Smoking-induced long-lasting modifications of human platelet serotonin catabolism through a MAO epigenetic regulation

Postulating that serotonin, secreted from smoking-activated platelets, could be involved in smoking-induced vascular modifications, we studied 115 men distributed in smokers (S), former smokers (FS) and never smokers (NS). The platelet serotonin content was similar in S and NS but lower in FS. This was unexpected because the monoamine oxidase (MAO) activity, which catabolizes serotonin, was inhibited during smoking. However, the amount of platelet MAO was higher in S and FS than in NS. The persistent elevated MAO amount in FS prompted us to study the methylation of its gene promoter in an additional series of patients: it was markedly lower for S and FS vs. NS due to cigarette smoke-induced increase of nucleic acid demethylase activity. This smoking-induced demethylation of the MAO gene promoter, resulting in high MAO amount persisting long after quitting smoking, has cardiovascular consequences and could impact fields such as behavior, mental health, and cancer

Smoking Related Diseases: The Central Role of Monoamine Oxidase

Smoking is a major risk factor of morbidity and mortality. It is well established that monoamine oxidase (MAO) activity is decreased in smokers. Serotonin (5-HT), a major substrate for MAO that circulates as a reserve pool stored in platelets, is a marker of platelet activation. We recently reported that smoking durably modifies the platelet 5-HT/MAO system by inducing a demethylation of the MAO gene promoter resulting in high MAO protein concentration persisting more than ten years after quitting smoking. The present data enlarges the results to another MAO substrate, norepinephrine (NE), further confirming the central role of MAO in tobacco use-induced diseases. Thus, MAO could be a readily accessible and helpful marker in the risk evaluation of smoking-related diseases, from cardiovascular and pulmonary diseases to depression, anxiety and cancer. The present review implements the new finding of epigenetic regulation of MAO and suggests that smoking-induced MAO demethylation can be considered as a hallmark of smoking-related cancers similarly to other aberrant DNA methylations

Étude biochimique et génétique des anomalies de la voie sérotonine-mélatonine comme facteurs de vulnérabilité à l autisme

Les troubles du spectre autistique (TSA) sont définis par l association de troubles des interactions sociales, de troubles du langage et de comportements stéréotypés et intérêts restreints. Cette entité recouvre en réalité des situations cliniques très hétérogènes, tant par le spectre de sévérité des symptômes que par la variété des comorbidités et signes associés. Si l étiologie génétique semble prépondérante, les mécanismes moléculaires impliqués semblent complexes et hétérogènes, et les associations génotype-phénotype inconstantes. Une stratégie possible pour décomposer cette hétérogénéité clinique et génétique consiste à s appuyer sur des endophénotypes, ou phénotypes intermédiaires, pour définir des catégories plus homogènes sur le plan physiopathologique. Parmi les nombreux endophénotypes biologiques décrits dans les TSA, l augmentation de la sérotonine sanguine est l un des mieux documentés, mais les mécanismes en sont encore inconnus. Des déficits en mélatonine (qui est un dérivé de la sérotonine) ont également été rapportés par plusieurs études. L objectif de cette thèse était de caractériser les anomalies de la voie sérotonine-mélatonine dans les TSA, et d en étudier les mécanismes et les corrélats cliniques. L exploration exhaustive de la voie sérotonine-mélatonine à partir de prélèvements sanguins dans une grande cohorte de plus de 200 patients avec TSA et leurs apparentés a permis d estimer la prévalence de l hypersérotoninémie dans les TSA à 45%, et celle du déficit en mélatonine à environ 60%. Cette étude a mis en évidence des anomalies du catabolisme de la sérotonine ainsi que des anomalies de la synthèse de la mélatonine, et a ainsi permis de proposer des mécanismes biochimiques à ces deux endophénotypes. Les anomalies de synthèse de la mélatonine, qui pourraient s accompagner d une augmentation de la N-acétylsérotonine, ont été confirmées sur des échantillons de glandes pinéales et de tractus gastro-intestinal (sources majeures de mélatonine et de sérotonine de l organisme) issus de patients avec TSA. Les gènes impliqués dans la synthèse de la mélatonine (gènes codant pour les enzymes AANAT et ASMT) ont été étudiés dans les TSA, ainsi que dans des pathologies neurodéveloppementales connexes. Les anomalies de la synthèse de mélatonine pourraient être associées aux troubles du sommeil, fréquents chez les patients avec TSAAutism Spectrum Disorders (ASD) are defined by three core symptoms: social interaction impairments, language impairments, and stereotyped behavior and restricted interests. Beyond this definition lie extremely diverse clinical situations, in terms of symptoms severity as well as comorbidities and associated features. The aetiology of ASD is considered to be mostly genetic, but the molecular mechanisms involved seem to be complex and heterogeneous, and the genotype-phenotype associations elusive. One possible strategy for decomposing the clinical and genetic complexity is to focus on endophenotypes, or intermediate phenotypes, to define more homogeneous pathophysiological categories. Among many biological endophenotypes reported in ASD, the increase of blood serotonin is well documented but still unexplained. Deficits in melatonin (which chemically derives from serotonin) have also been described. The aim of this work was to characterize the impairments of the serotonin-melatonin pathway in ASD, and to address their mechanisms and clinical correlates. Based on a comprehensive assessment of the serotonin-melatonin pathway from blood samples in a large cohort of 200 patients with ASD and their relatives, the prevalence of hyperserotonemia in ASD was estimated to be 45%, and that of melatonin deficit about 60%. Impairments of serotonin catabolism were shown, as well as impairments of melatonin synthesis, thus providing biochemical mechanisms for both endophenotypes. Abnormal melatonin synthesis, which may involve an increase in N-acetylserotonin, was confirmed on pineal gland and gastro-intestinal tract samples (i.e. the major sources of melatonin and serotonin) from patients with ASD. The genes involved in melatonin synthesis (coding for AANAT and ASMT enzymes) were studied in ASD and in related neurodevelopmental disorders. Abnormal melatonin synthesis may be associated with sleep disorders, frequently observed in patients with ASDPARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF

