6 research outputs found
Susceptibility of intestinal mucosa to xenobiotics : role in the physiopathology of inflammatory bowel diseases (IBD) : example of Rac1 gene
Les Maladies Inflammatoires Chroniques de lâIntestin (MICI) regroupent la maladie de Crohn (MC) et la Rectocolite HĂ©morragique (RCH), deux maladies qui se caractĂ©risent par lâinflammation de la paroi dâune partie du tube digestif, source de lĂ©sions destructrices (ulcĂ©rations). Ces pathologies complexes sont influencĂ©es par de multiples facteurs gĂ©nĂ©tiques et environnementaux. Dâune part, de nombreux gĂšnes de susceptibilitĂ© pour ces maladies ont Ă©tĂ© identifiĂ©s, mais ils ne permettent dâexpliquer quâune fraction mineure du dĂ©veloppement des MICI. Dâautre part, certaines Ă©tudes montrent quâun dysfonctionnement du processus de prise en charge des xĂ©nobiotiques dans la muqueuse digestive peut jouer un rĂŽle dans lâinitiation et/ou la progression des MICI. Notre travail a consistĂ©, dans un premier temps, en lâĂ©tude du profil dâexpression de gĂšnes codant pour des protĂ©ines impliquĂ©es dans le mĂ©tabolisme et le transport des xĂ©nobiotiques. Une stratĂ©gie de RT-PCR quantitative en temps rĂ©el, permettant lâanalyse simultanĂ©e de lâexpression de 377 gĂšnes, a Ă©tĂ© utilisĂ©e. Cette analyse a Ă©tĂ© rĂ©alisĂ©e sur des Ă©chantillons de muqueuse intestinale de sujets tĂ©moins et de patients atteints de MC, ainsi que sur cinq lignĂ©es de cellules Ă©pithĂ©liales intestinales.Cette Ă©tude a permis dâidentifier les systĂšmes de prise en charge des xĂ©nobiotiques prĂ©sents dans la muqueuse intestinale saine. Des profils dâexpression diffĂ©rents ont Ă©tĂ© mis en Ă©vidence entre les tissus intestinaux sains et inflammatoires, mais Ă©galement entre les tissus intestinaux et les lignĂ©es cellulaires intestinales, ce qui suggĂšre des diffĂ©rences majeures dans les processus de prise en charge cellulaire des xĂ©nobiotiques, et, par consĂ©quent des diffĂ©rences de susceptibilitĂ© Ă lâeffet des composĂ©s toxiques exogĂšnes. Dans un second temps, la petite protĂ©ine G, Rac1, a Ă©tĂ© Ă©tudiĂ©e. Cette protĂ©ine est impliquĂ©e dans la rĂ©paration des ulcĂ©rations de lâĂ©pithĂ©lium intestinal et a rĂ©cemment Ă©tĂ© identifiĂ©e comme la cible des mĂ©tabolites actifs des mĂ©dicaments thiopuriniques, largement prescrits dans le traitement des MICI. La nature et lâĂ©tendue de la variabilitĂ© de la sĂ©quence nuclĂ©otidique du gĂšne Rac1 a Ă©tĂ© Ă©valuĂ©e, chez des volontaires sains et des patients atteints de MICI, Ă lâaide dâune stratĂ©gie basĂ©e sur le couplage de lâanalyse du polymorphisme de conformation de fragments dâADN simple brin gĂ©nĂ©rĂ©s par rĂ©action de polymĂ©risation en chaine (PCR-SSCP) et du sĂ©quençage. Des Ă©tudes in silico et in vitro des consĂ©quences fonctionnelles des polymorphismes dâintĂ©rĂȘts ont ensuite Ă©tĂ© effectuĂ©es dans des lignĂ©es cellulaires intestinales (HT29 et Caco-2) et lymphocytaires (Jurkat). Cela nous a conduits Ă mieux caractĂ©riser le promoteur de Rac1 par une analyse de dĂ©lĂ©tion sĂ©quentielle et par des techniques de ChIP et dâEMSA.Cette Ă©tude nous a permis de dĂ©montrer pour la premiĂšre fois lâexistence de polymorphismes gĂ©nĂ©tiques fonctionnels de Rac1 et dâidentifier son promoteur minimal, ainsi que des facteurs de transcription Ă lâorigine de la rĂ©gulation de cette protĂ©ine.Crohnâs disease (CD) and Ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) of the gastrointestinal tract. These are multifactorial polygenic diseases with probable genetic heterogeneity. An emerging concept suggesting that dysfunction(s) of the processing of xenobiotics in the intestinal mucosa may be an important event in the initiation and progression of IBD has been discussed. Firstly, in this study, a precise and reliable characterization of the global expression profile of genes which code enzymes, transporters and nuclear factors involved in the processing of xenobiotics has been performed in intestinal epithelium of controls or patients with IBD, and in 5 intestinal cell lines. A quantitative real-time RT-PCR analysis using TaqMan Low Density Arrays (TLDA) was performed to simultaneously measure the expression of 377 genes.This work has identified genes encoding proteins that are involved in the metabolism and the disposition of xenobiotics in the healthy intestinal mucosa. Different genes expression profile between healthy and inflammatory intestinal tissues and between healthy intestinal tissues and intestinal cell lines were found. These tissues will consequently display distinctive susceptibility toward environmental chemicals and their toxic effects.Secondly, the small G protein, Rac1, which regulates cutaneous and mucosal intestinal wound healing and is identified as a target of active metabolites of thiopurine drugs, used in the treatment of IBD, has been studied. We searched for sequence variations by analysing the nucleotide sequence of the promoter and the coding sequence of Rac1 in genomic DNA from healthy volunteers and patients with IBD, using a PCR-single strand conformation polymorphism (SSCP) strategy and sequencing. The functional consequences of variations, that have been identified, were then analysed in silico and in vitro, in human intestinal cell lines (HT29 and Caco-2) and leukemia T-lymphocyte cell line (Jurkat). Via various deletion constructs, a putative regulatory region was identified and characterized further by chromatin immunoprecipitation and electrophoretic mobility shift assays.This work provides the first evidence that a functional genetic polymorphism of Rac1 activity exists. Furthermore, this study characterizes the proximal promoter of Rac1 gene and demonstrates the presence of consensus binding sites for numerous transcription factors, which could influence gene expression
