Search

International audience; Polymer nanoparticles (NPs) are extensively studied as drug delivery systems for various therapeutic indications, including drug and imaging agent delivery to the brain. Despite intensive research, their toxicological profile has yet to be fully characterized. In particular, the more subtle effects of nanomaterials on inflammatory processes have scarcely been investigated. Surface properties of NPs are amongst parameters governing interactions between living cells and NPs. They could considerably influence the toxicity and inflammatory response of the cells exposed to NPs.Polymeric NPs investigated here present a core-shell structure. The core is constituted of hydrophobic poly(lactic acid) (PLA) block and the surface is composed of a shell of hydrophilic block of polyethylene glycol (PEG). The effect of PEG chain length coating on the expression of genes involved in the inflammation response was investigated in two vascular endothelial cell lines (bEnd.3 and HUVEC) by qPCR. Moreover, ROS generation following NP uptake was evaluated. PEGylated NPs induce a mild and transient activation of inflammatory cytokine and chemokine genes. However, differences in PEG chain length did not show any significant effect on cytokine and chemokine gene expression and PEGylated NPs did not trigger ROS generation. The present results could contribute significantly to a deeper understanding of nanomaterial interactions and toxicity with vascular endothelial cells, guiding scientists in material coating choices.

L’association d’un inhibiteur du cytochrome P450 (CYP) 3A4 avec une statine entraine une interaction medicamenteuse. Trois solutions peuvent etre envisagees avec le medecin selon les medicaments prescrits : la substitution de l’inhibiteur du CYP3A4, la diminution de la posologie de la statine ou son remplacement par une autre statine n’interagissant pas ou peu avec les inhibiteurs du CYP3A4.

International audience; Advanced drug delivery system utilizing a nanocarrier is the major application of nanotechnology on pharmacotherapeutics. However, despite the promising benefits and a leading trend in pharmaceutical research, nanomedicine development suffers from a poor clinical translation problem as only a handful of nanomedicine products reach the market yearly. The conventional pharmacokinetic study generally focuses only on monitoring the level of a free drug but ignores the nanocarrier's role in pharmacokinetics. One hurdle is that it is difficult to directly track intact nanocarriers in vivo to explore their pharmacokinetics. Although several imaging techniques such as radiolabeling, nuclear imaging, fluorescence imaging, etc., have been developed over the past few years, currently, one method that can successfully track the intact nanocarriers in vivo directly is by Förster resonance energy transfer (FRET). This review summarizes the application of FRET as the in vivo nanoparticle tracker for studying the in vivo pharmacokinetics of the organic nanocarriers and gives elaborative details on the techniques utilized.

International audience; To understand how nanoparticles (NPs) interact with biological barriers and to ensure they maintain their integrity over time, it is crucial to study their in vivo pharmacokinetic (PK) profiles. Many methods of tracking have been used to describe the in vivo fate of NPs and to evaluate their PKs and structural integrity. However, they do not deliver the same level of information and this may cause misinterpretations. Here, the authors review and discuss the different methods for in vivo tracking of organic NPs. Among them, Förster resonance energy transfer (FRET) presents great potential to track NPs' integrity. However, FRET still requires validated methods to extract and quantify NPs in biological fluids and tissues.

In pharmaceutical studies, a course of bacteriology based on case studies provided by the teacher was transformed in a course based on a combination of student/teacher co-creation of cases and peer reviewing. Our objectives were to describe the perception of students about the new format and to assess the impact of changing on the learning outcomes. For teaching evaluation, we used a questionnaire and focus groups. The assessment of learning outcome was performed by comparing the students’ scores in final tests with the previous and the revised course formats. The students embraced the creation of cases in small groups with the teacher. In addition, they reported a perception of weakened hierarchy between the teacher and themselves, an increase of their self-confidence and a better ability to transfer their learning to their professional activities in community pharmacies. Lastly, their opinion about the transferability of this format in other disciplines were divided.

Background Acute myeloid leukemia mainly affects adult patients. Complete remission for patients younger than 60 years, who are candidates for standard induction therapy, is achieved in 60%-80% of cases. However, the prognosis is still poor for older patients, who are unfit for intensive chemotherapy, and only a few therapies are available. Hypomethylating agents, such as decitabine, are approved for such patients. The current dosing regimen consists of one administration per day, for 5 days, each 4 weeks. Methods Here, we present the synthesis of a decitabine prodrug, combined with its encapsulation into a lipid-based nanocapsule formulation. Decitabine (C12)2 was synthetized, then loaded into nanocapsules. Its stability in phosphate buffer ans human plasma was checked. Its activity was evaluated by Cell proliferation assays and cell-cycle analysis on human erythroleukemia cells. Then its pharmacokinetics was determined on a rat model. Results Decitabine (C12)2 was obtained with a yield of 50%. Drug loading into nanocarriers of 27.45±0.05 nm was 5.8±0.5 mg/mL. The stability of decitabine was improved and its activity on leukemia cells was not altered. Finally, pharmacokinetics studies showed a prolonged mean residence time of the drug. Conclusion Decitabine (C12)2 as a prodrug showed high encapsulation efficiency, a good stability in plasma with no impact on its activity on leukemia cells and improved pharmacokinetics.

