References of "De Tullio, Pascal"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailPyruvate dehydrogenase kinase/lactate axis: a therapeutic target for neovascular age-related macular degeneration identified by metabolomics
LAMBERT, Vincent ULiege; hansen, Sylvain; Schoumacher, Matthieu ULiege et al

in Journal of Molecular Medicine (2020)

Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in aging populations. Here, we applied metabolomics to human sera of patients with nAMD during an active (exudative ... [more ▼]

Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in aging populations. Here, we applied metabolomics to human sera of patients with nAMD during an active (exudative) phase of the pathology and found higher lactate levels and a shift in the lipoprotein profile (increased VLDL-LDL/HDL ratio). Similar metabolomics changes were detected in the sera of mice subjected to laser-induced choroidal neovascularization (CNV). In this experimental model, we provide evidence for two sites of lactate production: first, a local one in the injured eye, and second a systemic site associated with the recruitment of bone marrow–derived inflammatory cells. Mechanistically, lactate promotes the angiogenic response and M2-like macrophage accumulation in the eyes. The therapeutic potential of our findings is demonstrated by the pharmacological control of lactate levels through pyruvate dehydrogenase kinase (PDK) inhibition by dichloroacetic acid (DCA). Mice treated with DCA exhibited normalized lactate levels and lipoprotein profiles, and inhibited CNV formation. Collectively, our findings implicate the key role of the PDK/lactate axis in AMD pathogenesis and reveal that the regulation of PDK activity has potential therapeutic value in this ocular disease. The results indicate that the lipoprotein profile is a traceable pattern that is worth considering for patient follow-up. [less ▲]

Detailed reference viewed: 14 (4 ULiège)
Full Text
Peer Reviewed
See detailHeparin-Coated Liposomes Improve Antiplasmodial Activity and Reduce the Toxicity of Poupartone B
Ledoux, Allison ULiege; Mamede, Lucia; Palazzo, Claudio et al

in Planta Medica International Open (2020), 7(e), 7380

Poupartone B is an alkyl cyclohexenone derivative isolated from Poupartia borbonica. This compound demonstrated promising antimalarial activity (IC50 < 1 μg/mL), however, it was not de- void of toxicity ... [more ▼]

Poupartone B is an alkyl cyclohexenone derivative isolated from Poupartia borbonica. This compound demonstrated promising antimalarial activity (IC50 < 1 μg/mL), however, it was not de- void of toxicity. Thus, to reduce the adverse side effects of this natural bioactive molecule, a delivery strategy involving a na- nostructure was formulated. Additionally, poupartone B-load- ed liposomes were coated with heparin, a glycosaminoglycan that is known to target proteins on the surface of Plasmodium falciparum-infected red blood cells. The quantification of the compound in the formulation was performed by HPLC-DAD, while heparin was quantitated by 1H NMR spectroscopy. The liposomes’ antiplasmodial activity was tested on artemisinin- resistant P. falciparum isolate, and toxicity was evaluated on human HeLa cells and zebrafish embryos. Throughout this re- search, the formulation demonstrated higher antiplasmodial activities against both P. falciparum strains and a significant decrease of in vitro toxicity. The formulation improved the se- lectivity index 2 times in vitro and proved to be 3 times less toxic than the compound alone in the zebrafish embryo acute toxicity test. Hence, the use of this strategy to deliver natural products in Plasmodium-infected cells, particularly those with a narrow therapeutic margin, is proposed. [less ▲]

Detailed reference viewed: 45 (8 ULiège)
Full Text
Peer Reviewed
See detailCombining rapid 2D NMR experiments with novel pre-processing workflows and MIC quality measures for metabolomics
Féraud, Baptiste; Martineau, Estelle; Leenders, Justine et al

in Metabolomics (2020), 16

Abstract Introduction The use of 2D NMR data sources (COSY in this paper) allows to reach general metabolomics results which are at least as good as the results obtained with 1D NMR data, and this with a ... [more ▼]