Molecular organization of the human serotonin transporter at the air/water interface

AbstractThe serotonin transporter (SERT) is the target of several important antidepressant and psychostimulant drugs. It has been shown that under defined conditions, the transporter spread at the air/water interface was able to bind its specific ligands. In this paper, the interfacial organization of the protein has been assessed from dynamic surface pressure and ellipsometric measurements. For areas comprising between 10 400 and 7100 Å2/molecule, ellipsometric measurements reveal an important change in the thickness of the SERT film. This change was attributed to the reorientation of the transporter molecules from a horizontal to their natural predictive transmembrane orientation. The thickness of the SERT film at 7100 Å2/molecule was found to be approximately equal to 84 Å and coincided well with the theoretical value estimated from the calculations based on the dimensions of α-helices containing membrane proteins. These data suggest that the three-dimensional arrangement of the SERT may be represented as a box with lengths dz=83–85 Å and dy or dx=41–47 Å

Multifaceted Regulations of the Serotonin Transporter: Impact on Antidepressant Response

Serotonin transporter, SERT (SLC64A for solute carrier family 6, member A4), is a twelve transmembrane domain (TMDs) protein that assumes the uptake of serotonin (5-HT) through dissipation of the Na+ gradient established by the electrogenic pump Na/K ATPase. Abnormalities in 5-HT level and signaling have been associated with various disorders of the central nervous system (CNS) such as depression, obsessive-compulsive disorder, anxiety disorders, and autism spectrum disorder. Since the 50s, SERT has raised a lot of interest as being the target of a class of antidepressants, the Serotonin Selective Reuptake Inhibitors (SSRIs), used in clinics to combat depressive states. Because of the refractoriness of two-third of patients to SSRI treatment, a better understanding of the mechanisms regulating SERT functions is of priority. Here, we review how genetic and epigenetic regulations, post-translational modifications of SERT, and specific interactions between SERT and a set of diverse partners influence SERT expression, trafficking to and away from the plasma membrane and activity, in connection with the neuronal adaptive cell response to SSRI antidepressants

Intentional overdose with insulin: prognostic factors and toxicokinetic/toxicodynamic profiles

International audienc

Smoking Induces Long-Lasting Effects through a Monoamine-Oxidase Epigenetic Regulation

BACKGROUND: Postulating that serotonin (5-HT), released from smoking-activated platelets could be involved in smoking-induced vascular modifications, we studied its catabolism in a series of 115 men distributed as current smokers (S), never smokers (NS) and former smokers (FS) who had stopped smoking for a mean of 13 years. METHODOLOGY/PRINCIPAL FINDINGS: 5-HT, monoamine oxidase (MAO-B) activities and amounts were measured in platelets, and 5-hydroxyindolacetic acid (5-HIAA)--the 5-HT/MAO catabolite--in plasma samples. Both platelet 5-HT and plasma 5-HIAA levels were correlated with the 10-year cardiovascular Framingham relative risk (P<0.01), but these correlations became non-significant after adjustment for smoking status, underlining that the determining risk factor among those taken into account in the Framingham risk calculation was smoking. Surprisingly, the platelet 5-HT content was similar in S and NS but lower in FS with a parallel higher plasma level of 5-HIAA in FS. This was unforeseen since MAO-B activity was inhibited during smoking (P<0.00001). It was, however, consistent with a higher enzyme protein concentration found in S and FS than in NS (P<0.001). It thus appears that MAO inhibition during smoking was compensated by a higher synthesis. To investigate the persistent increase in MAO-B protein concentration, a study of the methylation of its gene promoter was undertaken in a small supplementary cohort of similar subjects. We found that the methylation frequency of the MAOB gene promoter was markedly lower (P<0.0001) for S and FS vs. NS due to cigarette smoke-induced increase of nucleic acid demethylase activity. CONCLUSIONS/SIGNIFICANCE: This is one of the first reports that smoking induces an epigenetic modification. A better understanding of the epigenome may help to further elucidate the physiopathology and the development of new therapeutic approaches to tobacco addiction. The results could have a larger impact than cardiovascular damage, considering that MAO-dependent 5-HT catabolism is also involved in addiction, predisposition to cancer, behaviour and mental health