International audience

Nanomedicines have been developed for more than four decades to optimize the pharmacokinetics (PK) of drugs, especially absorption, distribution, and stability in vivo. Unfortunately, only a few drug products have reached the market. One reason among others is the lack of proper PK modeling and evaluation, which impedes the optimization of these promising drug delivery systems. In this review, we discuss the specificity of nanomedicines and propose key parameters to take into account for future accurate PK evaluation of nanomedicine. We believe that this could help these innovative drug products to reach to market and change the fate of many diseases.

International audience; Type 2 diabetes (TD2) is a progressive disease characterized by hyperglycemia that results from alteration in insulin secretion, insulin resistance, or both. A number of alterations involving different tissues and organs have been reported to the development and the progression of T2D, and more relevantly, through cell-to-cell communication pathways. Recent studies demonstrated that miRNAs are considerably implicated to cell-to-cell communication during T2D. Physical activity (PA) is associated with decreasing risks of developing T2D and acts as insulin-like factor. Cumulative evidence suggest that this effect could be mediated in part through improving insulin sensitivity in T2D and obese patients and modulating miRNAs synthesis and release in healthy patients. Therefore, the practice of PA should ideally be established before the initiation of T2D. This review describes cell-to-cell communications involved in the pathophysiology of T2D during PA.

International audience; The aim of this study was to design and develop a novel hybrid formulation based on lipid nanocapsules containing bevacizumab (BVZ), an effective therapeutic antibody, on the surface and triamcinolone acetonide (TA) in the inner core (BVZ-TA-LNC) intended to improve ocular therapy. Hence, a phase inversion-insertion one step method was developed to drug loading and surface modification of lipid nanocapsules by post-insertion of a bifunctional polymer, followed by antibody oupling using “click” chemistry. The covalent bond and antibody capacity binding to its specific antigen were confirmed by thermal analysis and immunoassay, respectively. BVZTA- LNC presented nanometric size (102 nm), negative surface potential (−19 mV) and exhibiting 56% of TA in the lipid core. BVZ-TA-LNC tended to prevent the endothelial cell migration and significantly prevented the capillary formation induced by the vascular endothelium growth factor (VEGF). The novel hybrid system allowed the co-loading of two different therapeutic molecules and may be promising to mprove the therapy of eye disorders that occur with inflammation and/or neovascularization.

Polyphenols consumption has been associated with a lower risk of cardiovascular diseases (CVDs) notably through nitric oxide (NO)- and estrogen receptor &alpha, (ER&alpha, )-dependent pathways. Among polyphenolic compounds, chalcones have been suggested to prevent endothelial dysfunction and hypertension. However, the involvement of both the NO and the ER&alpha, pathways for the beneficial vascular effects of chalcones has never been demonstrated. In this study, we aimed to identify chalcones with high vasorelaxation potential and to characterize the signaling pathways in relation to ER&alpha, signaling and NO involvement. The evaluation of vasorelaxation potential was performed by myography on wild-type (WT) and ER&alpha, knock-out (ER&alpha, KO) mice aorta in the presence or in absence of the eNOS inhibitor N&omega, nitro-L-arginine methyl ester (L-NAME). Among the set of chalcones that were synthesized, four (3, 8, 13 and 15) exhibited a strong vasorelaxant effect (more than 80% vasorelaxation) while five compounds (6, 10, 11, 16, 17) have shown a 60% relief of the pre-contraction and four compounds (12, 14, 18, 20) led to a lower vasorelaxation. We were able to demonstrate that the vasorelaxant effect of two highly active chalcones was either ER&alpha, dependent and NO-independent or ER&alpha, independent and NO-dependent. Thus some structure-activity relationships (SAR) were discussed for an optimized vasorelaxant effect.

