Publications by authors named "Pierre Van Antwerpen"

96 Publications

Coffee Leaves: An Upcoming Novel Food?

Planta Med 2021 Sep 24. Epub 2021 Sep 24.

RD3 Department-Unit of Pharmacognosy, Bioanalysis and Drug Discovery, Faculty of Pharmacy, Université libre de Bruxelles, Brussels, Belgium.

Unlike those of coffee beans, the healthy properties of coffee leaves have been overlooked for a long time, even if they are consumed as a beverage by local communities of several African countries. Due to the presence of xanthines, diterpenes, xanthones, and several other polyphenol derivatives as main secondary metabolites, coffee leaves might be useful to prevent many daily disorders. At the same time, as for all bioactive molecules, careless use of coffee leaf infusions may be unsafe due to their adverse effects, such as the excessive stimulant effects on the central nervous system or their interactions with other concomitantly administered drugs. Moreover, the presence of some toxic diterpene derivatives requires careful analytical controls on manufactured products made with coffee leaves. Accordingly, knowledge about the properties of coffee leaves needs to be increased to know if they might be considered a good source for producing new supplements. The purpose of the present review is to highlight the biosynthesis, metabolism, and distribution of the 4 main classes of secondary metabolites present in coffee leaves, their main pharmacological and toxicological aspects, and their main roles . Differences in coffee leaf chemical composition depending on the coffee species will also be carefully considered.
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http://dx.doi.org/10.1055/a-1533-0021DOI Listing
September 2021

Mass Spectrometry for the Monitoring of Lipoprotein Oxidations by Myeloperoxidase in Cardiovascular Diseases.

Molecules 2021 Aug 30;26(17). Epub 2021 Aug 30.

RD3-Pharmacognosy, Bioanalysis and Drug Discovery, Faculty of Pharmacy, Université Libre de Bruxelles, 1050 Brussels, Belgium.

Oxidative modifications of HDLs and LDLs by myeloperoxidase (MPO) are regularly mentioned in the context of atherosclerosis. The enzyme adsorbs on protein moieties and locally produces oxidizing agents to modify specific residues on apolipoproteins A-1 and B-100. Oxidation of lipoproteins by MPO (Mox) leads to dysfunctional Mox-HDLs associated with cholesterol-efflux deficiency, and Mox-LDLs that are no more recognized by the LDL receptor and become proinflammatory. Several modification sites on apoA-1 and B-100 that are specific to MPO activity are described in the literature, which seem relevant in patients with cardiovascular risk. The most appropriate analytical method to assess these modifications is based on liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). It enables the oxidized forms of apoA-1and apoB-100 to be quantified in serum, in parallel to a quantification of these apolipoproteins. Current standard methods to quantify apolipoproteins are based on immunoassays that are well standardized with good analytical performances despite the cost and the heterogeneity of the commercialized kits. Mass spectrometry can provide simultaneous measurements of quantity and quality of apolipoproteins, while being antibody-independent and directly detecting peptides carrying modifications for Mox-HDLs and Mox-LDLs. Therefore, mass spectrometry is a potential and reliable alternative for apolipoprotein quantitation.
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http://dx.doi.org/10.3390/molecules26175264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434463PMC
August 2021

Acute effects of hypouricemia on endothelium, oxidative stress, and arterial stiffness: A randomized, double-blind, crossover study.

Physiol Rep 2021 Sep;9(17):e15018

Department of Cardiology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.

We hypothesized acute moderate and drastic reductions in uric acid concentration exert different effects on arterial function in healthy normotensive and hypertensive adults. Thirty-six adults (aged 58 [55;63] years) with or without primary hypertension participated in a three-way, randomized, double-blind, crossover study in which [placebo] and [febuxostat] and [febuxostat and rasburicase] were administered. Febuxostat and rasburicase reduce the uric acid concentration by xanthine oxidoreductase inhibition and uric acid degradation into allantoin, respectively. Endothelial function was assessed in response to acetylcholine, sodium nitroprusside, heating (with and without nitric oxide synthase inhibition) using a laser Doppler imager. Arterial stiffness was determined by applanation tonometry, together with blood pressure, renin-angiotensin system activity, oxidative stress, and inflammation. Uric acid concentration was 5.1 [4.1;5.9], 1.9 [1.2;2.2] and 0.2 [0.2;0.3] mg/dL with [placebo], [febuxostat] and [febuxostat-rasburicase] treatments, respectively (p < 0.0001). Febuxostat improved endothelial response to heat particularly when nitric oxide synthase was inhibited (p < 0.05) and reduced diastolic and mean arterial pressure (p = 0.008 and 0.02, respectively). The augmentation index decreased with febuxostat (ANOVA p < 0.04). Myeloperoxidase activity profoundly decreased with febuxostat combined with rasburicase (p < 0.0001). When uric acid dropped, plasmatic antioxidant capacity markedly decreased, while superoxide dismutase activity increased (p < 0.0001). Other inflammatory and oxidant markers did not differ. Acute moderate hypouricemia encompasses minor improvements in endothelial function, blood pressure, and arterial stiffness. Clinical Trial Registration: NCT03395977, https://clinicaltrials.gov/ct2/show/NCT03395977.
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http://dx.doi.org/10.14814/phy2.15018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387791PMC
September 2021

Untargeted metabolomics approach to discriminate mistletoe commercial products.

Sci Rep 2021 07 9;11(1):14205. Epub 2021 Jul 9.

Univ. Grenoble Alpes, CNRS, DPM, 38000, Grenoble, France.

Mistletoe (Viscum album L.) is used in German-speaking European countries in the field of integrative oncology linking conventional and complementary medicine therapies to improve quality of life. Various companies sell extracts, fermented or not, for injection by subcutaneous or intra-tumoral route with a regulatory status of anthroposophic medicinal products (European Medicinal Agency (EMA) assessment status). These companies as well as anthroposophical physicians argue that complex matrices composed of many molecules in mixture are necessary for activity and that the host tree of the mistletoe parasitic plant is the main determining factor for this matrix composition. The critical point is that parenteral devices of European mistletoe extracts do not have a standard chemical composition regulated by EMA quality guidelines, because they are not drugs, regulatory speaking. However, the mechanism of mistletoe's anticancer activity and its effectiveness in treating and supporting cancer patients are not fully understood. Because of this lack of transparency and knowledge regarding the matrix chemical composition, we undertook an untargeted metabolomics study of several mistletoe extracts to explore and compare their fingerprints by LC-(HR)MS(/MS) and H-NMR. Unexpectedly, we showed that the composition was primarily driven by the manufacturer/preparation method rather than the different host trees. This differential composition may cause differences in immunostimulating and anti-cancer activities of the different commercially available mistletoe extracts as illustrated by structure-activity relationships based on LC-MS/MS and H-NMR identifications completed by docking experiments. In conclusion, in order to move towards an evidence-based medicine use of mistletoe, it is a priority to bring rigor and quality, chemically speaking.
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http://dx.doi.org/10.1038/s41598-021-93255-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270909PMC
July 2021

Fc Glycosylation Characterization of Human Immunoglobulins G Using Immunocapture and LC-MS.