Abstract Introduction The use of 2D NMR data sources (COSY in this paper) allows to reach general metabolomics results which are at least as good as the results obtained with 1D NMR data, and this with a less advanced and less complex level of preprocessing. But a major issue still exists and can largely slow down a generalized use of 2D data sources in metabolomics: the experiment duration. Objective The goal of this paper is to overcome the experiment duration issue in our recently published MIC strategy by considering faster 2D COSY acquisition techniques: a conventional COSY with a reduced number of transients and the use of the Non-Uniform Sampling (NUS) method. These faster alternatives are all submitted to novel 2D pre-processing workflows and to Metabolomic Informative Content analyses. Eventually, results are compared to those obtained with conventional COSY spectra. Methods To pre-process the 2D data sources, the Global Peak List (GPL) workflow and the Vectorization workflow are used. To compare this data sources and to detect the more informative one(s), MIC (Metabolomic Informative Content) indexes are used, based on clustering and inertia measures of quality. Results Results are discussed according to a multi-factor experimental design (which is unsupervised and based on human urine samples). Descriptive PCA results and MIC indexes are shown, leading to the direct and objective comparison of the different data sets. Conclusion In conclusion, it is demonstrated that conventional COSY spectra recorded with only one transient per increment and COSY spectra recorded with 50% of non-uniform sampling provide very similar MIC results as the initial COSY recorded with four transients, but in a much shorter time. Consequently, using techniques like the reduction of the number of transients or NUS can really open the door to a potential high-throughput use of 2D COSY spectra in metabolomics. [less ▲]

Detailed reference viewed: 22 (1 ULiège)
Full Text
Peer Reviewed
See detailNew Insight into exudative Age-related Macular Degeneration (AMD): A Metabolomics Approach
Schoumacher, Matthieu ULiege; LAMBERT, Vincent ULiege; Hansen, Sylvain et al

Conference (2019, December 11)

Age-related macular degeneration (AMD) is common disease and leading causes of vision loss among people aged 50 and older. Late-stage AMD (called exudative) is characterized by choroidal ... [more ▼]

Age-related macular degeneration (AMD) is common disease and leading causes of vision loss among people aged 50 and older. Late-stage AMD (called exudative) is characterized by choroidal neovascularization (CNV) and results in complete loss of central vision acuity leading to severe visual impairment and legal blindness. Currently, AMD diagnosis relies on ophthalmologic exams and treatments of the exudative form using anti-angiogenic drugs targeting vascular endothelial growth factors (VEGF). Despite these advances, the identification of therapeutic treatments and related biomarkers are essentials. In this study, we applied a NMR-based metabolomics approach on a cohort of AMD patients and on a laser-induced murine CNV experimental model that mimics the pathology angiogenesis’s development phase. Sera from controls and AMD patients (in active and non-active pathology’s phases) and from induced and non-induced mice have been collected and submitted to a metabolomics study, using a multivariate approach. This approach allows differentiation between active and non-active AMD patients and between laser-induced and the control mice groups. Moreover, the discriminating spectral zones are the same in both human and mice’s models, leading to the emergence of putative biomarkers of the exudative AMD. Among those, lactate and lipoprotein emerges as a key metabolite in both settings. Here we suggest metabolomics as a novel option for patients’ follow-up and new therapeutical strategies targeting lactate metabolism for AMD. [less ▲]

Detailed reference viewed: 16 (1 ULiège)
Peer Reviewed
See detailFrom Metabolomics Study of Age Related Macular Degeneration (AMD) to the Development of New Pyruvate Dehydrogenase Kinase (PDK) Inhibitors
Arslan, Deniz ULiege; LAMBERT, Vincent ULiege; Noël, Agnès ULiege et al

Poster (2019, December 11)

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small zone of ... [more ▼]

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small zone of the retina specialized for the high-acuity vision. Exudative AMD, called “wet AMD”, is characterized by the formation of new blood vessels growing under the retina according to a process named choroidal neovascularization (CNV). Currently, the aetiology and pathogenesis of wet AMD remain unclear. Nevertheless, a recent metabolomics study performed on the serum of “wet” AMD patients and on a CNV murine model, that mimics the effect of “wet” AMD, has demonstrated that lactate is clearly involved in the severity and the evolution of the pathology and of CNV. According to this study, we suggest a new therapeutic approach of AMD based on the normalization of blood lactate level. The modulation of the lactate plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate Dehydrogenase Kinase (PDK) inhibitors significantly decrease the CNV. Starting from these results, development of new PDK inhibitors could open the way to innovative treatment for AMD disease. [less ▲]