In situ chemical reduction (ISCR) has been identified as a possible way for the remediation of soils contaminated by chlordecone (CLD). Evidences provided by the literature indicate an association between the development of prostate cancer and CLD exposure (Multigner et al. 2010). In a previous in vitro study, we demonstrated that the two main dechlorinated CLD derivatives formed by ISCR, CLD-1Cl, and CLD-3Cl have lower cytotoxicity and proangiogenic properties than CLD itself (Legeay et al. 2017). By contrast, nothing is known on the in vivo proangiogenic effect of these dechlorinated derivatives. Based on in vitro data, the aims of this study were therefore to evaluate the in vivo influence of CLD and three of its dechlorinated metabolites in the control of neovascularization in a mice model of prostate cancer. The proangiogenic effect of CLD and three of its dechlorinated derivatives, CLD-1Cl, CLD-3Cl, and CLD-4Cl, was evaluated on a murine model of human prostate tumor (PC-3) treated, at two exposure levels: 33 μg/kg and 1.7 μg/kg respectively reflecting acute and chronic toxic exposure in human. The results of serum measurements show that, for the same ingested dose, the three metabolite concentrations were significantly lower than that of CLD. Dechlorination of CLD lead therefore to molecules that are biologically absorbed or metabolized, or both, faster than the parent molecule. Prostate tumor growth was lower in the groups treated by the three metabolites compared to the one treated by CLD. The vascularization measured on the tumor sections was inversely proportional to the rate of dechlorination, the treatment with CLD-4Cl showing no difference with control animals treated with only the vehicle oil used for all substances tested. We can therefore conclude that the proangiogenic effect of CLD is significantly decreased following the ISCR-resulting dechlorination. Further investigations are needed to elucidate the molecular mechanisms by which dechlorination of CLD reduces proangiogenic effects in prostate tumor.

La mise en place d’une contraception estroprogestative chez une patiente traitee par lamotrigine peut entrainer une diminution de l’efficacite de ce medicament et, par consequent, une perte du controle des crises d’epilepsie ou des troubles bipolaires. Une induction enzymatique de l’ethinylestradiol est notamment en cause dans cette interaction. Le pharmacien peut proposer au medecin de substituer le contraceptif par un autre.

Background: Among polyphenolic compounds suggested to prevent cardiovascular diseases (CVDs) and to explain the “French paradox”, the anthocyanidin delphinidin (Dp) has been reported to support at least partly the vascular beneficial effects of dietary polyphenolic compounds including those from fruits and related products as red wine. It has also been highlighted that Dp interacts directly with the active site of estrogen receptor α (ERα), leading to activation of endothelial NO synthase (eNOS) pathway thus contributing to the prevention of endothelial dysfunction in mice aorta. However, anthocyanidins have very low bioavailability and despite a well described in vitro efficacy, the very high hydrophilicity and physicochemical instability of Dp might explain the lack of in vivo reported effects. Objective: The aim of this study was to identify new Dp analogues with increased lipophilicity and vasorelaxation potential by a chemical modulation of its structure and to characterize the signaling pathway notably in relation with ERα signaling and nitric oxide (NO) production. Method: OCH3-substituted delphinidin analogues were obtained through the coupling of the corresponding acetophenones with substituted benzaldehydes. Prediction of resorption of the flavylium derivatives was performed with the calculated logP and induction of vasorelaxation was performed by myography on WT and ERαKO mice thoracic aorta rings and compared to Dp. NO production was evaluated in vitro on human primary endothelial cells. Results: Eight Dp analogues were synthesized including four new flavylium derivatives. Two compounds (9 and 11) showed a strong increase of vasorelaxation potential and a theoretically increased bioavailability compared to Dp. Interestingly, 9 and 11 induced increased O2 - or NO endothelial production respectively and revealed a novel NO-dependent ERα-independent relaxation compared to Dp. We suggested that this mechanism may be at least in part supported by the inhibition of vascular cyclic nucleotide phosphodiesterase (PDEs). Conclusion: The current study demonstrated that pharmacomodulation of the Dp backbone by replacement of OH groups by OCH3 groups of the A and B rings led to the identification and characterization of two compounds (9 and 11) with enhanced physio-chemical properties that could be associated to higher permeability capability and pharmacological activity for the prevention of CVDs compared to Dp.