Methods Mol Biol 2021 ;2271:57-71

Pharmacognosy, Bioanalysis and Drug Discovery and Analytical Platform, RD3 Department, Faculty of Pharmacy, Université libre de Bruxelles, Brussels, Belgium.

Immunoglobulins G (IgG) are proteins produced by the immune system of higher life forms that play a central role in the defense against microbial pathogens. IgG bind pathogens with the hypervariable Fab component and mediate a diversity of effector functions by binding to immune effector cells via their crystallizable (Fc) component. All IgG Fc carry a polymorphic N-glycan that regulates its binding properties and thereby its effector functions. The glycosylation profile of IgG Fc is modulated by physiological and pathological conditions, including infectious diseases and inflammatory disorders. Characterization of IgG Fc glycosylation profiles is a promising approach to understand the pathogenesis of diseases involving the immune system and to develop novel biomarkers of disease activity. Measuring the proportion of the different IgG Fc glycoforms remains an analytical challenge, that requires a sensitive and reproducible analytical approach.This chapter describes an optimized approach for the preparation and the analysis of Fc N-glycans from total serum or plasma IgG using magnetic beads, RapiFluor MS label©, and LC-MS.
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http://dx.doi.org/10.1007/978-1-0716-1241-5_4DOI Listing
June 2021

Does the Phytochemical Diversity of Wild Plants Like the Correlate with Geographical Origin?

Molecules 2021 Mar 17;26(6). Epub 2021 Mar 17.

Département de Pharmacochimie Moléculaire (DPM), Univiversité Grenoble Alpes, CNRS, 38000 Grenoble, France.

Secondary metabolites are essential for plant survival and reproduction. Wild undomesticated and tropical plants are expected to harbor highly diverse metabolomes. We investigated the metabolomic diversity of two morphologically similar trees of tropical Africa, and , known for particular secondary metabolites named the cassaine-type diterpenoids. To assess how the metabolome varies between and within species, we sampled leaves from individuals of different geographic origins but grown from seeds in a common garden in Cameroon. Metabolites were analyzed using reversed phase LC-HRMS(/MS). Data were interpreted by untargeted metabolomics and molecular networks based on MS/MS data. Multivariate analyses enabled us to cluster samples based on species but also on geographic origins. We identified the structures of 28 cassaine-type diterpenoids among which 19 were new, 10 were largely specific to and five to . Our results showed that the metabolome allows an unequivocal distinction of morphologically-close species, suggesting the potential of metabolite fingerprinting for these species. Plant geographic origin had a significant influence on relative concentrations of metabolites with variations up to eight () and 30 times () between origins of the same species. This shows that the metabolome is strongly influenced by the geographical origin of plants (i.e., genetic factors).
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http://dx.doi.org/10.3390/molecules26061668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002556PMC
March 2021

Priming of mesenchymal stem cells with a hydrosoluble form of curcumin allows keeping their mesenchymal properties for cell-based therapy development.

J Cell Mol Med 2021 05 26;25(10):4877-4881. Epub 2021 Mar 26.

Department of Clinical Sciences, Anaesthesiology and Equine Surgery, Faculty of Veterinary Medicine, B41, University of Liege, Sart Tilman, Liège, Belgium.

Mesenchymal stem cells are increasingly studied for their use as drug-carrier in addition to their intrinsic potential for regenerative medicine. They could be used to transport molecules with a poor bioavailability such as curcumin in order to improve their clinical usage. This natural polyphenol, well-known for its antioxidant and anti-inflammatory properties, has a poor solubility that limits its clinical potential. For this purpose, the use of NDS27, a curcumin salt complexed with hydroxypropyl-beta-cyclodextrin (HPβCD), displaying an increased solubility in aqueous solution, is preferred. This study aims to evaluate the uptake of NDS27 into skeletal muscle-derived mesenchymal stem cells (mdMSCs) and the effects of such uptake onto their mesenchymal properties. It appeared that the uptake of NDS27 into mdMSCs is concentration-dependent and not time-dependent. The use of a concentration of 7 µmol/L which does not affect the viability and proliferation also allows preservation of their adhesion, invasion and T cell immunomodulatory abilities.
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http://dx.doi.org/10.1111/jcmm.16403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107093PMC
May 2021

Effects of hyperoxia and cardiovascular risk factors on myocardial ischaemia-reperfusion injury: a randomized, sham-controlled parallel study.

Exp Physiol 2021 May 5;106(5):1249-1262. Epub 2021 Apr 5.

Hospital Erasme, Anderlecht, Belgium.

New Findings: What is the central question of this study? The beneficial effects of supplemental oxygen in patients with acute myocardial infarction are still uncertain: what are the effects of ischaemia-reperfusion injury during hyperoxia and normoxia in mature rats with and without cardiovascular risk factors? What is the main finding and its importance? Despite elevated baseline oxidative stress in rodents with cardiovascular risk factors, hyperoxic reperfusion limited myocardial necrosis and anti/pro-oxidant imbalance in spontaneously hypertensive and Zucker rats. In contrast, this effect was exacerbated in healthy Wistar rats. These results suggest that oxygen supplementation may not be harmful in patients with acute myocardial injury.