Detailed reference viewed: 46 (15 ULiège)
Full Text
Peer Reviewed
See detailMetabolomics toward a personalized approach of vascular diseases
Leenders, Justine ULiege; vega de Ceninga, Melina; Chakfé, Nabil et al

in European Symposium on Vascular biomaterials 2019 (2019, October 17)

Personalized medicine could be described as the study of the most appropriate and tailored way to treat patients. This promising paradigm change in medicine care aims to place the patient at the center of ... [more ▼]

Personalized medicine could be described as the study of the most appropriate and tailored way to treat patients. This promising paradigm change in medicine care aims to place the patient at the center of the medical management and is expected to significantly improve the quality of life of the patient and to reduce the healthcare cost and the duration of hospital stay. It must combine modern and innovative tools to measure, integrate and model informative data that could help clinicians. Because it provides a unique insight into the relationships between physiological status, lifestyle, pathologies and patients, and because it correlates with a patient’s disease phenotype, metabolomics is particularly adapted to obtain relevant and helpful information for a personalized approach to treatment. Even if vascular care has evolved enormously in the last decades, with the development of innovative surgery and endovascular techniques, the improvement of the diagnostics tools and the optimization of new treatments, cardiovascular diseases (CVD) remain linked to a high prevalence and mortality. Then, application of an innovative personalized approach of CVD is mandatory and metabolomics represents clearly a well-adapted and powerful tool. This area of metabolomics is clearly emerging and, even if the number of studies involving “omics” sciences in CVD still remains limited in comparison with other pathologies such as cancer, cardiovascular metabolomics studies are notably in progression. [less ▲]

Detailed reference viewed: 39 (3 ULiège)
Full Text
Peer Reviewed
See detailGut Microbiota and Fecal Levels of Short-Chain Fatty Acids Differ Upon 24-Hour Blood Pressure Levels in Men
Huart, Justine ULiege; Leenders, Justine ULiege; Taminiau, Bernard ULiege et al

in Hypertension (2019)

Gut microbiota may influence blood pressure (BP), namely via end products of carbohydrate fermentation. After informed consent, male volunteers were prospectively categorized into 3 groups upon European ... [more ▼]

Gut microbiota may influence blood pressure (BP), namely via end products of carbohydrate fermentation. After informed consent, male volunteers were prospectively categorized into 3 groups upon European Society of Hypertension criteria based on 24-hour ambulatory BP measurements: (1) hypertension, (2) borderline hypertension, and (3) normotension. Stool, urine and serum samples were collected in fasting conditions. Gut microbiota was characterized by 16S amplicon sequencing. Metabolomics, including quantification of short-chain fatty acids, was conducted using nuclear magnetic resonance. Two-way ANOVA combined with Tukey post hoc test, as well as multiple permutation test and Benjamini-Hochberg-Yekutieli false discovery rate procedure, was used. The cohort included 54 males: 38 hypertensive (including 21 under treatment), 7 borderline, and 9 normotensive. No significant difference was observed between groups concerning age, body mass index, smoking habits, and weekly alcohol consumption. The genus Clostridium sensu stricto 1 positively correlated with BP levels in nontreated patients (n=33). This correlation was significant after multiple permutation tests but was not substantiated following false discovery rate adjustment. Short-chain fatty acid levels were significantly different among groups, with higher stool levels of acetate, butyrate, and propionate in hypertensive versus normotensive individuals. No difference was observed in serum and urine metabolomes. Correlation between stool metabolome and 24-hour BP levels was evidenced, with R2 reaching 0.9. Our pilot study based on 24-hour ambulatory BP measurements, 16S amplicon sequencing, and metabolomics supports an association between gut microbiota and BP homeostasis, with changes in stool abundance of short-chain fatty acids. [less ▲]

Detailed reference viewed: 143 (43 ULiège)
Full Text
Peer Reviewed
See detailNew insight in Metabolomics based study of Age Related Macular Degeneration (AMD): Lipoprotein profile and patients follow-up
Schoumacher, Matthieu ULiege; LAMBERT, Vincent ULiege; Hansen, Sylvain et al

Poster (2019, June 23)

