A Translational Metabonomic Assessment of Aristolochic Acid- Induced Nephropathies

Aristolochic acid nephropathy (AAN) is a global term including any form of toxic interstitial nephropathy that is caused either by the ingestion of plants containing aristolochic acids (AA) as part of traditional phytotherapies or by the environmental contaminants in food. Originally, AAN was reported in Belgium in individuals having ingested slimming pills containing powdered root extracts of a Chinese herb, Aristolochia fangchi. However, it is estimated that exposure to AA affects thousands of people all over the world, particularly in the Balkans, Taiwan and China. Despite warnings from the Regulatory Agencies regarding the safety of products containing AA, many AAN cases remain frequently described worldwide. This chapter aims at giving a global picture of AAN through the descriptions of clinical cases and animal models, which were developed to better understand the mode of action of AA when inducing acute/chronic kidney diseases. Major advances in the translational research on biomarkers of AAN are reviewed, with an intended emphasis on the “omics” assessment of this nephrotoxicity

Etude des mécanismes d'internalisation hépatique de systèmes moléculaires et nanoparticulaires, agents de contraste pour l'imagerie par résonance magnétique nucléaire

Les pathologies du foie représentent une des causes les plus fréquentes de mortalité. Ceci provient sans doute de la difficulté de poser le diagnostic à un stade précoce de leur développement malgré les très bonnes performances de l'échographie et de la tomographie de rayons X. On espère que l'IRM dont les résultats spectaculaires dans le diagnostic des tumeurs cérébrales sont aujourd'hui incontestés améliorera la situation. Malheureusement, comme les autres techniques et en dépit de son excellent contraste inhérent, l'IRM se heurte aussi au problème de la mise en évidence des maladies hépatiques. Afin de remédier à cette situation, la recherche s'est orientée vers l'élaboration de produits de contraste spécifiques. La stratégie suivie jusqu'ici est double: d'une part, des complexes d'ions paramagnétiques sont développés pour favoriser leur incorporation par les hépatocytes, et, d'autre part, des nanoparticules superparamagnétiques sont synthétisées afin de cibler les cellules de Kupffer, les macrophages fixes du foie.Doctorat en science

Targeting Metabolic Reprogramming to Improve Breast Cancer Treatment: An In Vitro Evaluation of Selected Metabolic Inhibitors Using a Metabolomic Approach

Characteristic metabolic adaptations are recognized as a cancer hallmark. Breast cancer, like other cancer types, displays cellular respiratory switches—in particular, the Warburg effect—and important fluctuations in the glutamine and choline metabolisms. This cancer remains a world health issue mainly due to the side effects associated with chemotherapy, which force a reduction in the administered dose or even a complete discontinuation of the treatment. For example, Doxorubicin is efficient to treat breast cancer but unfortunately induces severe cardiotoxicity. In the present in vitro study, selected metabolic inhibitors were evaluated alone or in combination as potential treatments against breast cancer. In addition, the same inhibitors were used to possibly potentiate the effects of Doxorubicin. As a result, the combination of CB-839 (glutaminase inhibitor) and Oxamate (lactate dehydrogenase inhibitor) and the combination of CB-839/Oxamate/D609 (a phosphatidylcholine-specific phospholipase C inhibitor) caused significant cell mortality in both MDA-MB-231 and MCF-7, two breast cancer cell lines. Furthermore, all inhibitors were able to improve the efficacy of Doxorubicin on the same cell lines. Those findings are quite encouraging with respect to the clinical goal of reducing the exposure of patients to Doxorubicin and, subsequently, the severity of the associated cardiotoxicity, while keeping the same treatment efficacy

First-line toxicological models for genotoxicity and nephrotoxicity assessment of herbal products

info:eu-repo/semantics/publishe

Metabolome profiling of normotensive and hypertensive rats during the early stages of pregnancy

Hypertensive disorders during pregnancy are a leading cause of maternal and fetal mortality worldwide. During a first pregnancy, some women may develop gestational hypertension, representing a major risk to the mother and child especially when associated with preeclampsia. This pathological condition arises from a defect in placentation that is the starting point of hypertension in pregnancy. The impact of hypertension and/or pregnancy on the metabolome of rats was assessed by 1H-NMR spectroscopy. This approach revealed specific metabolic patterns in urine, plasma and tissue samples associated with hypertension and/or pregnancy. In particular, alterations in the contents of fatty acids, amino acids and glycoproteins in plasma samples and tissue extracts were indicative of the development of a "metabolic syndrome”. Also, changes in urinary creatinine already reported by other authors as potential biomarkers of an alteration in glomerular filtration due to hypertension were confirmed in our study. Finally, changes in sarcosine were also noticed, which could be seen as indicative of the invasion of cytotrophoblast during the development of the placenta. These results support the use of 1H-NMR-based metabonomics as a promising tool to provide new information on metabolic changes associated with the physiopathology of hypertension and pregnancy in rats

Investigation of Mitochondrial Adaptations to Modulation of Carbohydrate Supply during Adipogenesis of 3T3-L1 Cells by Targeted 1H-NMR Spectroscopy