Abstract: Recent studies on O supplementation in acute coronary syndrome patients are equivocal. We tested the hypothesis that oxidative stress is increased in rodents with cardiovascular risk factors and enhances ischaemia-reperfusion injury in the presence of hyperoxia. A total of 43 Wistar rats (WR), 30 spontaneously hypertensive rats (SHR) and 33 obese Zucker rats (ZR) were randomized in a sham procedure (one-third) or underwent a left anterior descending ligation of the coronary artery for 60 min (two-thirds). This was followed by 3 h of reperfusion while animals were randomized either in a hyperoxic (HR) or a normoxic reperfusion (NR) group. Myocardial infarction size and oxidative stress biomarkers (myeloperoxidase (MPO), malondialdehyde and total free thiols) were assessed in blood samples. Baseline troponin T was higher in SHR and ZR than in WR (both P < 0.001). Baseline total MPO was elevated in ZR in comparison to SHR and WR (both P < 0.001). SHR had lower thiol concentration compared to WR and ZR (P < 0.000001). HR was associated with a lower troponin T rise in SHR and ZR than in NR (both P < 0.001), while the reverse occurred in WR (P < 0.001). In SHR, HR limited total MPO increase as compared to NR (P = 0.0056) and the opposite effect was observed with total MPO in WR (P = 0.013). NR was associated with a drastic reduction of total thiols as compared to HR both in SHR and in ZR (both P < 0.001). Despite a heightened baseline oxidative stress level, HR limited myocardial necrosis and anti/pro-oxidant imbalance in SHR and ZR whereas this effect was exacerbated in healthy WR.
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http://dx.doi.org/10.1113/EP089320DOI Listing
May 2021

Anti-inflammatory, antioxidant effects, and bioaccessibility of Tigzirt propolis.

J Food Biochem 2021 04 19;45(4):e13663. Epub 2021 Feb 19.

Laboratory of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium.

This work aims to assess the anti-inflammatory effects of Tigzirt propolis native to Algeria. We divided 48 male Wistar rats into 8 groups. We orally administered ethyl acetate extract of propolis (EAP), pure polyphenols compounds, or diclofenac 5 days before induction of inflammation by of carrageenan (100 μg/ml, i.p.). We determined the development of paw edema, biological parameters, myeloperoxidase activity, TNF-α, and prostaglandin E2 and measured the oxidative status parameters, as well. Finally, we analyzed the absorption and bioaccessibility of propolis in rats' plasma using GC-MS after orally dosing rats (250 mg/kg). The pretreatment by 200 and 250 mg/kg of propolis significantly reduced the edema rates after the third hour. Propolis can restore the disruption of homeostasis as well as markers of inflammation induced by carrageenan in Wistar rats, and an increase of the enzymatic activities. Furthermore, the inflammation was better resolved in rats that received propolis than in those treated with pure polyphenols. PRACTICAL APPLICATIONS: Propolis is a natural mixture that bees produce by mixing gathered resin and gums to bee saliva and wax. Our research investigated the effect of Tigzirt propolis on the inhibition of biomarkers of inflammation and the development of paw edema. Propolis extract helped to reduce PGE2, TNF-α, myeloperoxidase, and malondialdehyde levels and increase the total antioxidant levels in plasma. Our findings emphasized the use of phenolic extract of propolis in industries such as nutraceuticals for the prevention of inflammatory diseases. It can also protect the body against damage under oxidative stress.
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http://dx.doi.org/10.1111/jfbc.13663DOI Listing
April 2021

Selenocompounds and Sepsis: Redox Bypass Hypothesis for Early Diagnosis and Treatment: Part A-Early Acute Phase of Sepsis: An Extraordinary Redox Situation (Leukocyte/Endothelium Interaction Leading to Endothelial Damage).

Antioxid Redox Signal 2021 Jul 25;35(2):113-138. Epub 2021 Mar 25.

Intensive Care Department, Erasme University Hospital, Brussels, Belgium.

Sepsis is a health disaster. In sepsis, an initial, beneficial local immune response against infection evolves rapidly into a generalized, dysregulated response or a state of chaos, leading to multiple organ failure. Use of life-sustaining supportive therapies creates an unnatural condition, enabling the complex cascades of the sepsis response to develop in patients who would otherwise die. Multiple attempts to control sepsis at an early stage have been unsuccessful. Major events in early sepsis include activation and binding of leukocytes and endothelial cells in the microcirculation, damage of the endothelial surface layer (ESL), and a decrease in the plasma concentration of the antioxidant enzyme, selenoprotein-P. These events induce an increase in intracellular redox potential and lymphocyte apoptosis, whereas apoptosis is delayed in monocytes and neutrophils. They also induce endothelial mitochondrial and cell damage. Neutrophil production increases dramatically, and aggressive immature forms are released. Leukocyte cross talk with other leukocytes and with damaged endothelial cells amplifies the inflammatory response. The release of large quantities of reactive oxygen, halogen, and nitrogen species as a result of the leukocyte respiratory burst, endothelial mitochondrial damage, and ischemia/reperfusion processes, along with the marked decrease in selenoprotein-P concentrations, leads to peroxynitrite damage of the ESL, reducing flow and damaging the endothelial barrier. Endothelial barrier damage by activated leukocytes is a time-sensitive event in sepsis, occurring within hours and representing the first step toward organ failure and death. Reducing or stopping this event is necessary before irreversible damage occurs.
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http://dx.doi.org/10.1089/ars.2020.8063DOI Listing
July 2021

M2 Monocyte Polarization in Dialyzed Patients Is Associated with Increased Levels of M-CSF and Myeloperoxidase-Associated Oxidative Stress: Preliminary Results.

Biomedicines 2021 Jan 16;9(1). Epub 2021 Jan 16.

Laboratory of Experimental Medicine (ULB 222 Unit), CHU-Charleroi, ISPPC Hôpital Vésale, Université libre de Bruxelles, 6110 Montigny-Le-Tilleul, Belgium.

Cardiovascular diseases represent a major issue in terms of morbidity and mortality for dialysis patients. This morbidity is due to the accelerated atherosclerosis observed in these patients. Atherosclerosis is a chronic inflammatory disease characterized by key players such as monocytes, macrophages, or oxidized LDLs. Monocytes-macrophages are classified into subsets of polarized cells, with M1 and M2 macrophages considered, respectively, as pro- and anti-inflammatory. (1) Methods: The monocyte subsets and phenotypes were analyzed by flow cytometry. These data were completed by the quantification of plasma M-CSF, IL-8, CRP, Mox-LDLs, Apo-B, Apo-AI, chloro-tyrosine, and homocitrulline concentrations. The statistical differences and associations between two continuous variables were assessed using the Mann-Whitney U test and Spearman's correlation coefficient, respectively. (2) Results: Hemodialyzed patients showed a significant increase in their concentrations of CRP, M-CSF, and IL-8 (inflammation biomarkers), as well as chloro-tyrosine and homocitrulline (myeloperoxidase-associated oxidative stress biomarkers). Moreover, we observed a higher percentage of M2 monocytes in the plasma of hemodialysis patients as compared to the controls. (3) Conclusions: Our data suggest that oxidative stress and an inflammatory environment, which is amplified in hemodialysis patients, seems to favor an increase in the concentration of circulating M-CSF, therefore leading to an increase in M2 polarization among circulating monocytes.
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http://dx.doi.org/10.3390/biomedicines9010084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830480PMC
January 2021

A patent review of myeloperoxidase inhibitors for treating chronic inflammatory syndromes (focus on cardiovascular diseases, 2013-2019).