Age-related macular degeneration (AMD) is common disease and leading causes of vision loss among people aged 50 and older. Late-stage AMD (called exudative) is characterized by choroidal ... [more ▼]

Age-related macular degeneration (AMD) is common disease and leading causes of vision loss among people aged 50 and older. Late-stage AMD (called exudative) is characterized by choroidal neovascularization (CNV) and results in complete loss of central vision acuity leading to severe visual impairment and legal blindness. Currently, AMD diagnosis relies on ophthalmologic exams and treatments of the exudative form using anti-angiogenic drugs targeting vascular endothelial growth factors (VEGF). Despite these advances, the identification of therapeutic treatments and related biomarkers are essentials. In this study, we applied a NMR-based metabolomics approach on a cohort of AMD patients and on a laser-induced murine CNV experimental model that mimics the pathology angiogenesis’s development phase. Sera from controls and AMD patients (in active and non-active pathology’s phases) and from induced and non-induced mice have been collected and submitted to a metabolomics study, using a multivariate approach. This approach allows differentiation between active and non-active AMD patients and between laser-induced and the control mice groups. Moreover, the discriminating spectral zones are the same in both human and mice’s models, leading to the emergence of putative biomarkers of the exudative AMD. Among those, lipoprotein profile is interesting while some studies highlighted HDL cholesterol and oxidized LDL with early and para-inflammatory AMD stages. Our primary studies show similar evolution in lipoprotein profile through the different human and mice’ groups. These data suggest that investigate lipoprotein profile could be the turning point in the pathologic process’s comprehension occurring during the apparition and/or the development of pathologic CNV process. [less ▲]

Detailed reference viewed: 15 (1 ULiège)
Full Text
Peer Reviewed
See detailNew insight in Metabolomics based study of Age Related Macular Degeneration (AMD): Lipoprotein profile and patients follow-up.
Schoumacher, Matthieu ULiege; LAMBERT, Vincent ULiege; Hansen, Sylvain et al

Conference (2019, May 23)

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly population in developed countries. 90% of all vision loss due to AMD result from the exudative form of this ... [more ▼]

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly population in developed countries. 90% of all vision loss due to AMD result from the exudative form of this pathology, which is characterized by a choroidal neovascularization (CNV). Currently, diagnosis of AMD relies on ophthalmologic exams and treatments of the exudative form are based on the use of anti-angiogenic drug targeting vascular endothelial growth factors. Despite these advance, several clinical challenges have to be overcome. Among those, the identification of biomarkers that could allow to refine patient stratification, to follow disease progression and evaluate responses to treatment are mandatory. For this purpose, we decide to apply NMR-based metabolomics approach on both AMD patients and on a laser-induced murine choroidal neovascularization experimental model. In the clinical study, the metabolomics approach does not allow a complete differentiation between control and AMD patients. However, focusing only on AMD group, a clear-cut separation between active and non-active phases could be highlighted. In the mice model, discrimination between laser-induced and control mice occurs only when CNV is installed. In both human and animal studies, lactate and lipoprotein profile were identified as the main biomarkers. Mechanistically, we demonstrated that lactate, plays a critical role in the onset of the inflammatory and angiogenic phases and could be correlated with the CNV development. Then, controlling lactate level appears as a new therapeutic approach of AMD On the other hand, lipoprotein profile is of particular interest for patient follow-up. Indeed, evaluation of lipoprotein profile change trough a simple methods allowed us to establish clear modification of profiles according to the active or non-active status of the patient and to the induced or non-induced status of the mice. This work focuses on the lipoprotein profile and on the development of a methodology that could be used to characterize and compared the different profiles in the human and the mice studies. [less ▲]

Detailed reference viewed: 20 (2 ULiège)
Full Text
Peer Reviewed
See detailDeath following consumption of MDAI and 5-EAPB
DEVILLE, Marine ULiege; DUBOIS, Nathalie ULiege; Cieckiewicz, Ewa et al

in Forensic Science International (2019), 299

5-(2-ethylaminopropyl)benzofuran (5-EAPB) and 5,6-methylenedioxy-2-aminoindane (MDAI) are two new psychoactive substances (NPS) exhibiting MDMA-like properties. In this paper, we report the case of a 28 ... [more ▼]

