AGE-RELATED MACULAR DEGENERATION (AMD): FROM METABOLOMICS APPROACH TO THE INHIBITION OF PDK AS A NEW THERAPEUTIC TARGET

Age-related Macular Degeneration (AMD) is a leading cause of vision loss in the western world among people aged 50 or older. 90% of all vision loss due to AMD results from the exudative form, which is characterized by choroidal neovascularization (CNV). Age-related changes that induce pathologic CNV are incompletely understood. A successful application of anti-VEGF approaches in the clinic is obviously a turning point in AMD treatment. Nevertheless, despite such important advances, critical issues remain to be addressed. To better understand the aetiology of this pathology, we used and improved a murine model of laser-induced choroidal neovascularization and applied a 1H NMR metabolomics study. This approach leads to the emergence of different putative biomarkers and to the validation of the CNV model for an experimental study of AMD. Among these “biomarkers”, lactate appears to be clearly involved in the development of AMD. The modulation of their plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate Dehydrogenase Kinase inhibitors (PDK) significantly decrease the impact of laser induced CNV. Starting from these results, the development of new PDHK inhibitors could open the way to innovative treatment opportunities in AMD diseas

Sperm Motility and Lactate production at different sperm concentrations

Lactate production is associated with total spermatozoa concentration. It negatively affects preservation of total and progressive motility, showing an effect of by-products of anaerobic metabolism on long-term storage. Moreover, our data show that non-progressive motile spermatozoa are highly associated to lactate concentration, and thus, anaerobic glycolysis. More studies are required to determine relative contributions of aerobiosis and anaerobiosis to spermatozoa motility under different storage conditions.Peer reviewe

Glucose use and lactate production by equine fresh semen in human and equine extender

This study shows that this human semen extender doesn’t support equine semen preservation. Sperm cells’ glucose consumption and lactate production seem to be negligible, as these parameters were not affected by sperm concentrations in our study. Our results suggest that spermatozoa are able to cleave complex carbohydrates as glucose concentration in INRA96 increased over time

Challenge testing with Brochothrix thermosphacta on minced pork meat shows interest to couple metagenetics to metabolomics to study food spoilage

The spoilage of perishable foods is mainly caused by bacterial activity. The risk of unwanted bacterial growth is particularly high in the minced pork meat. In this work, the natural microbial contaminants of the minced pork meat were followed by 16S ribosomal DNA deep sequencing (metagenetics) during aging tests at different temperatures. Brochothrix thermosphacta MM008 strain was selected as one of the main contaminants responsible for the spoilage of the meat. Minced pork meat previously sterilized by gamma irradiation was inoculated with B. thermosphacta MM008 for challenge tests measuring growth and then incubated at different temperatures. Minced meat samples were taken and analyzed by H-NMR 1D at time 0 and at final time (from 14 to 19 days, depending on the incubation temperature). Orthogonal partial least square discriminant analysis (OPLS-DA) showed that samples, regardless of the incubation temperature, could be splitted into 3 groups according to their spectral profile: 1) samples taken at time 0, 2) samples inoculated with B. thermosphacta and taken at final time, 3) samples uninoculated, taken at final time. From the analysis of the metabolomics data, higher concentrations of glycerol, glucose, taurine, lactate, carnitine, betaine and glycine were identified in the samples of uninoculated minced pork meat and an increased production of creatine, acetate and acetone was found in the samples of minced pork meat inoculated with B. thermosphacta MM008. These observations showed that -omics technologies (metagenetics and metabolomics) could be used conclusively to study microbial spoilage of minced pork meat

3-Methyl-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1,1-Dioxide

peer reviewe

N-Aryl-N'-(chroman-4-yl)ureas and thioureas display in vitro anticancer activity and selectivity on apoptosis-resistant glioblastoma cells: screening, synthesis of simplified derivatives, and structure-activity relationship analysis.

A series of chroman derivatives previously reported as potassium channel openers, as well as some newly synthesized simplified structures, were examined for their in vitro effects on the growth of three human high-grade glioma cell lines: U373, T98G, and Hs683. Significant in vitro growth inhibitory activity was observed with 2,2-dimethylchroman-type nitro-substituted phenylthioureas, such as compounds 4o and 4p. Interestingly, most tested phenylureas were found to be slightly less active, but more cell selective (normal versus tumor glial cells, such as 3d, 3e, and 3g), thus less toxic, than the corresponding phenylthioureas. No significant differences were observed in terms of chroman-derivative-induced growth inhibitory effects between glioma cells sensitive to pro-apoptotic stimuli (Hs683 glioma cells) and glioma cells associated with various levels of resistance to pro-apoptotic stimuli (U373 and T98G glioma cells), a feature that suggests non-apoptotic-mediated growth inhibition. Flow cytometry analyses confirmed the absence of pro-apoptotic effects for phenylthioureas and phenylureas when analyzed in U373 glioma cells and demonstrated U373 cell cycle arrest in the G0/G1 phase. Computer-assisted phase-contrast videomicroscopy revealed that 3d and 3g displayed cytostatic effects, while 3e displayed cytotoxic ones. As a result, this work identified phenylurea-type 2,2-dimethylchromans as a new class of antitumor agents to be further explored for an innovative therapeutic approach for high-grade glioma and/or for a possible new mechanism of action