Expert Opin Ther Pat 2020 Aug 18;30(8):595-608. Epub 2020 Jun 18.

Microbiology, Bioorganic and Macromolecular Chemistry, Faculty of Pharmacy, Universite Libre De Bruxelles , Bruxelles, Belgium.

Introduction: Myeloperoxidase (MPO) is an immune enzyme found in neutrophils and macrophages. It produces the highly oxidative compound HOCl from HO and Cl ions inside the phagosome of the neutrophil. Leakage of the enzyme outside the cell causes oxidative damages for the biomolecules promoting many inflammatory diseases such as atherosclerosis. Thus, there is a real interest to develop potent inhibitors of MPO as non-steroidal anti-inflammatory agents. This review highlights the several published MPO inhibitors, their activity, and the challenges met during the development of these compounds.

Areas Covered: This article covers the patent literature published on MPO inhibitors from 2013 to 2019, as well as the potential use of these compounds as therapeutics for inflammatory syndromes, especially that plays an important role in the initiation and progression of atherosclerosis.

Expert Opinion: To date, many MPO inhibitors with different structures have been studied, many of which have prominent inhibitory activities. Furthermore, the specificity of these drugs offers hope for the targeted therapy of inflammatory syndromes. Although many data have proved that MPO can contribute to several chronic inflammatory syndromes, the usefulness of MPO inhibitors in preventing and treating inflammatory disorders is still under investigation.
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http://dx.doi.org/10.1080/13543776.2020.1780210DOI Listing
August 2020

Severe Hypouricemia Impairs Endothelium-Dependent Vasodilatation and Reduces Blood Pressure in Healthy Young Men: A Randomized, Placebo-Controlled, and Crossover Study.

J Am Heart Assoc 2019 12 22;8(23):e013130. Epub 2019 Nov 22.

Department of Cardiology Erasme Hospital Université Libre de Bruxelles Brussels Belgium.

Background Uric acid (UA) is a plasmatic antioxidant that has possible effects on blood pressure. The effects of UA on endothelial function are unclear. We hypothesize that endothelial function is not impaired unless significant UA depletion is achieved through selective xanthine oxidase inhibition with febuxostat and recombinant uricase (rasburicase). Methods and Results Microvascular hyperemia, induced by iontophoresis of acetylcholine and sodium nitroprusside, and heating-induced local hyperemia after iontophoresis of saline and a specific nitric oxide synthase inhibitor were assessed by laser Doppler imaging. Blood pressure and renin-angiotensin system markers were measured, and arterial stiffness was assessed. CRP (C-reactive protein), allantoin, chlorotyrosine/tyrosine ratio, homocitrulline/lysine ratio, myeloperoxidase activity, malondialdehyde, and interleukin-8 were used to characterize inflammation and oxidative stress. Seventeen young healthy men were enrolled in a randomized, double-blind, placebo-controlled, 3-way crossover study. The 3 compared conditions were placebo, febuxostat alone, and febuxostat together with rasburicase. The allantoin (μmol/L)/UA (μmol/L) ratio differed between sessions (<0.0001). During the febuxostat-rasburicase session, heating-induced hyperemia became altered in the presence of nitric oxide synthase inhibition; and systolic blood pressure, angiotensin II, and myeloperoxidase activity decreased (≤0.03 versus febuxostat). The aldosterone concentration decreased in the febuxostat-rasburicase group (=0.01). Malondialdehyde increased when UA concentration decreased (both <0.01 for febuxostat and febuxostat-rasburicase versus placebo). Other parameters remained unchanged. Conclusions A large and short-term decrease in UA in humans alters heat-induced endothelium-dependent microvascular vasodilation, slightly reduces systolic blood pressure through renin-angiotensin system activity reduction, and markedly reduces myeloperoxidase activity when compared with moderate UA reduction. A moderate or severe hypouricemia leads to an increase in lipid peroxidation through loss of antioxidant capacity of plasma. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03395977.
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http://dx.doi.org/10.1161/JAHA.119.013130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912967PMC
December 2019

A new potential anti-cancer beta-carboline derivative decreases the expression levels of key proteins involved in glioma aggressiveness: A proteomic investigation.

Drug Dev Res 2020 02 9;81(1):32-42. Epub 2019 Sep 9.

Department of Pharmacotherapy and Pharmaceutics, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.

Gliomas remain highly fatal due to their high resistance to current therapies. Deregulation of protein synthesis contributes to cancer onset and progression and is a source of rising interest for new drugs. CM16, a harmine derivative with predicted high blood-brain barrier penetration, exerts antiproliferative effects partly through translation inhibition. We evaluated herein how CM16 alters the proteome of glioma cells. The analysis of the gel-free LC/MS and auto-MS/MS data showed that CM16 induces time- and concentration-dependent significant changes in the total ion current chromatograms. In addition, we observed spontaneous clustering of the samples according to their treatment condition and their proper classification by unsupervised and supervised analyses, respectively. A two-dimensional gel-based approach analysis allowed us to identify that treatment with CM16 may downregulate four key proteins involved in glioma aggressiveness and associated with poor patient survival (HspB1, BTF3, PGAM1, and cofilin), while it may upregulate galectin-1 and Ebp1. Consistently with the protein synthesis inhibition properties of CM16, HspB1, Ebp1, and BTF3 exert known roles in protein synthesis. In conclusion, the downregulation of HspB1, BTF3, PGAM1 and cofilin bring new insights in CM16 antiproliferative effects, further supporting CM16 as an interesting protein synthesis inhibitor to combat glioma.
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http://dx.doi.org/10.1002/ddr.21600DOI Listing
February 2020

Dysregulation of Macropinocytosis Processes in Glioblastomas May Be Exploited to Increase Intracellular Anti-Cancer Drug Levels: The Example of Temozolomide.

Cancers (Basel) 2019 Mar 22;11(3). Epub 2019 Mar 22.

Department of Pharmacotherapy and Pharmaceuticals, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium.