(1) Background: White adipose tissue (WAT) is a dynamic and plastic tissue showing high sensitivity to carbohydrate supply. In such a context, the WAT may accordingly modulate its mitochondrial metabolic activity. We previously demonstrated that a partial replacement of glucose by galactose in a culture medium of 3T3-L1 cells leads to a poorer adipogenic yield and improved global mitochondrial health. In the present study, we investigate key mitochondrial metabolic actors reflecting mitochondrial adaptation in response to different carbohydrate supplies. (2) Methods: The metabolome of 3T3-L1 cells was investigated during the differentiation process using different glucose/galactose ratios and by a targeted approach using 1H-NMR (Proton nuclear magnetic resonance) spectroscopy; (3) Results: Our findings indicate a reduction of adipogenic and metabolic overload markers under the low glucose/galactose condition. In addition, a remodeling of the mitochondrial function triggers the secretion of metabolites with signaling and systemic energetical homeostasis functions. Finally, this study also sheds light on a new way to consider the mitochondrial metabolic function by considering noncarbohydrates related pathways reflecting both healthier cellular and mitochondrial adaptation mechanisms; (4) Conclusions: Different carbohydrates supplies induce deep mitochondrial metabolic and function adaptations leading to overall adipocytes function and profile remodeling during the adipogenesis

PPARs: Interference with Warburg’ Effect and Clinical Anticancer Trials

The metabolic/cell signaling basis of Warburg’s effect (“aerobic glycolysis”) and the general metabolic phenotype adopted by cancer cells are first reviewed. Several bypasses are adopted to provide a panoramic integrated view of tumoral metabolism, by attributing a central signaling role to hypoxia-induced factor (HIF-1) in the expression of aerobic glycolysis. The cancer metabolic phenotype also results from alterations of other routes involving ras, myc, p53, and Akt signaling and the propensity of cancer cells to develop signaling aberrances (notably aberrant surface receptor expression) which, when present, offer unique opportunities for therapeutic interventions. The rationale for various emerging strategies for cancer treatment is presented along with mechanisms by which PPAR ligands might interfere directly with tumoral metabolism and promote anticancer activity. Clinical trials using PPAR ligands are reviewed and followed by concluding remarks and perspectives for future studies. A therapeutic need to associate PPAR ligands with other anticancer agents is perhaps an important lesson to be learned from the results of the clinical trials conducted to date

Protective Effect of Nebivolol against Oxidative Stress Induced by Aristolochic Acids in Endothelial Cells.

Aristolochic acids (AAs) are powerful nephrotoxins that cause severe tubulointerstitial fibrosis. The biopsy-proven peritubular capillary rarefaction may worsen the progression of renal lesions via tissue hypoxia. As we previously observed the overproduction of reactive oxygen species (ROS) by cultured endothelial cells exposed to AA, we here investigated in vitro AA-induced metabolic changes by 1H-NMR spectroscopy on intracellular medium and cell extracts. We also tested the effects of nebivolol (NEB), a β-blocker agent exhibiting antioxidant properties. After 24 h of AA exposure, significantly reduced cell viability and intracellular ROS overproduction were observed in EAhy926 cells; both effects were counteracted by NEB pretreatment. After 48 h of exposure to AA, the most prominent metabolite changes were significant decreases in arginine, glutamate, glutamine and glutathione levels, along with a significant increase in the aspartate, glycerophosphocholine and UDP-N-acetylglucosamine contents. NEB pretreatment slightly inhibited the changes in glutathione and glycerophosphocholine. In the supernatants from exposed cells, a decrease in lactate and glutamate levels, together with an increase in glucose concentration, was found. The AA-induced reduction in glutamate was significantly inhibited by NEB. These findings confirm the involvement of oxidative stress in AA toxicity for endothelial cells and the potential benefit of NEB in preventing endothelial injury.info:eu-repo/semantics/publishe

Three optimized and validated (using accuracy profiles) LC methods for the determination of pentamidine and new analogs in rat plasma

Three novel LC-UV methods for the determination of pentamidine (PTMD) and two of its new analogs in rat plasma are described. The chromatographic conditions (wavelength, acetonitrile percentage in the mobile phase, internal standard) were optimized to have an efficient selectivity. A pre-step of extraction was simultaneously developed for each compound. For PTMD, a solid phase extraction (SPE) with Oasis® HLB cartridges was selected, while for the analogs we used protein precipitation with acetonitrile. SPE for PTMD gave excellent results in terms of extraction yield (99.7 ± 2.8) whereas the recoveries for the analogs were not so high but were reproducible as well (64.6 ± 2.6 and 36.8 ± 1.6 for analog 1 and 2, respectively). By means of a recent strategy based on accuracy profiles (β-expectation tolerance interval), the methods were successfully validated. β was fixed at 95% and the acceptability limits at ±15% as recommended by the FDA. The method was successfully validated for PTMD (29.6-586.54 ng/mL), analog 1 (74.23-742.3 ng/mL) and analog 2 (178.12-890.6 ng/mL). The first concentration level tested was considered as the LLOQ (lower limit of quantification) for PTMD and analog 1 whereas for analog 2, the LLOQ was not the first level tested and was raised to 178.12 ng/mL. © 2010 Elsevier B.V. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Metabonomic profiling of chronic intermittent hypoxia in a mouse model

Chronic intermittent hypoxia (ChIH) is a dominant feature of obstructive sleep apnoea (OSA) and is associated to metabolic alterations and oxidative stress (OS). Although management of OSA is well established, the research of new biomarkers that are independent of confounding factors remains necessary to improve the early detection of comorbidity and therapeutic follow-up. In this study, the urinary metabonomic profile associated to intermittent hypoxia was evaluated in a mouse model. When exposed to intermittent hypoxia, animals showed a significant alteration in energy metabolism towards anaerobic pathways and signs of OS imbalance. A compensatory response was observed over time. Our data also indicates an excess production of vitamin B3, liver function modulations and a stimulation of creatine synthesis which could be used to evaluate the ChIH repercussions. As well, TMAO and allantoin could constitute interesting biomarker candidates, respectively in the context of cardiovascular risk and OS associated to OSA.SCOPUS: ar.jinfo:eu-repo/semantics/publishe