41 and 1.27 in SKBR3 and MCF-7 cells, respectively. CONCLUSION: The combined chemo-radiotherapy might improve the breast cancer treatment outcome.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Apoptose/efeitos dos fármacos , Neoplasias da Mama/terapia , Quimiorradioterapia/métodos , Ciclopentanos/administração & dosagem , Desoxiglucose/administração & dosagem , Pirimidinas/administração & dosagem , Neoplasias da Mama/patologia , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Humanos , Células MCF-7 , Dosagem Radioterapêutica , Resultado do Tratamento
17.
Breast ; 33: 97-103, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28351000

RESUMO

INTRODUCTION: Nanoparticles are promising as a new approach to enhance chemo- radiotherapy efficiency in breast cancer mainly via targeted therapy. MATERIALS & METHODS: SKBR3 and T47D breast cancer cells were treated with superparamagnetic mesoporous hydroxyapatite nanocomposites (SPmHANs)conjugated with 1 µM doxorubicin and 0.5 mM 2-Deoxy-d-Glucose and irradiated with 1 and 2 Gy gamma rays in vitro. The treatment toxicity and also the apoptosis/necrosis ratio were measured by MTT assay and also ELISA cell death detection PLUS, respectively. RESULTS: The decreased cell viability with the combined treatment, with determined 42% loading efficiency for 200 ppm 2DG and 93% for5ppm doxorubicin on SPmHANs in PH about 7.4 and 5.5, were calculated to 60.9% and 68% compared to radiotherapy alone inT47D and SKBR3 cells (both with p < 0.05), respectively. CONCLUSION: Breast cancer cure may boost from The combined targeted nanoparticle treatment with doxorubicin and 2-Deoxy-d-Glucose may boost breast cancer radiotherapy by improved chemodrug localization, increased cytotoxicity in tumor cells and decreased single modality treatment doses.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/terapia , Desoxiglucose/administração & dosagem , Doxorrubicina/administração & dosagem , Nanopartículas/administração & dosagem , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Quimiorradioterapia/métodos , Terapia Combinada , Feminino , Humanos , Nanopartículas/química , Doses de Radiação , Radiação Ionizante
18.
J Neurosci Res ; 95(11): 2195-2206, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28150440

RESUMO

Metabolic abnormalities found in epileptogenic tissue provide considerable evidence of brain hypometabolism, while major risk factors for acquired epilepsy all share brain hypometabolism as one common outcome, suggesting that a breakdown of brain energy homeostasis may actually precede epileptogenesis. However, a causal link between deficient brain energy metabolism and epilepsy initiation has not been yet established. To address this issue we developed an in vivo model of chronic energy hypometabolism by daily intracerebroventricular (i.c.v.) injection of the nonmetabolizable glucose analog 2-deoxy-D-glucose (2-DG) and also investigated acute effects of 2-DG on the cellular level. In hippocampal slices, acute glycolysis inhibition by 2-DG (by about 35%) led to contrasting effects on the network: a downregulation of excitatory synaptic transmission together with a depolarization of neuronal resting potential and a decreased drive of inhibitory transmission. Therefore, the potential acute effect of 2-DG on network excitability depends on the balance between these opposing pre- and postsynaptic changes. In vivo, we found that chronic 2-DG i.c.v. application (estimated transient inhibition of brain glycolysis under 14%) for a period of 4 weeks induced epileptiform activity in initially healthy male rats. Our results suggest that chronic inhibition of brain energy metabolism, characteristics of the well-established risk factors of acquired epilepsy, and specifically a reduction in glucose utilization (typically observed in epileptic patients) can initiate epileptogenesis. © 2017 Wiley Periodicals, Inc.


Assuntos
Encéfalo/metabolismo , Encéfalo/fisiopatologia , Metabolismo Energético/fisiologia , Epilepsia/metabolismo , Epilepsia/fisiopatologia , Glicólise/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Desoxiglucose/administração & dosagem , Metabolismo Energético/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Camundongos , Técnicas de Cultura de Órgãos , Ratos , Ratos Sprague-Dawley
19.
Cancer Biomark ; 18(4): 367-374, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28106540

RESUMO

BACKGROUND: Breast cancer is one of the most common type of female cancer worldwide and represents 14% of cancer-related deaths in women. Early detection is the most important factor for treatment and prognosis of breast cancer. In most countries, the women are currently screened with mammography only. Even though there has been considerable progress in the detection, surgical therapy, hormonal and target therapy of breast cancer, there are about ∼ 3500 000 women who die from breast cancer each year. Therefore, there is an urgent need to explore the new techniques for early detection of breast cancer. Magnetic resonance imaging (MRI) has the potential to improve breast cancer detection at an early stage because of its higher sensitivity. Glucose transporter (Glut) is a cellular transmembrane receptor that plays key roles in cell glucose metabolism and over-expressed in breast cancer cells. 2-deoxy-D-glucose having a similar structure to D-glucose can specifically interact with Glut. METHODS: In the present study, we constructed a 2-deoxy-D-glucose-functionalized superparamagnetic iron oxide (SPIO) nanoparticles that coated with meso-2,3-dimercaptosuccinic acid (γ-Fe2O3@DMSA-DG NPs). The aim of this study is to evaluate the efficacy of new constructed MRI contrast agent (γ-Fe2O3@DMSA-DG NPs) in detecting human breast cancers. RESULTS: Our results showed that breast cancer cells MDA-MD-231, MCF7 and ZR-75-1 had a high uptake rate of γ-Fe2O3@DMSA-DG NPs than human breast fibroblast cell HUM-CELL-0056. There was a significant difference of T2 relaxation times and signal intensity between breast cancer cells and human breast fibroblast cells labeled with γ-Fe2O3@DMSA-DG NPs when MIR. CONCLUSION: Our results indicated that γ-Fe2O3@DMSA-DG NPs may be used as a new MRI contrast agent for detection of breast cancer.


Assuntos
Neoplasias da Mama/diagnóstico , Rastreamento de Células/métodos , Detecção Precoce de Câncer , Nanopartículas de Magnetita/administração & dosagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Desoxiglucose/administração & dosagem , Desoxiglucose/química , Feminino , Compostos Férricos/administração & dosagem , Compostos Férricos/química , Fibroblastos/metabolismo , Humanos , Células MCF-7 , Imagem por Ressonância Magnética , Nanopartículas de Magnetita/química , Succímero/química
20.
Oncotarget ; 7(47): 77664-77682, 2016 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-27765910

RESUMO

Mutation of p53 occasionally results in a gain of function, which promotes tumor growth. We asked whether destabilizing the gain-of-function protein would kill tumor cells. Downregulation of the gene reduced cell proliferation in p53-mutant cells, but not in p53-null cells, indicating that the former depended on the mutant protein for survival. Moreover, phenformin and 2-deoxyglucose suppressed cell growth and simultaneously destabilized mutant p53. The AMPK pathway, MAPK pathway, chaperone proteins and ubiquitination all contributed to this process. Interestingly, phenformin and 2-deoxyglucose also reduced tumor growth in syngeneic mice harboring the p53 mutation. Thus, destabilizing mutant p53 protein in order to kill cells exhibiting "oncogene addiction" could be a promising strategy for combatting p53 mutant tumors.


Assuntos
Desoxiglucose/administração & dosagem , Mutação , Neoplasias/patologia , Fenformin/administração & dosagem , Proteína Supressora de Tumor p53/genética , Células A549 , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desoxiglucose/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Introdução de Genes , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Metástase Neoplásica , Fenformin/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
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