Macropinocytosis is a clathrin-independent endocytosis of extracellular fluid that may contribute to cancer aggressiveness through nutrient supply, recycling of plasma membrane and receptors, and exosome internalization. Macropinocytosis may be notably triggered by epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR), two well-known markers for glioblastoma aggressiveness. Therefore, we studied whether the expression of key actors of macropinocytosis is modified in human glioma datasets. Strong deregulation has been evidenced at the mRNA level according to the grade of the tumor, and 38 macropinocytosis-related gene signatures allowed discrimination of the glioblastoma (GBM) samples. Honokiol-induced vacuolization was then compared to vacquinol-1 and MOMIPP, two known macropinocytosis inducers. Despite high phase-contrast morphological similarities, honokiol-induced vacuoles appeared to originate from both endocytosis and ER. Also, acridine orange staining suggested differences in the macropinosomes' fate: their fusion with lysosomes appeared very limited in 3-(5-methoxy -2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one (MOMIPP)-treated cells. Nevertheless, each of the compounds markedly increased temozolomide uptake by glioma cells, as evidenced by LC-MS. In conclusion, the observed deregulation of macropinocytosis in GBM makes them prone to respond to various compounds affecting their formation and/or intracellular fate. Considering that sustained macropinocytosis may also trigger cell death of both sensitive and resistant GBM cells, we propose to envisage macropinocytosis inducers in combination approaches to obtain dual benefits: increased drug uptake and additive/synergistic effects.
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http://dx.doi.org/10.3390/cancers11030411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468498PMC
March 2019

Apoliporotein L3 interferes with endothelial tube formation via regulation of ERK1/2, FAK and Akt signaling pathway.

Atherosclerosis 2018 12 19;279:73-87. Epub 2018 Oct 19.

Laboratory of Molecular Biology of Inflammation, IBMM, Faculty of Sciences, Université Libre de Bruxelles, Gosselies, Belgium. Electronic address:

Background And Aims: Endothelial cells are main actors in vascular homeostasis as they regulate vascular pressure and permeability as well as hemostasis and inflammation. Disturbed stimuli delivered to and by endothelial cells correlate with the so-called endothelial dysfunction and disrupt this homeostasis. As constituents of the inner layer of blood vessels, endothelial cells are also involved in angiogenesis. Apolipoprotein Ls (APOL) comprise a family of newly discovered apolipoproteins with yet poorly understood function, and are suggested to be involved in inflammatory processes and cell death mechanisms. Here we investigate the role of APOLs in endothelial cells stimulated with factors known to be involved in atherogenesis and their possible contribution to endothelial dysfunction with an emphasis on inflammation driven-angiogenesis in vitro.

Methods: Using the CRISPR/Cas9 technique, we analyzed the effect of APOL3 gene knock out in HMEC-1 endothelial cells on cell migration, tubulogenesis, endothelial permeability, intracellular signal transduction as assessed by kinase phosphorylation, and angiogenesis gene expression (measured by qRT-PCR).

Results: Our results indicate that among the family, APOL3 was the only member induced by myeloperoxidase, oxidized LDL, VEGF and FGF treatments. APOL3 invalidation increased endothelial permeability, reduced wound repair and tubule formation in vitro, the latter only in MPO and VEGF-induced conditions. Accordingly, some pro-angiogenic signaling pathways (ERK1/2 and FAK but not Akt) and some pro-angiogenic genes were partially inhibited in APOL3 knock out cells.

Conclusions: These findings suggest the involvement of APOL3 in angiogenesis in vitro and as a modulator of MAPK and FAK signaling in endothelial cells.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.10.023DOI Listing
December 2018

Validation of a LC/MSMS method for simultaneous quantification of 9 nucleotides in biological matrices.

Talanta 2019 Feb 3;193:206-214. Epub 2018 Oct 3.

RD3 - Pharmacognosy, Bioanalysis and Drug Development, Faculty of Pharmacy, Université Libre de Bruxelles, Campus Plaine CP 205/05, Boulevard du Triomphe, B-1050 Bruxelles, Belgium; Analytical Platform of the Faculty of Pharmacy, Université Libre de Bruxelles, Campus Plaine CP 205/05, Boulevard du Triomphe, B-1050 Bruxelles, Belgium.

Nucleotides play a role in inflammation processes: cAMP and cGMP in the endothelial barrier function, ADP in platelet aggregation, ATP and UTP in vasodilatation and/or vasoconstriction of blood vessels, UDP in macrophages activation. The aim of this study is to develop and validate a LC/MS-MS method able to quantify simultaneously nine nucleotides (AMP, cAMP, ADP, ATP, GMP, cGMP, UMP, UDP and UTP) in biological matrixes (cells and plasma). The method we developed, has lower LOQ's than others and has the main advantage to quantify all nucleotides within one single injection in less than 10 min. The measured nucleotides concentrations obtained with this method are similar to those obtained with assay kits commercially available. Analysis of plasma and red blood cells from healthy donors permits to estimate the physiological concentration of those nucleotides in human plasma and red blood cells, such information being poorly available in the literature. Furthermore, the protocol presented in this paper allowed us to observe that AMP, ADP, ATP concentrations are modified in human red blood cells and plasma after a venous stasis of 4 min compared to physiological blood circulation. Therefore, this specific method enables future studies on nucleotides implications in chronic inflammatory diseases but also in other pathologies where nucleotides are implicated in.
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http://dx.doi.org/10.1016/j.talanta.2018.10.003DOI Listing
February 2019

The soluble curcumin derivative NDS27 inhibits superoxide anion production by neutrophils and acts as substrate and reversible inhibitor of myeloperoxidase.

Chem Biol Interact 2019 Jan 18;297:34-43. Epub 2018 Oct 18.

Department of Clinical Sciences, Anesthesiology and Equine Surgery, Faculty of Veterinary Medicine, B 41, University of Liege, Sart Tilman, Liège, Belgium; Centre of Oxygen, Research and Development-CIRM, Institute of Chemistry B 6a, University of Liege, Sart Tilman, Liège, Belgium.

