22 research outputs found
Adaptation de la bactérie psychrotrophe Carnobacterium maltaromaticum LMA 28 au tractus digestif de mammifères
Contribution a l'etude ethnopharmacologique et etude pharmacologique d'Euphorbia hirta L. : proprietes psychotropes, analgesiques, anti-pyretiques et anti-inflammatoires
SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc
Contribution à l'étude ethnopharmacologique et étude pharmacologique d'Euphorbia hirta L. : propriétés psychotropes, analgésiques, anti-pyrétiques et anti-inflammatoires
The following procedures have been conducted : the bibliographical synthesis of the traditional therapeutic indications of Euphorbia hirta L. of previous botanical, toxicological, chemical and pharmacological studies, the verification of some of this data and the realisation of a pharmacological study initially orientad on the psychotropic properties. The botanical characteristics of Euphorbiaceae, the low toxicity of Euphorbia hirta L., the presence of the various chemical groups previously isolated (polyphenols,terpenes, organic acids, amino acids, saccharids, saponosids, inorganic salts), and the absence of alcaloids and cyanogentic by-products, have been confirmed. A mong the numerous traditional indications of E. hirta L. mentioned in literature (gastro-intestinal, genital, skin and mucosa, kidney and liver affections; cardio-respiratory troubles ; sedative, analgesic, febrifuge and anti-inflammatory properties), the study of psychotropic effects has resulted in the discovery of sedative effects beginning with 100 mg/Kg, dose-dependent, (forced exploration and free exploration tests on mice), and of light anxiolytic effects with low doses (25 and 12.5 mg/kg). The absence of hypnotic, neuroleptic, anti-depressive, anti_histaminic, anti_convulsivant and myorelaxant properties, as well the absence of affinity for benzodiazepine receptors (in vivo and in vitro techniques) enable to suggest a psychopharmacological profile such as non-benzodiazepine minor tranquilizer. Considering these results and because of the frequent coexistence of sedative effects and analgesic effects for E. hirta L., the following facts have been brought to light : a morphinometic central analgesic activity starting with 20mg/Kg and anti pyretic and anti-inflammatory effects in acute processes (100 mg/kg). The existence of a tolerance to sedative and analgesic effects and the absence of cross-tolerance with morphine have been proven. Taken orally E. hirta L. is efficient only after dissolution in a labrafil-type excipientOnt pu être menées de front la synthèse bibliographique des indications thérapeutiques traditionnelles conférées à Euphorbia Hirta L., des études botaniques, toxicologiques, chimiques et pharmacologiques antérieures, la vérification de certaines de ces données et la réalisation d'une étude pharmacologique initialement axée sur les propriétés psychotropes. Les caractéristiques botaniques des euphorbiaceae, la faible toxicité d'E. hirta L. (dl 50 de l'extrait aqueux, par voie i.p., chez la souris: 8,82 g/Kg) et la présence des différents groupes chimiques antérieurement isolés (polyphénols, terpènes, acides organiques et aminés, saccharides, saponosides, sels minéraux) ont pu être confirmées, ainsi que l'absence d'alcaloïdes et de dérivés cyanogénétiques. Parmi les nombreuses indications traditionnelles d'E. hirta L. mentionnées dans la littérature (affections gastro-intestinales, génitales, de la peau et des muqueuses, rénales, hépatiques; troubles cardio-respiratoires; propriétés sédatives, analgésiques, fébrifuges et anti-inflammatoires), l'étude des effets sédatifs dès 100 mg/kg, dose-dépendants (tests comportementaux contraignants et non contraignants réalisés sur la souris), ainsi que de légers effets anxiolytiques à faible dose (25 et 12,5 mg/kg). L'absence de propriétés hypnotiques, neuroleptiques, anti-dépressives, anti-histaminiques, anti-convulsivantes et myorelaxantes, ainsi que l'absence d'affinité pour les sites récepteurs aux benzodiazépines (techniques in vivo et in vitro), ont permis de suggérer un profil psychopharmacologique de type tranquillisants mineurs non benzodiazépiniques. De par ces résultats et en raison de la coexistence fréquente d'effets sédatifs avec des effets analgésiques par ailleurs mentionnés pour E. hirta L., il a été mis en évidence une activité analgésique centrale morphinomimétique des 20 mg/kg, des effets anti-pyrétiques et anti-inflammatoires dans les processus aigus (100 mg/kg). Ont été démontrées l'existence d'une tolérance à l'égard des effets sédatifs et analgésiques et l'absence de tolérence croisée avec la morphine. Par voie orale, E. hirta L. n'est efficace qu'après dissolution dans un excipient du type labrafi
Genotoxic and CYP 1A enzyme effects consecutive to the food transfer of oil spill contaminants from mussels to mammals
The transfer of polycyclic aromatic hydrocarbons (PAHs) from bivalves,
through the food chain to vertebrates was of concern. Our research aimed at
estimating potential effects for consumers resulting from the ingestion of
seafood contaminated by oil spill pollutants.