5-(2-ethylaminopropyl)benzofuran (5-EAPB) and 5,6-methylenedioxy-2-aminoindane (MDAI) are two new psychoactive substances (NPS) exhibiting MDMA-like properties. In this paper, we report the case of a 28-years old man, known as drug addict, found dead at home, with two unidentified powders next to him. External examination by the forensic pathologist was unremarkable but no autopsy was performed. Powders, blood and urine (which were the only samples available) were submitted to general unknown screening by high pressure liquid chromatography with a diode array detector (HPLC-DAD) and ultra high pressure liquid chromatography with a time-of-flight detector (UPLC-TOF-MS), after liquid–liquid extraction for biological samples, or simple dilution for powders. Analysis revealed 68% of MDAI in one powder and 87% of 5-EAPB in the other one. Significant levels of the same substances were found in blood (MDAI: 2.09 mg/L and 5-EAPB: 6.45 mg/L). The cause of death was therefore attributed to the consumption of these NPS since screening for other drugs of abuse and for alcohol was negative (oxazepam was found in urine only). 5-methylaminopropylbenzofuran (5-MAPB) and 5-aminopropylbenzofuran (5-APB) were also found in blood (0.089 and 0.546 mg/L, respectively) and urine (1.00 and 4.88 mg/L, respectively). In addition to the inherent complexity of NPS identification by itself, another analytical difficulty in this case was the identification of the EAPB positional isomer. Our routine screening methods were not able to distinguish the positional isomer, but an additional classical gas chromatography technique was able to make the distinction. Anyway, in our case, this issue was simplified thanks to the availability of a relatively pure powder that was analyzed by nuclear magnetic resonance (NMR). [less ▲]

Detailed reference viewed: 46 (7 ULiège)
Full Text
Peer Reviewed
See detailTGFBI, an ECM interacting protein, enhances glycolysis and promotes pancreatic cancer cell migration
Costanza, Brunella ULiege; Rademaker, Gilles ULiege; Tiamiou, Assia ULiege et al

in International Journal of Cancer (2019)

Pancreatic cancer (PDAC) remains a deadly malignancy with no efficient therapy available up-to-date. Glycolysis is the main provider of energetic substrates to sustain cancer dissemination of PDAC ... [more ▼]

Pancreatic cancer (PDAC) remains a deadly malignancy with no efficient therapy available up-to-date. Glycolysis is the main provider of energetic substrates to sustain cancer dissemination of PDAC. Accordingly, altering the glycolytic pathway is foreseen as a sound approach to trigger pancreatic cancer regression. Here, we show for the first time that high TGFBI expression in PDAC patients is associated with a poor outcome. We demonstrate that, although usually secreted by stromal cells, PDAC cells synthesize and secrete TGFBI in quantity correlated with their migratory capacity. Mechanistically, we show that TGFBI activates FAK signaling pathway through its binding to integrin αVβ5, leading to a significant enhancement of glycolysis and to the acquisition of an invasive phenotype. Finally, we show that TGFBI silencing significantly inhibits PDAC tumor development in a chick chorioallantoic membrane assay model. Our study highlights TGFBI as an oncogenic ECM interacting protein that bears the potential to serve as a target for new anti-PDAC therapeutic strategies. [less ▲]

Detailed reference viewed: 201 (43 ULiège)
Full Text
Peer Reviewed
See detailMetabolomics as an Innovative Tool for a Personalised Approach to Vascular Disease
De Tullio, Pascal ULiege; Leenders, Justine ULiege; Vega de Ceniga, Melina et al

in European Journal of Vascular and Endovascular Surgery (2019), 57(3), 329

Detailed reference viewed: 28 (8 ULiège)
Full Text
Peer Reviewed
See detailTwo data pre‑processing workflows to facilitate the discovery of biomarkers by 2D NMR metabolomics
Feraud, Baptiste; Leenders, Justine ULiege; Martineau, Estelle et al

in Metabolomics (2019), 15(63),

Abstract Introduction The pre-processing of analytical data in metabolomics must be considered as a whole to allow the construction of a global and unique object for any further simultaneous data analysis ... [more ▼]