A water-soluble curcumin lysinate incorporated into hydroxypropyl-β-cyclodextrin (NDS27) has been developed and shown anti-inflammatory properties but no comparative study has been made in parallel with its parent molecule, curcumin on polymorphonuclear neutrophils (PMNs) and myeloperoxidase (MPO) involved in inflammation. The effect of NDS27, its excipients (hydroxypropyl-β-cyclodextrin and lysine), curcumin lysinate and curcumin were compared on the release of superoxide anion by PMNs using a chemiluminescence assay and on the enzymatic activity of MPO. It was shown that curcumin and NDS27 exhibit similar inhibition activities on superoxide anion release by stimulated PMNs but also on MPO peroxidase and halogenation activities. The action mechanism of curcumin and NDS27 on the MPO activity was refined by stopped-flow and docking analyses. We demonstrate that both curcumin and NDS27 are reversible inhibitors of MPO by acting as excellent electron donors for redox intermediate Compound I (∼10 M s) but not for Compound II (∼10 M s) in the peroxidase cycle of the enzyme, thereby trapping the enzyme in the Compound II state. Docking calculations show that curcumin is able to enter the enzymatic pocket of MPO and bind to the heme cavity by π-stacking and formation of hydrogen bonds involving substituents from both aromatic rings. Hydroxypropyl-β-cyclodextrin is too bulky to enter MPO channel leading to the binding site suggesting a full release of curcumin from the cyclodextrin thereby allowing its full access to the active site of MPO. In conclusion, the hydroxypropyl-β-cyclodextrin of NDS27 enhances curcumin solubilization without affecting its antioxidant capacity and inhibitory activity on MPO.
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http://dx.doi.org/10.1016/j.cbi.2018.10.008DOI Listing
January 2019

Synthesis and photophysical studies of a multivalent photoreactive Ru-calix[4]arene complex bearing RGD-containing cyclopentapeptides.

Beilstein J Org Chem 2018 16;14:1758-1768. Epub 2018 Jul 16.

Laboratoire de Chimie Organique et Photochimie, Université libre de Bruxelles, Avenue F.D. Roosevelt 50, CP 160/08, 1050 Bruxelles, Belgium.

Photoactive ruthenium-based complexes are actively studied for their biological applications as potential theragnostic agents against cancer. One major issue of these inorganic complexes is to penetrate inside cells in order to fulfil their function, either sensing the internal cell environment or exert a photocytotoxic activity. The use of lipophilic ligands allows the corresponding ruthenium complexes to passively diffuse inside cells but limits their structural and photophysical properties. Moreover, this strategy does not provide any cell selectivity. This limitation is also faced by complexes anchored on cell-penetrating peptides. In order to provide a selective cell targeting, we developed a multivalent system composed of a photoreactive ruthenium(II) complex tethered to a calix[4]arene platform bearing multiple RGD-containing cyclopentapeptides. Extensive photophysical and photochemical characterizations of this Ru(II)-calixarene conjugate as well as the study of its photoreactivity in the presence of guanosine monophosphate have been achieved. The results show that the ruthenium complex should be able to perform efficiently its photoinduced cytotoxic activity, once incorporated into targeted cancer cells thanks to the multivalent platform.
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http://dx.doi.org/10.3762/bjoc.14.150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071717PMC
July 2018

Myeloperoxidase promotes tube formation, triggers ERK1/2 and Akt pathways and is expressed endogenously in endothelial cells.

Arch Biochem Biophys 2018 09 19;654:55-69. Epub 2018 Jul 19.

Laboratory of Experimental Medicine (ULB 222 Unit), CHU de Charleroi, A. Vésale Hospital, Université Libre de Bruxelles, Montigny-le-Tilleul, Belgium.

Myeloperoxidase is a member of the mammalian peroxidase family, mainly expressed in the myeloblastic cell lineage. It is considered a major bactericidal agent as it is released in the phagosome where it catalyzes the formation of reactive oxygen species. It is also released in the extracellular spaces including blood where it is absorbed on (lipo)proteins and endothelial cell surface, interfering with endothelial function. We performed RNA sequencing on MPO-treated endothelial cells, analyzed their transcriptome and validated the profile of gene expression by individual qRT-PCR. Some of the induced genes could be grouped in several functional networks, including tubulogenesis, angiogenesis, and blood vessel morphogenesis and development as well as signal transduction pathways associated to these mechanisms. MPO treatment mimicked the effects of VEGF on several signal transduction pathways, such as Akt, ERK or FAK involved in angiogenesis. Accordingly MPO, independently of its enzymatic activity, stimulated tube formation by endothelial cells. RNA interference also pointed at a role of endogenous MPO in tubulogenesis and endothelium wound repair in vitro. These data suggest that MPO, whether from endogenous or exogenous sources, could play a role in angiogenesis and vascular repair in vivo.
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http://dx.doi.org/10.1016/j.abb.2018.07.011DOI Listing
September 2018

Differential Effects of E-Cigarette on Microvascular Endothelial Function, Arterial Stiffness and Oxidative Stress: A Randomized Crossover Trial.

Sci Rep 2018 07 10;8(1):10378. Epub 2018 Jul 10.

Department of Cardiology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium.

Propylene glycol and glycerol are electronic cigarettes vehicles allowing liquid vaporization and nicotine transport. The respective effects of these different constituents on the cardiovascular system are unknown. We assessed the differential effects of vehicles (propylene glycol and glycerol) and nicotine on microcirculatory function, arterial stiffness, hemodynamic parameters and oxidative stress. Twenty-five tobacco smokers were exposed to vaping with and without nicotine, and sham vaping, in a randomized, single blind, 3-period crossover design study. Neither sham-vaping nor vaping in the absence of nicotine resulted in modifications of cardiovascular parameters or oxidative stress. In contrast, vaping with nicotine: 1) impaired acetylcholine mediated vasodilation (mean ± standard error mean) (area under curve, perfusion unit (PU), 3385 ± 27PU to 2271 ± 27PU, p < 0.0001); 2) increased indices of arterial stiffness, namely augmentation index corrected for heart rhythm (-3.5 ± 1.5% to 1.9 ± 2.3%; p = 0.013) and pulse wave velocity (4.9 ± 0.1 m.s to 5.3 ± 0 m.s; p < 0.0001); 3) increased systolic and diastolic blood pressures as well as heart rate (all p < 0.0001) and finally; 4) raised plasma myeloperoxidase (median [interquartile range]) (13.6 ng.ml [10-17.7] to 18.9 ng.ml [12.2-54.4], p = 0.005). Our findings demonstrated that high temperature e-cigarette vehicle vaporization does not alter micro- and macro-vascular function, and oxidative stress, and that these effects are solely attributable to nicotine.
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http://dx.doi.org/10.1038/s41598-018-28723-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039507PMC
July 2018

Human peroxidasin 1 promotes angiogenesis through ERK1/2, Akt, and FAK pathways.