Background Acute myeloid leukemia mainly affects adult patients. Complete remission for patients younger than 60 years, who are candidates for standard induction therapy, is achieved in 60%–80% of cases. However, the prognosis is still poor for older patients, who are unfit for intensive chemotherapy, and only a few therapies are available. Hypomethylating agents, such as decitabine, are approved for such patients. The current dosing regimen consists of one administration per day, for 5 days, each 4 weeks. Methods Here, we present the synthesis of a decitabine prodrug, combined with its encapsulation into a lipid-based nanocapsule formulation. Decitabine (C12)2 was synthetized, then loaded into nanocapsules. Its stability in phosphate buffer ans human plasma was checked. Its activity was evaluated by Cell proliferation assays and cell-cycle analysis on human erythroleukemia cells. Then its pharmacokinetics was determined on a rat model. Results Decitabine (C12)2 was obtained with a yield of 50%. Drug loading into nanocarriers of 27.45±0.05 nm was 5.8±0.5 mg/mL. The stability of decitabine was improved and its activity on leukemia cells was not altered. Finally, pharmacokinetics studies showed a prolonged mean residence time of the drug. Conclusion Decitabine (C12)2 as a prodrug showed high encapsulation efficiency, a good stability in plasma with no impact on its activity on leukemia cells and improved pharmacokinetics.

International audience; Diabetes notably increases the risk for endothelial dysfunction, a main precursor for microvascular complications. While endoplasmic reticulum stress (ERS) and protein tyrosine phosphatase 1B (PTP1B) have been associated with endothelial dysfunction in resistance vessels, whether these mechanisms also contribute to diabetes mediated endothelial dysfunction in conduit arteries remains unknown. Herein, we tested the hypothesis that diabetes induces macrovascular endothelial dysfunction via endothelial ERS-induced, PTP1B-mediated apoptosis. We showed that diabetes concomitantly increased the expression of PTP1B and of markers of ERS, including GRP78, XBP1, splXBP1 and CHOP in human vessels. Exposure of aortic rings from wild-type mice to the ERS inducers tunicamycin and thapsigargin markedly reduced endothelium-dependent relaxation. Global and endothelial-specific deletion of PTP1B as well as pharmacological inhibition protected aortic rings from ERS-mediated endothelial dysfunction. Nitric oxide synthase inhibition with L-NAME abolished relaxation in the presence and absence of ERS, but neither reactive oxygen species scavenging with tempol or peg-catalase, nor cyclooxygenase inhibition with indomethacin prevented ERS-mediated endothelial dysfunction. However, both p38-MAPK and JNK inhibition protected aortic rings from ERS-mediated endothelial dysfunction. In HUVECs, PTP1B deletion prevented ERS-induced PARP cleavage and apoptosis. Lastly, acute ERS inhibition in aortic rings and selective deficiency of endothelial PTP1B in mice protected mice from diabetes-induced endothelial dys-function. Altogether, these data support the contribution of the p38/JNK-apoptosis pathway in ERS-mediated endothelial dysfunction and present endothelial PTP1B as a major regulator of endothelial cell viability in conduit vessels and a potential target for the management of macrovascular diseases in diabetes.

International audience; N,N-diethyl-m-toluamide (DEET) induces favorable repellency against insects by acting on the sensory nervous system. According to emerging literature reports, DEET side effects in humans involve new molecular targets including the cholinergic system, acetylcholinesterase (AChE), muscarinic M1 and M3 receptor and the participation of the second messenger nitric oxide (NO). Most of these molecular events targeted by DEET have previously been characterized in insects while they have been considered as marginal compared to classical repellent properties. Despite these uncommon actions in insects, there is no consensus on the effects in human. Based on these data, this review provides new insights on side effects in human and more largely in mammals by identifying the unusual properties of DEET in insects, which seem to be correlated with adverse effects in mammals. These data will be very helpful to understand better the toxicological effects observed in order to protect non-target organisms from the toxicity.

Bisphenol A (BPA) is an endocrine disruptor with an oestrogenic activity that is widely produced for the manufacture of polycarbonate plastic, epoxy resin, and thermal paper. Its ubiquitous presence in the environment contributes to broad and continuous human exposure, which has been associated with deleterious health effects. Despite numerous controversial discussions and a lack of consensus about BPA's safety, growing evidence indicates that BPA exposure positively correlates with an increased risk of developing obesity. An updated analysis of the epidemiological, in vivo, and in vitro studies indicates that BPA should be considered an obesogenic environmental compound. Precisely, BPA exposure during all life stages correlates with increased body weight and/or body mass index. Developmental periods that include prenatal, infancy, and childhood appear to be critical windows with increased sensitivity to BPA effects. Finally, blood analysis and in vitro data clearly demonstrate that BPA promotes adipogenesis, lipid and glucose dysregulation, and adipose tissue inflammation, thus contributing to the pathophysiology of obesity. Future prevention efforts should now be employed to avoid BPA exposure, and more research to determine in depth the critical time windows, doses, and impact of long-term exposure of BPA is warranted in order to clarify its risk assessment.

