Does Early Mismatched Nutrition Predispose to Hypertension and Atherosclerosis, in Male Mice?

BACKGROUND: A link between early mismatched nutritional environment and development of components of the metabolic syndrome later in life has been shown in epidemiological and animal data. The aim of this study was to investigate whether an early mismatched nutrition produced by catch-up growth after fetal protein restriction could induce the appearance of hypertension and/or atherosclerosis in adult male mice. METHODOLOGY/PRINCIPAL FINDINGS: Wild-type C57BL6/J or LDLr-/- dams were fed a low protein (LP) or a control (C) diet during gestation. Catch-up growth was induced in LP offspring by feeding dams with a control diet and by culling the litter to 4 pups against 8 in controls. At weaning, male mice were fed either standard chow or an obesogenic diet (OB), leading to 4 experimental groups. Blood pressure (BP) and heart rate (HR) were assessed in conscious unrestrained wild-type mice by telemetry. Atherosclerosis plaque area was measured in aortic root sections of LDLr-/- mice. We found that: (1) postnatal OB diet increased significantly BP (P<0.0001) and HR (P<0.008) in 3-month old OB-C and OB-LP offspring, respectively; (2) that maternal LP diet induced a significant higher BP (P<0.009) and HR (P<0.004) and (3) an altered circadian rhythm in addition to higher plasma corticosterone concentration in 9 months-old LP offspring; (4) that, although LP offspring showed higher plasma total cholesterol than control offspring, atherosclerosis assessed in aortic roots of 6-mo old mice featured increased plaque area due to OB feeding but not due to early mismatched nutrition. CONCLUSIONS/SIGNIFICANCE: These results indicate a long-term effect of early mismatched nutrition on the appearance of hypertension independently of obesity, while no effect on atherosclerosis was noticed at this age

Developmental programming of adulthood obesity and cardiovascular disease in the mouse by maternal nutritional imbalance

A link between early malnutrition and development of components of the metabolic syndrome later in life has been shown in epidemiological and animal data. Moreover, studies now tend to demonstrate that not only fetal environment is important for developmental programming but postnatal milieu could also participate to this process. The “predictive adaptive response” hypothesis stipulates that not only a suboptimal environment during fetal life will lead to development of metabolic disorders later in life but more likely is a mismatch between the early environment and that one really encountered later on that increases the risk of developing later disease. Based on this hypothesis, we examined the effect of an early mismatched environment produced by fetal protein restriction and postnatal catch-up growth on the development of obesity and cardiovascular disease in male mice. We focussed our study on the analysis of adipose tissue with in vitro examination of differentiation, proliferation of preadipocytes. We also investigated in vivo the development of overweight in adult mice and we measured the expression of specific adipose tissue molecules with microarray. Finally, we investigated the development of hypertension and atherosclerosis in parallel to obesity. Our results indicated that postnatal catch-up growth after fetal protein restriction favours the development of obesiy in adult male mice. Early mismatched nutrition also influenced the capacity of proliferation of preadipocyte as well as the expression of adipose tissue specific molecules involved mainly in lipid biosynthesis. Finally, early nutrition also induced hypertension in adult male mice while no influence of fetal protein restriction and postnatal catch-up growth was observed on atherosclerosis development.(BIOL 3) -- UCL, 200

Biological basis for increased sensitivity to radiation therapy in HPV-positive head and neck cancers

Although development of head and neck squamous cell carcinomas (HNSCCs) is commonly linked to the consumption of tobacco and alcohol, a link between human papillomavirus (HPV) infection and a subgroup of head and neck cancers has been established. These HPV-positive tumors represent a distinct biological entity with overexpression of viral oncoproteins E6 and E7. It has been shown in several clinical studies that HPV-positive HNSCCs have a more favorable outcome and greater response to radiotherapy. The reason for improved prognosis of HPV-related HNSCC remains speculative, but it could be owned to multiple factors. One hypothesis is that HPV-positive cells are intrinsically more sensitive to standard therapies and thus respond better to treatment. Another possibility is that HPV-positive tumors uniquely express viral proteins that induce an immune response during therapy that helps clear tumors and prevents recurrence. Here, we will review current evidence for the biological basis of increased radiosensitivity in HPV-positive HNSCC. © 2014 V. Bol and V. Grégoire

Impact of Oxygenation Status on (18)F-FDG Uptake in Solid Tumors

The influence of changes in tumor oxygenation (monitored by EPR oximetry) on the uptake of (18)F-FDG tracer was evaluated using micro-PET in two different human tumor models. The (18)F-FDG uptake was higher in hypoxic tumors compared to tumors that present a pO2 value larger than 10 mmHg

The increase in tumor oxygenation under carbogen breathing induces a decrease in the uptake of [(18)F]-fluoro-deoxy-glucose

We investigated the impact of oxygenation status (measured by EPR oximetry) on the uptake of (18)F-FDG (measured by PET) in two different tumor models during a carbogen breathing challenge. We observed a significant drop in (18)F-FDG uptake under carbogen breathing that suggests a rapid metabolic adaptation to the oxygen environment

Potential role of hypoxia imaging using (18)F-FAZA PET to guide hypoxia-driven interventions (carbogen breathing or dose escalation) in radiation therapy.