Abstract Introduction The pre-processing of analytical data in metabolomics must be considered as a whole to allow the construction of a global and unique object for any further simultaneous data analysis or multivariate statistical modelling. For 1D 1H-NMR metabolomics experiments, best practices for data pre-processing are well defined, but not yet for 2D experiments (for instance COSY in this paper). Objective By considering the added value of a second dimension, the objective is to propose two workflows dedicated to 2D NMR data handling and preparation (the Global Peak List and Vectorization approaches) and to compare them (with respect to each other and with 1D standards). This will allow to detect which methodology is the best in terms of amount of metabolomic content and to explore the advantages of the selected workflow in distinguishing among treatment groups and identifying relevant biomarkers. Therefore, this paper explores both the necessity of novel 2D pre-processing workflows, the evaluation of their quality and the evaluation of their performance in the subsequent determination of accurate (2D) biomarkers. Methods To select the more informative data source, MIC (Metabolomic Informative Content) indexes are used, based on clustering and inertia measures of quality. Then, to highlight biomarkers or critical spectral zones, the PLS-DA model is used, along with more advanced sparse algorithms (sPLS and L-sOPLS). Results Results are discussed according to two different experimental designs (one which is unsupervised and based on human urine samples, and the other which is controlled and based on spiked serum media). MIC indexes are shown, leading to the choice of the more relevant workflow to use thereafter. Finally, biomarkers are provided for each case and the predictive power of each candidate model is assessed with cross-validated measures of RMSEP. Conclusion In conclusion, it is shown that no solution can be universally the best in every case, but that 2D experiments allow to clearly find relevant cross peak biomarkers even with a poor initial separability between groups. The MIC measures linked with the candidate workflows (2D GPL, 2D vectorization, 1D, and with specific parameters) lead to visualize which data set must be used as a priority to more easily find biomarkers. The diversity of data sources, mainly 1D versus 2D, may often lead to complementary or confirmatory results. [less ▲]

Detailed reference viewed: 18 (3 ULiège)
Full Text
Peer Reviewed
See detailSelective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models
Depetter, Yves; Geurs, Silke; De Vreese, Rob et al

in International Journal of Cancer (2019)

Our study investigates the biochemical and functional impact of selective histone deacetylase 6 (HDAC6) inhibitors, a promising class of novel therapeutics, in several cancer models. Selective HDAC6 ... [more ▼]

Our study investigates the biochemical and functional impact of selective histone deacetylase 6 (HDAC6) inhibitors, a promising class of novel therapeutics, in several cancer models. Selective HDAC6 inhibitors (Tubathian A, Tubastatin A, Tubacin and Ricolinostat) and a non-selective HDAC inhibitor (Vorinostat) were evaluated on cancer cell lines derived from multiple tumour types in both an in vitro and in vivo setting as potential cancer therapeutics. Selective HDAC6 inhibitors resulted in α-tubulin acetylation with no impact on histone acetylation but failed to show any anti-cancer properties. Only the use of high concentrations of selective HDAC6 inhibitors resulted in co-inhibition of other HDAC enzymes and consequently in reduced growth, migratory and/or invasive activity of cancer cells in vitro as well as in vivo. The specificity of HDAC6 inhibition was confirmed using a CRISPR/Cas9 knockout cell line. Our results suggest that selective HDAC6 inhibitors may fall short as potential single agent anti-cancer drugs and prove that many previous data regarding this promising class of compounds need to be interpreted with great care due to their use in high concentrations resulting in low selectivity and potential off-target effects. [less ▲]

Detailed reference viewed: 29 (1 ULiège)
See detailFluxomics of AMD using mass spectrometry from 10 µL of mice whole blood; investigation of DCA treatment
Kok, Miranda; Nix, Cindy ULiege; Nys, Gwenaël ULiege et al

Poster (2018, December 19)

Detailed reference viewed: 31 (4 ULiège)
Peer Reviewed
See detailFrom Metabolomics Study of Age Related Macular Degeneration (AMD) to the Development of New Pyruvate Dehydrogenase Kinase Inhibitors (PDK)
Arslan, Deniz ULiege; LAMBERT, Vincent ULiege; Elmoualij, Benaïssa ULiege et al

Poster (2018, November 23)

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small zone of ... [more ▼]