Polymorphismes génétiques de Rac1 (une petite GTPase pléïotropique)
LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF
Severe Serotonin Syndrome in an Autistic New Psychoactive Substance User After Consumption of Pills Containing Methoxphenidine and α-Methyltryptamine
International audienc
Comparaison des donnĂ©es analytiques et anamnestiques des consommations de drogues et psychotropes chez des usagers d'opiacĂ©s en traitement de substitution. Ătude de faisabilitĂ©
L'Ă©tude observationnelle - nommĂ©e "AnalyTox-Op" - vise Ă
comparer les données analytiques et anamnestiques des consommations de
drogues et psychotropes, mesurées chez les toxicomanes suivis dans des
Centres Spécialisés de Soins aux Toxicomanes (CSST). Cette étude
de faisabilité a porté sur 32 sujets. La recherche de substances a
été effectuée sur des échantillons urinaires par des
techniques immunologiques et confirmée par des techniques
chromatographiques plus spécifiques (CPG-SM et CLHP-BD). Une concordance
complÚte n'est retrouvée que chez 13 des 32 participants.
NĂ©anmoins, on observe une trĂšs bonne concordance entre les
déclarations et les résultats analytiques pour les traitements de
substitution aux opiacés (méthadone et buprénorphine haut
dosage) : 88 % et pour les médicaments psychotropes prescrits pour la
prise en charge de la toxicomanie. En revanche, une sous-déclaration
notoire est constatée pour les substances illicites, notamment la
cocaïne (22 %) et les opiacés à usage non thérapeutique
(22Â %). Cette Ă©tude sera prochainement Ă©tendue Ă l'analyse
d'un grand nombre d'Ă©chantillons urinaires, en suivant les mĂȘmes
modalités, afin d'établir si de tels pourcentages de discordances
sont retrouvés de maniÚre significative
Association between road traffic accidents and drugs belonging to the antiseizure medications class: A pharmacovigilance analysis in VigiBase
International audienc
Trends in Fatal Poisoning Among Drug Users in France From 2011 to 2021
Importance The DRAMES (DĂ©cĂšs en Relation avec lâAbus de MĂ©dicaments Et de Substances) register is a database of drug-related deaths with the aim of identifying the psychoactive substances associated with and estimating the trends in these deaths. Our novel approach is based on the collection of data on all deaths for which toxicology experts have performed analyses. Objective To describe drug-related deaths in France and report trends over an 11-year period. Design, Setting, and Participants This case series used a national register to assess 4460 drug-related deaths that occurred from 2011 to 2021 in France. Data analyses were performed from January 1, 2012, to December 31, 2022. Main Outcomes and Measures Demographic characteristics; medical and substance abuse history; forensic autopsy findings; and toxicology reports. Results Among the 4460 deceased individuals (mean [SD] age, 37.8 [10.5] years), the mortality rate was highest among men (sex ratio, 4.4:1). Of the deaths involving a single or predominant drug, the legal substitution product, methadone, was the leading cause of death during the entire study period, ahead of heroinâ44.7% and 35.9% for methadone vs 15.8% and 21.8% for heroin in 2011 and 2021, respectively. Between 2011 and 2021, most of the drug-related deaths shifted from licit to illicit drugs, and statistically significant variations were found for buprenorphine, cocaine, heroin, methadone, and other licit opioids. Deaths related to polydrug use increased from 23.2% in 2011 to 30.6% in 2021. In this context, opioids remained associated with most deaths, with at least 1 opioid being involved in approximately 9 of 10 cases (85.9%) in 2021. However, the main trend was the dramatic increase in drug combinations with cocaine, from less than one-third of cases in 2011 (30.8%) to more than half in 2021 (57.8%). Conclusions and Relevance This case series assessment of 4460 drug-related deaths found that opioids used alone or in combination were the main contributor to drug-related deaths, despite having a lower prevalence than other drugs. This finding is similar to that of other countries; however, in France licit methadone was the leading cause of opioid-related deaths (ahead of heroin) during the study period. Deaths associated with use of cannabis, new psychoactive substances, and stimulants (including amphetamine-type stimulants and cocaine, especially in combination) have increased and should be closely monitored