This article belongs to the Special Issue Diet and Metabolic Dysfunction; International audience; Obesity and being overweight are linked with a cluster of metabolic and vascular disorders that have been termed the metabolic syndrome. This syndrome promotes the incidence of cardiovascular diseases that are an important public health problem because they represent a major cause of death worldwide. Whereas there is not a universally-accepted set of diagnostic criteria, most expert groups agree that this syndrome is defined by an endothelial dysfunction, an impaired insulin sensitivity and hyperglycemia, dyslipidemia, abdominal obesity and hypertension. Epidemiological studies suggest that the beneficial cardiovascular health effects of diets rich in green tea are, in part, mediated by their flavonoid content, with particular benefits provided by members of this family such as epigallocatechin gallate (EGCG). Although their bioavailability is discussed, various studies suggest that EGCG modulates cellular and molecular mechanisms of various symptoms leading to metabolic syndrome. Therefore, according to in vitro and in vivo model data, this review attempts to increase our understanding about the beneficial properties of EGCG to prevent metabolic syndrome.

Ethoxidine, a benzo[c]phenanthridine derivative, has been identified as a potent inhibitor of topoisomerase I in cancer cell lines. Our group has reported paradoxical properties of ethoxidine in cellular processes leading to angiogenesis on endothelial cells. Because low concentration ethoxidine is able to favor angiogenesis, the present study aimed to investigate the ability of 10−9 M ethoxidine to modulate neovascularization in a model of mouse hindlimb ischemia. After inducing unilateral hindlimb ischemia, mice were treated for 21 days with glucose 5% or with ethoxidine, to reach plasma concentrations equivalent to 10–9 M. Laser Doppler analysis showed that recovery of blood flow was 1.5 fold higher in ethoxidine-treated mice in comparison with control mice. Furthermore, CD31 staining and angiographic studies confirmed an increase of vascular density in ethoxidine-treated mice. This ethoxidine-induced recovery was associated with an increase of NO production through an enhancement of eNOS phosphorylation on its activator site in skeletal muscle from ischemic hindlimb. Moreover, real-time RT-PCR and western blots have highlighted that ethoxidine has pro-angiogenic properties by inducing a significant enhancement in vegf transcripts and VEGF expression, respectively. These findings suggest that ethoxidine could contribute to favor neovascularization after an ischemic injury by promoting the NO pathway and VEGF expression.

International audience; Chlordecone (CLD) is a chlorinated hydrocarbon insecticide, now classified as a persistent organic pollutant. Several studies have previously reported that chronic exposure to CLD leads to hepatotoxicity, neurotoxicity, raises early child development and pregnancy complications, and increases the risk of liver and prostate cancer. In situ chemical reduction (ISCR) has been identified as a possible way for the remediation of soils contaminated by CLD. In the present study, the objectives were (i) to evaluate the genotoxicity and the mutagenicity of two CLD metabolites formed by ISCR, CLD-5a-hydro, or CLD-5-hydro (5a- or 5- according to CAS nomenclature; CLD-1Cl) and tri-hydroCLD (CLD-3Cl), and (ii) to explore the angiogenic properties of these molecules. Mutagenicity and genotoxicity were investigated using the Ames's technique on Salmonella typhimurium and the in vitro micronucleus micromethod with TK6 human lymphoblastoid cells. The proangiogenic properties were evaluated on the in vitro capillary network formation of human primary endothelial cells. Like CLD, the dechlorinated derivatives of CLD studied were devoid of genotoxic and mutagenic activity. In the assay targeting angiogenic properties, significantly lower microvessel lengths formed by endothelial cells were observed for the CLD-3Cl-treated cells compared to the CLD-treated cells for two of the three tested concentrations. These results suggest that dechlorinated CLD derivatives are devoid of mutagenicity and genotoxicity and have lower proangiogenic properties than CLD.

International audience

The insect repellent N,N-diethyl-m-toluamide (DEET) has been reported to inhibit AChE (acetylcholinesterase) and to possess potential carcinogenic properties with excessive vascularization. In the present paper, we demonstrate that DEET specifically stimulates endothelial cells that promote angiogenesis which increases tumor growth. DEET activates cellular processes that lead to angiogenesis including proliferation, migration and adhesion. This is associated with an enhancement of NO production and VEGF expression in endothelial cells. M3 silencing or the use of a pharmacological M3 inhibitor abrogates all of these effects which reveals that DEET-induced angiogenesis is M3 sensitive. The experiments involving calcium signals in both endothelial and HEK cells overexpressing M3 receptors, as well as binding and docking studies demonstrate that DEET acts as an allosteric modulator of the M3 receptor. In addition, DEET inhibited AChE which increased acetylcholine bioavailability and binding to M3 receptors and also strengthened proangiogenic effects by an allosteric modulation.

National audience