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small zone of the retina specialized for the high-acuity vision. Exudative AMD, called “wet AMD”, is characterized by the formation of new blood vessels growing under the retina according to a process named choroidal neovascularization (CNV). Currently, the aetiology and pathogenesis of wet AMD remain unclear. Nevertheless, a recent metabolomics study performed on the serum of “wet” AMD patients and on a CNV murine model, that mimics the effect of “wet” AMD, has demonstrated that lactate is clearly involved in the severity and the evolution of the pathology and of CNV. According to this study, we suggest a new therapeutic approach of AMD based on the normalization of blood lactate level. The modulation of the lactate plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate Dehydrogenase Kinase (PDK) inhibitors significantly decrease the CNV. PDK and its four isoforms (PDK1-4) regulate the activity of the pyruvate dehydrogenase complex (PDH), a mitochondrial enzyme that plays a major role in the metabolic pathway of glucose, by reversible phosphorylation. Starting from these results, development of new PDK inhibitors could open the way to innovative treatment for AMD disease. Different analogues of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (fig.1) have been already synthetized and pharmacologically evaluated. Various pharmacomodulations were then considered. After a structural activity relationship study, the selectivity of the drugs towards the different isoforms will be determined. [less ▲]

Detailed reference viewed: 46 (13 ULiège)
Full Text
Peer Reviewed
See detailNMR-based metabolomics study of Age-related Macular Degeneration (AMD): patient follow-up and new target discovery
Schoumacher, Matthieu ULiege; LAMBERT, Vincent ULiege; Hansen, Sylvain et al

Poster (2018, September 19)

1. Introduction Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly population in developed countries. 90% of all vision loss due to AMD result from the exudative ... [more ▼]

1. Introduction Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly population in developed countries. 90% of all vision loss due to AMD result from the exudative form of this pathology, which is characterized by choroidal neovascularization (CNV). Currently, diagnosis of AMD relies on ophthalmologic exams and treatments of the exudative form are based on the use of anti-angiogenic drug targeting vascular endothelial growth factors (VEGF). Despite these advances, several clinical challenges have to be overcome, among these the choice of adapted therapeutic treatments and the identification of biomarkers as indicator of patient stratification, disease progression and treatment responses are essential. 2. Approach In this study, we decide to apply a NMR-based metabolomics approach on a cohort of AMD patients and on a laser-induced murine choroidal neovascularization experimental (CNV) model that mimics the development of the angiogenesis phase of the pathology(1). Sera from controls and exudative AMD patients (in active and non active phases of the pathology) and from induced and non-induced mice have been collected and submitted to a metabolomics study, using a multivariate approach. 3. Results and discussion Metabolomics approach does not allow a complete differentiation between control and AMD patients after PCA, PLS-DA and O-PLS_DA analysis. This is probably due to the high variability in patients in terms of AMD stages and phases, treatments and fasting status. However, when we focused on AMD patient, a separation between active and non-active phases could be highlighted. In the most controlled mice model, a separation occurs between laser-induced and control mice 5 to 7 days after induction, concomitantly with CNV formation (Figure 1). Moreover, an interesting point is that the discriminating spectral zones are the same in the human study and in the mice model, leading to the emergence of different putative biomarkers of the active phase of exudative AMD. Among those, lactate and lipoprotein profile are of particular interest to better understand the development of CNV. These results were confirmed by a quantification of lactate and by an evaluation of lipoproteins profiles. Figure 1. FITC-dextran–labeled flat-mounted choroid observed at day 3 (a), 5 (b) or 7 (c) after laser induction. (d-f) Score plot resulting PCA of NMR data collected. Mechanistically, we demonstrated that lactate, produced locally and by inflammatory cells, plays a critical role in the onset of the inflammatory and angiogenic phases and could be correlated with the CNV development. Modulation of blood lactate level trough the inhibition of pyruvate dehydrogenase kinase (PDK) led to a reduction of CNV (as efficient as anti-VEGF treatment) and then this receptor appears as a putative target to control exudative AMD. On the other hand, lipoprotein profile is of particular interest for patient follow-up. Indeed, this profile is clearly modified according to the active or non-active status of the patient and to the induced or non-induced status of the mice. 4. Conclusion This study demonstrates that metabolomics approach applied to AMD could lead to relevant outcomes for AMD patient follow-up and potential new treatment strategies. [less ▲]