Cardiovasc Res 2019 02;115(2):463-475

Laboratory of Experimental Medicine (ULB 222 Unit), Faculté de Médecine, CHU de Charleroi, A. Vésale Hospital, Université Libre de Bruxelles, Hôpital André Vésale, 706, Rue de Gozée, 6110 Montigny-le-Tilleul, Charleroi, Belgium.

Aims: The term angiogenesis refers to sprouting of new blood vessels from pre-existing ones. The angiogenic process involves cell migration and tubulogenesis requiring interaction between endothelial cells and the extracellular matrix. Human peroxidasin 1 (hsPxd01) is a multidomain heme peroxidase found embedded in the basement membranes. As it promotes the stabilization of extracellular matrix, we investigated its possible role in angiogenesis both in vitro and in vivo.

Methods And Results: We analysed the effects of peroxidasin 1 gene silencing and supplementation by recombinant hsPxd01 in TeloHAEC endothelial cells on cell migration, tubulogenesis in matrigel, and intracellular signal transduction as assessed by kinase phosphorylation and expression of pro-angiogenic genes as measured by qRT-PCR. We further evaluated the angiogenic potential of recombinant peroxidasin in a chicken chorioallantoic membrane model. RNA silencing of endogenous hsPxd01 significantly reduced tube formation and cell migration, whereas supplementation by the recombinant peroxidase promoted tube formation in vitro and stimulated vascularization in vivo through its catalytic activity. Moreover, recombinant hsPxd01 promoted phosphorylation of Extracellular signal-Regulated Kinases (ERK1/2), Protein kinase B (Akt), and Focal Adhesion Kinase (FAK), and induced the expression of pro-angiogenic downstream genes: Platelet Derived Growth Factor Subunit B (PDGFB), endothelial-derived Heparin Binding EGF-like growth factor (HB-EGF), CXCL-1, Hairy-Related Transcription Factor 1 (HEY-1), DNA-binding protein inhibitor (ID-2), Snail Family Zinc Finger 1 (SNAI-1), as well as endogenous hsPxd01. However, peroxidasin silencing significantly reduced Akt and FAK phosphorylation but induced ERK1/2 activation after supplementation by recombinant hsPxd01. While hsPxd01 silencing significantly reduced expression of HEY-1, ID-2, and PDGFB, it did not affect expression of SNAI-1, HB-EGF, and CXCL-1 after supplementation by recombinant hsPxd01.

Conclusion: Our findings suggest a role of enzymatically active peroxidasin 1 as a pro-angiogenic peroxidase and a modulator of ERK1/2, Akt and FAK signalling.
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http://dx.doi.org/10.1093/cvr/cvy179DOI Listing
February 2019

Data on myeloperoxidase-oxidized low-density lipoproteins stimulation of cells to induce release of resolvin-D1.

Data Brief 2018 Jun 4;18:1160-1171. Epub 2018 Apr 4.

Laboratory of Pharmaceutical Chemistry and Analytical Platform of the Faculty of Pharmacy, Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium.

This article present data related to the publication entitled "Native and myeloperoxidase-oxidized low-density lipoproteins act in synergy to induce release of resolvin-D1 from endothelial cells" (Dufour et al., 2018). The supporting materials include results obtained by Mox-LDLs stimulated macrophages and investigation performed on scavenger receptors. Linear regressions (RvD1 vs age of mice and RvD1 vs CL-Tyr/Tyr) and Data related to validation were also presented. The interpretation of these data and further extensive insights can be found in Dufour et al. (2018) [1].
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http://dx.doi.org/10.1016/j.dib.2018.03.131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996617PMC
June 2018

The other myeloperoxidase: Emerging functions.

Arch Biochem Biophys 2018 07 31;649:1-14. Epub 2018 Mar 31.

Pharmacognosy, Bioanalysis and Drug Discovery Unit, RD3, and Analytical Platform of the Faculty of Pharmacy, Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium. Electronic address:

Myeloperoxidase (MPO) is a member of the mammalian peroxidase family. It is mainly expressed in neutrophils, monocytes and macrophages. As a catalyzer of reactive oxidative species and radical species formation, it contributes to neutrophil bactericidal activity. Nevertheless MPO invalidation does not seem to have major health consequences in affected individuals. This suggests that MPO might have alternative functions supporting its conservation during evolution. We will review the available data supporting these non-canonical functions in terms of tissue specific expression, function and enzymatic activity. Thus, we discuss its cell type specific expression. We review in between others its roles in angiogenesis, endothelial (dys-) function, immune reaction, and inflammation. We summarize its pathological actions in clinical conditions such as cardiovascular disease and cancer.
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http://dx.doi.org/10.1016/j.abb.2018.03.037DOI Listing
July 2018

Native and myeloperoxidase-oxidized low-density lipoproteins act in synergy to induce release of resolvin-D1 from endothelial cells.

Atherosclerosis 2018 05 8;272:108-117. Epub 2018 Mar 8.

From the Laboratory of Pharmaceutical Chemistry and Analytical Platform of the Faculty of Pharmacy, Faculty of Pharmacy, Université Libre de Bruxelles, Brussels, Belgium.

Background And Aims: Oxidation of native low-density lipoproteins (LDLs-nat) plays an important role in the development of atherosclerosis. A major player in LDL-nat oxidation is myeloperoxidase (MPO), a heme enzyme present in azurophil granules of neutrophils and monocytes. MPO produces oxidized LDLs called Mox-LDLs, which cause a pro-inflammatory response in human microvascular endothelial cells (HMEC), monocyte/macrophage activation and formation of foam cells. Resolvin D1 (RvD1) is a compound derived from the metabolism of the polyunsaturated fatty acid DHA, which promotes resolution of inflammation at the ng/ml level.

Methods: In the present study, we used liquid chromatography-mass spectrometry (LC-MS/MS) to investigate the synthesis of RvD1 and its precursors - 17(S)-hydroxy docosahexaenoic acid (17S-HDHA) and docosahexaenoic acid (DHA) - by HMEC, in the presence of several concentrations of Mox-LDLs, copper-oxidized-LDLs (Ox-LDLs), and native LDLs or in mouse plasma. The LC-MS/MS method has been validated and applied to cell supernatants and plasma to measure production of RvD1 and its precursors in several conditions.

Results: Mox-LDLs played a significant role in the synthesis of RvD1 and 17S-HDHA from DHA compared to Ox-LDLs. Moreover, Mox-LDLs and LDLs-nat acted in synergy to produce RvD1. In addition, different correlations were found between RvD1 and M1 macrophages, age of mice or Cl-Tyr/Tyr ratio.