MOL#8268 1 Title Page. The natural mutation encoding a C-terminus truncated 5-HT 2B receptor is a gain of proliferative functions

Number of tables, 1 Number of references, 31 Number of words in the abstract, 230 Number of words in the Introduction, 744 Number of words in the Discussion. 1172 List of non-standard abbreviations receptor was identified in one patient diagnosed with pulmonary hypertension after intake of the anorexigen dexfenfluramine. Although reported to generate a lack of function, this C-terminus truncated 5-HT 2B receptor should somehow affect transduction pathways relevant to pulmonary hypertension. In our study, we investigated putative modifications in transduction of the R393X mutated 5-HT 2B receptor. In stably transfected cells, we confirmed the loss of IP 3 stimulation due to the G αq uncoupling, despite conserved ligand affinity between the normal and mutated receptors. We also observed a partial loss of nitric oxide synthase stimulation. However, the truncated R393X receptor presented (i) a strong gain of efficacy in cell proliferation as assessed by mitogen-activated protein kinase activity and thymidine incorporation, (ii) a preferential coupling to G α13 as shown by blocking antiserum, and (iii) an apparent lack of internalization upon agonist stimulation as observed by confocal microscopy. This work demonstrates that, in the 5-HT 2B receptor, the C-terminus including the palmitoylation and phosphorylation sites is absolutely required for proper transduction and internalization. For the first time, we show that the lack of C-terminus can generate a switch of coupling to G α13 , a reduced NO synthase activation and an increase in cell proliferation. All these modifications are relevant in pathophysiological vasoconstriction. MOL#8268 4 Introduction

Future development of apricot blossom blight under climate change in Southern France

International audienceClimate change will have several consequences for agro-systems, one of which will concern changes to the development of pathogens. Because of the losses it causes, particularly in organic farming, Monilinia laxa is an important pathogen affecting apricot crops. This study focuses on the consequences of climate change regarding blossom and twig blight (Monilinia laxa) of apricot. To achieve this, a Climatic Index of cumulated Blight risk (CIB) was built, to obtain the weighted sum of blossom blight incidence throughout the blooming period. An epidemiological model to calculate the incidence of blossom blight during every potentially infectious episode and based on biological parameters, was calibrated using a trap pot experiment where trees were placed in orchards and subject to various meteorological conditions. The CIB derived from this model was evaluated on field data, and was shown to be a robust and useful tool to predict the effects of climate change on the development of apricot blight. Then, using the CIB with a phenological model to predict blooming periods in the future, we estimated the risks of apricot blight until 2100 on four contrasted apricot cultivars and in three geographical zones under climate change scenarios RCP 4.5 and 8.5. This study revealed different effects of climate change depending on the cultivar and altitude. Apricot trees would bloom earlier (up to a difference of 50 days between 1950 and 2100) under climate change. Under the combined effects of these shifts of blooming period and changing climatic conditions, late cultivars such as Bergarouge might see a reduction in the risk of blossom blight (down to 31%) because of warmer but dryer blooming periods. Other varieties (e.g.: Bergeron) could experience an increase in this risk by up to 27% with a shift of the blooming period towards rainier conditions at the highest altitudes. The results of this study could be used to anticipate future changes as well as be used at present as a decision-support tool for farmers

Later cART Initiation in Migrant Men from Sub-Saharan Africa without Advanced HIV Disease in France

International audienceObjectiveTo compare the time from entry into care for HIV infection until combination antiretroviral therapy (cART) initiation between migrants and non migrants in France, excluding late access to care.MethodsAntiretroviral-naïve HIV-1-infected individuals newly enrolled in the FHDH cohort between 2002–2010, with CD4 cell counts &gt;200/μL and no previous or current AIDS events were included. In three baseline CD4 cell count strata (200–349, 350-499, ≥500/μL), we examined the crude time until cART initiation within three years after enrolment according to geographic origin, and multivariable hazard ratios according to geographic origin, gender and HIV-transmission group, with adjustment for baseline age, enrolment period, region of care, plasma viral load, and HBV/HBC coinfection.ResultsAmong 13338 individuals, 9605 (72.1%) were French natives (FRA), 2873 (21.4%) were migrants from sub-Saharan Africa/non-French West Indies (SSA/NFW), and 860 (6.5%) were migrants from other countries. Kaplan-Meier probabilities of cART initiation were significantly lower in SSA/NFW than in FRA individuals throughout the study period, regardless of the baseline CD4 stratum. After adjustment, the likelihood of cART initiation was respectively 15% (95%CI, 1–28) and 20% (95%CI, 2–38) lower in SSA/NFW men than in FRA men who had sex with men (MSM) in the 350-499 and ≥500 CD4 strata, while no difference was observed between other migrant groups and FRA MSM.ConclusionSSA/NFW migrant men living in France with CD4 &gt;350/μL at entry into care are more likely to begin cART later than FRA MSM, despite free access to treatment. Administrative delays in obtaining healthcare coverage do not appear to be responsible