Detailed reference viewed: 24 (1 ULiège)
Peer Reviewed
See detailMetabolomics for the discovery of new therapeutic approach and personalized medicine: the case of exudative Age-related Macular Degeneration.
LAMBERT, Vincent ULiege; Schoumacher, Matthieu ULiege; Lecomte, Julie ULiege et al

Conference (2018, September 19)

. Introduction Age-related Macular Degeneration (AMD) is the leading cause of blindness among the elderly population in developed countries. 90% of all vision loss due to AMD result from the exudative ... [more ▼]

. Introduction Age-related Macular Degeneration (AMD) is the leading cause of blindness among the elderly population in developed countries. 90% of all vision loss due to AMD result from the exudative form, which is characterized by choroidal neovascularization (CNV)1. Treatment is mainly based on regular intra-vitreal injection of anti-VEGF to stabilize CNV. Nevertheless, the comprehensive understanding of the pathogenesis and the evolution of this complex multi-factorial disease remain incomplete. Moreover, due to the long-term disease chronicity and to some resistance to treatment, a continuous follow-up of patients, a personalization of treatment and the discovery of new therapeutic approaches are mandatory. 2. Approach Metabolomics provides a unique and direct vision of the functional outcome of organism’s activities that could be correlated to pathologies and/or treatment administration. The links between metabolic changes, patient phenotypes, physiological and/or pathological status and treatment are now well established and have opened a new area for the application of metabolomics in target identification and in personalized medicine2. In order to study CNV occurrence and evolution and to get novel and innovative insights into AMD, we decided to apply a NMR-based metabolomics approach on both clinical and pre-clinical models (a murine laser-induced CNV model and patient’s cohorts). Sera samples coming from 97 healthy volunteers and 95 exudative AMD patients have been collected during ophthalmic exams at the CHU of Liège. Patients were separated into bleeder AMD group (patients with AMD in bleeding phase) and non-bleeder AMD group (patients with non-bleeding AMD). The CNV mice model mimics the exudative phase of AMD and allows the dynamic study of CNV evolution. 3. Results Metabolomics approach applied to the human cohorts led to a separation between healthy and non-healthy patients as well as between bleeder and non-bleeder groups. Few metabolites are linked to this discrimination. Among those, lactate and lipoproteins profile emerge as the main key metabolites. Higher lactate level was detected in patients during bleeding phase while low-density lipoproteins (LDL) and very low density lipoproteins (VLDL) levels seems to be increased in AMD patients. In the mice model, metabolomics profiles varied according to CNV occurrence. In this case again, lactate and lipoproteins profile were related to this evolution. Pharmacological normalization of lactate levels by blocking pyruvate deshydrogenase kinase (PDK) or by modulating LDH activity in the mice model, inhibits CNV formation, Moreover, CNV inhibition by anti-angiogenic drugs led also to a reduction of systemic lactate level. 4. Discussion Mechanistically, we have demonstrated through a combination of NMR measurements (both 1D and 2D), pharmacological modulation and molecular biology approaches, that lactate, initially produced in the eyes then at the systemic level, plays a critical role in the onset of the inflammatory and angiogenic phases. Targeting lactate level by a modulation of PDK appears to be an alternative to intra-vitreal injection of anti-VEGF and a putative new therapeutic approach to reduce CNV progression. Moreover, changes in lipoproteins profile could also be correlated with AMD and CNV progression and then could be a nice marker of the progression of the pathology. A longitudinal patients follow-up during anti-VEGF treatment is currently running while MS-based targeted metabolomics and lipidomics studies are planned to validate and deepen our first findings. Altogether, we demonstrated that metabolomics is a suitable tool to deep insight into pathologies and to identify some metabolites as functional, traceable and targetable molecules that open new perspectives for optimizing and personalizing treatment and patient follow-up. References 1. Ambati, J., & Fowler, B. (2012). Mechanisms of age-related macular degeneration. Neuron, 75(1), 26–39. http://doi.org/10.1016/j.neuron.2012.06.018 2. Jacob, M., Lopata, A. L., Dasouki, M., & Abdel Rahman, A. M. (2017). Metabolomics toward personalized medicine. Mass Spectrometry Reviews, (September). http://doi.org/10.1002/mas.21548 [less ▲]

Detailed reference viewed: 77 (29 ULiège)