Conclusions: These results suggest that although Mox-LDLs are known to be pro-inflammatory and deleterious in the context of atherosclerosis, they are also able to induce a pro-resolution effect by induction of RvD1 from HMEC. Finally, our data also suggest that HMEC can produce RvD1 on their own.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.03.012DOI Listing
May 2018

Myeloperoxidase-catalyzed oxidation of cyanide to cyanate: A potential carbamylation route involved in the formation of atherosclerotic plaques?

J Biol Chem 2018 04 1;293(17):6374-6386. Epub 2018 Mar 1.

From the Laboratory of Pharmaceutical Chemistry and

Protein carbamylation by cyanate is a post-translational modification associated with several (patho)physiological conditions, including cardiovascular disorders. However, the biochemical pathways leading to protein carbamylation are incompletely characterized. This work demonstrates that the heme protein myeloperoxidase (MPO), which is secreted at high concentrations at inflammatory sites from stimulated neutrophils and monocytes, is able to catalyze the two-electron oxidation of cyanide to cyanate and promote the carbamylation of taurine, lysine, and low-density lipoproteins. We probed the role of cyanide as both electron donor and low-spin ligand by pre-steady-state and steady-state kinetic analyses and analyzed reaction products by MS. Moreover, we present two further pathways of carbamylation that involve reaction products of MPO, namely oxidation of cyanide by hypochlorous acid and reaction of thiocyanate with chloramines. Finally, using an approach with mice on a high-fat diet and carrying the human MPO gene, we found that during chronic exposure to cyanide, mimicking exposure to pollution and smoking, MPO promotes protein-bound accumulation of carbamyllysine (homocitrulline) in atheroma plaque, demonstrating a link between cyanide exposure and atheroma. In summary, our findings indicate that cyanide is a substrate for MPO and suggest an additional pathway for cyanate formation and protein carbamylation that involves MPO either directly or via its reaction products hypochlorous acid or chloramines. They also suggest that chronic cyanide exposure could promote the accumulation of carbamylated proteins in atherosclerotic plaques.
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http://dx.doi.org/10.1074/jbc.M117.801076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5925816PMC
April 2018

Targeting Cytosolic Phospholipase A2α for Novel Anti-Inflammatory Agents.

Curr Med Chem 2018 ;25(21):2418-2447

Microbiology, Bioorganic and Macromolecular Chemistry, Faculty of Pharmacy, Universite Libre de Bruxelles, Campus de la Plaine, Boulevard du Triomphe, 1050 Bruxelles, Belgium.

Group IV cytosolic phospholipase A2 (cPLA2α) plays a critical role in inflammatory processes. It produces arachidonic acid which is the main source of the pro-inflammatory eicosanoids mediators that are important in innate immune system. In some cases, these proinflammatory mediators cause damages to the host tissues and therefore promote autoimmune diseases. Consequently, development of potent inhibitors against cPLA2α could improve the therapy of inflammatory diseases. In the last two decades, intense efforts have been done to find potent cPLA2α inhibitors. Several scaffolds have been developed with the use of structure activity relationship (SAR) studies, and potent inhibitors have been obtained. The poor absorption of these compounds from intestine was the main challenge for clinical application. This review illustrates the search for cPLA2α inhibitors, their SAR studies and biological effects.
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http://dx.doi.org/10.2174/0929867325666180117103919DOI Listing
July 2018

New Folate-Grafted Chitosan Derivative To Improve Delivery of Paclitaxel-Loaded Solid Lipid Nanoparticles for Lung Tumor Therapy by Inhalation.

Mol Pharm 2018 03 30;15(3):899-910. Epub 2018 Jan 30.

Center for Microscopy and Molecular Imaging (CMMI), B-6041 Gosselies , Belgium.

Inhaled chemotherapy for the treatment of lung tumors requires that drug delivery systems improve selectivity for cancer cells and tumor penetration and allow sufficient lung residence. To this end, we developed solid lipid nanoparticles (SLN) with modified surface properties. We successfully synthesized a new folate-grafted copolymer of polyethylene glycol (PEG) and chitosan, F-PEG-HTCC, with a PEG-graft ratio of 7% and a molecular weight range of 211-250 kDa. F-PEG-HTCC-coated, paclitaxel-loaded SLN were prepared with an encapsulation efficiency, mean diameter, and zeta potential of about 100%, 250 nm, and +32 mV, respectively. The coated SLN entered folate receptor (FR)-expressing HeLa and M109-HiFR cells in vitro and M109 tumors in vivo after pulmonary delivery. The coated SLN significantly decreased the in vitro half-maximum inhibitory concentrations of paclitaxel in M109-HiFR cells (60 vs 340 nM, respectively). We demonstrated that FR was involved in these improvements, especially in M109-HiFR cells. After pulmonary delivery in vivo, the coated SLN had a favorable pharmacokinetic profile, with pulmonary exposure to paclitaxel prolonged to up to 6 h and limited systemic distribution. Our preclinical findings therefore demonstrated the positive impact of the coated SLN on the delivery of paclitaxel by inhalation.
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http://dx.doi.org/10.1021/acs.molpharmaceut.7b00846DOI Listing
March 2018

Metabolomics fingerprint of coffee species determined by untargeted-profiling study using LC-HRMS.

Food Chem 2018 Apr 12;245:603-612. Epub 2017 Oct 12.

Laboratoire de Pharmacognosie, de Bromatologie et de Nutrition Humaine, Faculté de Pharmacie, Université Libre de Bruxelles, Campus Plaine, CP 205/09, 1050 Brussels, Belgium.

Coffee bean extracts are consumed all over the world as beverage and there is a growing interest in coffee leaf extracts as food supplements. The wild diversity in Coffea (Rubiaceae) genus is large and could offer new opportunities and challenges. In the present work, a metabolomics approach was implemented to examine leaf chemical composition of 9 Coffea species grown in the same environmental conditions. Leaves were analyzed by LC-HRMS and a comprehensive statistical workflow was designed. It served for univariate hypothesis testing and multivariate modeling by PCA and partial PLS-DA on the Workflow4Metabolomics infrastructure. The first two axes of PCA and PLS-DA describes more than 40% of variances with good values of explained variances. This strategy permitted to investigate the metabolomics data and their relation with botanic and genetic informations. Finally, the identification of several key metabolites for the discrimination between species was further characterized.
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http://dx.doi.org/10.1016/j.foodchem.2017.10.022DOI Listing
April 2018
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