BACKGROUND AND PURPOSE: Hypoxia-driven intervention (oxygen manipulation or dose escalation) could overcome radiation resistance linked to tumor hypoxia. Here, we evaluated the value of hypoxia imaging using (18)F-FAZA PET to predict the outcome and guide hypoxia-driven interventions. MATERIAL AND METHODS: Two hypoxic rat tumor models were used: rhabdomyosarcoma and 9L-glioma. For the irradiated groups, the animals were divided into two subgroups: breathing either room air or carbogen. (18)F-FAZA PET images were obtained just before the irradiation to monitor the hypoxic level of each tumor. Absolute pO2 were also measured using EPR oximetry. Dose escalation was used in Rhabdomyosarcomas. RESULTS: For 9L-gliomas, a significant correlation between (18)F-FAZA T/B ratio and tumor growth delay was found; additionally, carbogen breathing dramatically improved the tumor response to irradiation. On the contrary, Rhabdomyosarcomas were less responsive to hyperoxic challenge. For that model, an increase in growth delay was observed using dose escalation, but not when combining irradiation with carbogen. CONCLUSIONS: (18)F-FAZA uptake may be prognostic of outcome following radiotherapy and could assess the response of tumor to carbogen breathing. (18)F-FAZA PET may help to guide the hypoxia-driven intervention with irradiation: carbogen breathing in responsive tumors or dose escalation in tumors non-responsive to carbogen

Forced catch-up growth after fetal protein restriction alters the adipose tissue gene expression program leading to obesity in adult mice.

A mismatch between fetal and postnatal environment can permanently alter the body structure and physiology and so, contribute later to obesity and related disorders, as revealed by epidemiological studies. Early programming of adipose tissue might be central in this observation. Moreover, adipose tissue secretes adipokines that provide a molecular link between obesity and its related disorders. Therefore, our aim was to investigate whether a protein restriction during fetal life, followed by catch-up growth could lead to obesity in 9 month-old male mice and could alter the adipose tissue gene expression profile. Dams were fed a low protein (LP) or an isocaloric control (C) diet during gestation. Postnatal catch-up growth was induced in LP offspring by feeding dams with control diet and by culling LP litters to 4 pups instead of 8 in C. At weaning, male mice were fed by lab chow alone (C) or supplemented with a hypercaloric diet (HC), to induce obesity (C-C, C-HC, LP-C and LP-HC). At 9-mo, LP offspring featured increased relative fat mass, hyperglycemia, hypercholesterolemia and hyperleptinemia. Using a microarray designed to study the expression of 89 genes involved in adipose tissue differentiation/function, we demonstrated that the expression profile of several genes were dependent upon the maternal diet. Among the diverse genes showing altered expression, we could identify genes encoding several enzymes involved in lipid metabolism. These results indicated that offspring submitted to early mismatched nutrition exhibited alterations in adipose tissue gene expression that probably increases their susceptibility to overweight when challenged after weaning with a HC diet. Key words: fetal programming, catch-up growth, obesity, adipokines

Reprogramming of tumor metabolism by targeting mitochondria improves tumor response to irradiation.

Background. The Warburg phenotype identified decades ago describes tumor cells with increased glycolysis and decreased mitochondrial respiration even in the presence of oxygen. This particular metabolism also termed 'aerobic glycolysis' reflects an adaptation of tumor cells to proliferation in a heterogeneous tumor microenvironment. Although metabolic alterations in cancer cells are common features, their impact on the response to radiotherapy is not yet fully elucidated. This study investigated the impact of cellular oxygen consumption inhibition on the tumor response to radiotherapy. Material and methods. Warburg-phenotype tumor cells with impaired mitochondrial respiration (MD) were produced and compared in respect to their metabolism to the genetically matched parental cells (WT). After characterization of their metabolism we compared the response of MD cells to irradiation in vivo and in vitro to the genetically matched parental cells (WT). Results. We first confirmed that MD cells were exclusively glycolytic while WT cells exhibited mitochondrial respiration. We then used these cells for assessing the response of WT and MD tumors to a single dose of radiation and showed that the in vivo tumor growth delay of the MD group was increased, indicating an increased radiosensitivity compared to WT while the in vitro ability of both cell lines to repair radiation-induced DNA damage was similar. Conclusion. Taken together, these results indicate that in addition to intrinsic radiosensitivity parameters the tumor response to radiation will also depend on their metabolic rate of oxygen consumption

Synthesis of new 18F-radiolabeled silicon-based nitroimidazole compounds

The syntheses of new nitroimidazole compounds using silicon-[ 18F]fluorine chemistry for the potential detection of tumor hypoxia are described. [18F]silicon-based compounds were synthesized by coupling 2-nitroimidazole with silyldinaphtyl or silylphenyldi-tert-butyl groups and labeled by fluorolysis or isotopic exchange. Dinaphtyl compounds (6, 10) were labeled in 56-71% yield with a specific activity of 45 GBq/μmol, however these compounds ([18F]7 and [18F]11) were not stable in plasma. Phenyldi-tert-butyl compounds were labeled in 70% yield with a specific activity of 3 GBq/μmol by isotopic exchange, or in 81% yield by fluorolysis of siloxanes with a specific activity of 45 GBq/μmol. The labeled compound [18F]18 was stable in plasma and excreted by the liver and kidneys in vivo. In conclusion, the fluorosilylphenyldi-tert-butyl (SiFA) group is more stable in plasma than fluorosilyldiphenyl moiety. Thus, compound [ 18F]18 is suitable for further in vivo assessments. © 2013 Elsevier Ltd. All rights reserved