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1.
MAGMA ; 28(6): 591-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26449715

RESUMO

OBJECTIVE: (13)C metabolic MRI using hyperpolarized (13)C-bicarbonate enables preclinical detection of pH. To improve signal-to-noise ratio, experimental procedures were refined, and the influence of pH, buffer capacity, temperature, and field strength were investigated. MATERIALS AND METHODS: Bicarbonate preparation was investigated. Bicarbonate was prepared and applied in spectroscopy at 1, 3, 14 T using pure dissolution, culture medium, and MCF-7 cell spheroids. Healthy rats were imaged by spectral-spatial spiral acquisition for spatial and temporal bicarbonate distribution, pH mapping, and signal decay analysis. RESULTS: An optimized preparation technique for maximum solubility of 6 mol/L and polarization levels of 19-21% is presented; T1 and SNR dependency on field strength, buffer capacity, and pH was investigated. pH mapping in vivo is demonstrated. CONCLUSION: An optimized bicarbonate preparation and experimental procedure provided improved T1 and SNR values, allowing in vitro and in vivo applications.


Assuntos
Bicarbonatos/metabolismo , Espectroscopia de Prótons por Ressonância Magnética/métodos , Algoritmos , Animais , Isótopos de Carbono , Meios de Contraste , Gadolínio , Concentração de Íons de Hidrogênio , Mucosa Intestinal/metabolismo , Rim/metabolismo , Fígado/metabolismo , Miocárdio/metabolismo , Ratos , Ratos Endogâmicos Lew , Sensibilidade e Especificidade , Razão Sinal-Ruído , Células Tumorais Cultivadas
2.
J Cell Biochem ; 116(5): 822-35, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25530451

RESUMO

Characteristic of the tumor microenvironment are fluctuating gradients of reduced nutrient levels and released lactate. A fundamental issue is how tumor cells modulate their metabolic activity when both glucose and glutamine levels become limiting in the presence of high exogenous lactate. For functional analyses, the activities of pyruvate kinase, lactate dehydrogenase (LDH) and plasma membrane NADH oxidase (NOX) as well as cell growth were measured in breast cancer MCF-7 cells cultured in medium containing various concentrations of these metabolites. After 3 days at glucose concentrations below 2.5 mM, cell number was higher with 0.1 mM than with 1.0 mM glutamine, indicating that the glucose/glutamine balance is important for growth. On the other hand, NOX activity increased with increasing glucose >2.5 mM, but only with low glutamine (0.1 mM). Pyruvate kinase activity also increased, with LDH activity remaining 2-3-fold lower. Here NOX could have a complementary role in reoxidizing NADH for glycolysis. Exogenous lactate supported cell survival at limiting concentrations of glucose and glutamine while increasing NOX and pyruvate kinase activities as well as NADH levels. It is proposed that lactate supports cell survival by fuelling gluconeogenesis and/or the TCA cycle in mitochondria, from where NADH could be shuttled to the cytosol and reoxidized by NOX. Cell survival and the metabolic phenotype are thus interrelated to the dynamics of NADH and plasma membrane NOX activity, which are regulated by the balance of glucose/glutamine levels, in conjunction with lactate in a precarious tumor microenvironment.


Assuntos
Células MCF-7/metabolismo , NAD/metabolismo , Inanição , Microambiente Tumoral , Feminino , Glutamina/metabolismo , Glicólise , Humanos , Ácido Láctico/metabolismo
3.
Carcinogenesis ; 24(2): 327-34, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12584184

RESUMO

We showed previously that CYP1B1-null mice developed 10 times less lymphomas than wild-type mice after receiving 7,12-dimethylbenz[a]anthracene (DMBA). In this study a 10-fold lower dose was applied to differentiate between toxicity induced lymphomas (200 micro g/mouse/day) and tumor initiation (20 micro g/day). DMBA adducts to DNA of organs of mice, or to DNA of V79 cells expressing single mice or human cytochrome P450 isoenzymes were also measured. Mice were dosed three cycles of 5 days/week with DMBA in corn oil orally. Histopathology was determined at intermittent death or 1 year after dosing. DMBA-DNA adducts were assayed by (32)P-postlabeling. At 20 micro g/day, wild-type mice developed ovary (71%, stromal cells derived), skin (36%), uterus (64%) and lung (14%) hyperplasias. At this dose the CYP1B1-null mice developed no lymphomas, 25% ovary (epithelial cells derived), 8% skin, 58% uterus and 33% lung tumors. Oil control mice (n = 35) developed only eight, mostly different, hyperplasias. Wild-type mice had more DMBA-DNA adducts than the CYP1B1-null mice. The differences were highest in thymus, spleen, ovaries and testes (5-7-fold). Additionally, one specific DMBA-DNA adduct was reduced in CYP1B1-null mice. V79-cells expressed mouse CYP1B1 was 35 times more active than mouse CYP1A1 in forming DMBA-DNA adducts. Human CYP1B1 was 2.5 times less active than mouse CYP1B1 but 2.3-fold more active than human CYP1A1. CYP1B1 is the dominant enzyme in metabolizing DMBA to carcinogenic metabolites at high and low doses in mice, leading to an increased tumor rate of especially the ovaries at low doses of DMBA. Wild-type mice had more DMBA-DNA adducts than CYP1B1-null mice. Additionally, a specific adduct was less present in the CYP1B1-null mice. Human CYP1B1 was less active than mouse CYP1B1, but more active than human CYP1A1 in forming DMBA-DNA adducts. Thus, we expect CYP1B1 to be an important DMBA activating enzyme in humans also.


Assuntos
9,10-Dimetil-1,2-benzantraceno/toxicidade , Hidrocarboneto de Aril Hidroxilases/metabolismo , Carcinógenos/toxicidade , Adutos de DNA , Neoplasias Ovarianas/induzido quimicamente , Animais , Hidrocarboneto de Aril Hidroxilases/genética , Linhagem Celular , Cricetinae , Citocromo P-450 CYP1B1 , Feminino , Humanos , Camundongos
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