After the “Erika” wreck, mussels (Mytilus sp.) were collected
from sites of the Atlantic
coast impacted to various degrees by the oil slick and constituted
contaminated food for rats during 2 and 4 weeks. Genotoxic damage were
studied in rats by means of COMET assay carried out in liver, bone marrow
and peripheral blood. Biochemical and genomic effects such as the induction
of CYP 1A1 and the expression of cytochrome genes were measured in rat
livers.
The most sensitive biological parameter reflecting the transfer of
contaminants via the food appeared to be DNA breaks studied by means of the
COMET assay. Genotoxic damage, observed mainly in the liver, were rather
moderate and remained not persistent. This study underlined the
bioavailability of pollutants in fuel oil contaminated mussels for
consumers, and the complexity of the contamination consecutive to the oil
spill. The occurrence of related PAH compounds in addition to
non-substituted PAHs in fuel oils and mussels raised the question of their
implication in the registered effects
Age-related changes in regiospecific expression of Lipolysis Stimulated Receptor (LSR) in mice brain
International audienceThe regulation of cholesterol, an essential brain lipid, ensures proper neuronal development and function, as demonstrated by links between perturbations of cholesterol metabolism and neurodegenerative diseases, including Alzheimer's disease. The central nervous system (CNS) acquires cholesterol via de novo synthesis, where glial cells provide cholesterol to neurons. Both lipoproteins and lipoprotein receptors are key elements in this intercellular transport, where the latter recognize, bind and endocytose cholesterol containing glia-produced lipoproteins. CNS lipoprotein receptors are like those in the periphery, among which include the ApoB, E binding lipolysis stimulated lipoprotein receptor (LSR). LSR is a multi-meric protein complex that has multiple isoforms including α and α', which are seen as a dou-blet at 68 kDa, and β at 56 kDa. While complete inactivation of murine lsr gene is embryonic lethal, studies on lsr +/-mice revealed altered brain cholesterol distribution and cognitive functions. In the present study, LSR profiling in different CNS regions revealed regiospecific expression of LSR at both RNA and protein levels. At the RNA level, the hippocampus, hypo-thalamus, cerebellum, and olfactory bulb, all showed high levels of total lsr compared to whole brain tissues, whereas at the protein level, only the hypothalamus, olfactory bulb, and retina showed the highest levels of total LSR. Interestingly, major regional changes in LSR expression were observed in aged mice which suggests changes in cholesterol homeostasis in specific structures in the aging brain. Immunocytostaining of primary cultures of mature murine neurons and glial cells isolated from different CNS regions showed that LSR is expressed in both neurons and glial cells. However, lsr RNA expression in the cerebellum was predominantly higher in glial cells, which was confirmed by the immunocytostaining profile of cerebellar neurons and glia. Based on this observation, we would propose that LSR in glial cells may play a key role in glia-neuron cross talk, particularly in the feedback control of cholesterol synthesis to avoid cholesterol overload in neurons and to maintain proper functioning of the brain throughout life
Expression profile of hepatic genes related to lipid homeostasis in LSR heterozygous mice contributes to their increased response to high-fat diet
Perturbations of lipid homeostasis manifest as dyslipidemias and obesity, which are significant risk factors for atherosclerosis and diabetes.Lipoprotein receptors in the liver are key players in the regulation of lipid homeostasis, among which the hepatic lipolysis stimulated lipoprotein receptor, LSR, was recently shown to play an important role in the removal of lipoproteins from the circulation during the postprandial phase. Since heterozygous LSR+/- mice demonstrate moderate dyslipidemia and develop higher body weight gain in response to high-fat diet compared with littermate LSR+/+ controls, we questioned if LSR heterozygosity could affect genes related to hepatic lipid metabolism.A target-specific qPCR array for 84 genes related to lipid metabolism was performed on mRNA isolated from livers of 6 mo old female LSR+/- mice and LSR+/+ littermates following a 6 wk period on a standard (STD) or high-fat diet (60% kcal, HFD). Of the 84 genes studied, 32 were significantly downregulated in STD-LSR+/- mice compared with STD-LSR+/+, a majority of which were PPARα target genes involved in lipid metabolism and transport, and insulin and adipokine-signaling pathways. Of these 32 genes, 80% were also modified in HFD-LSR+/+, suggesting that STD-LSR+/- mice demonstrated a predisposition towards a "high-fat"-like profile, which could reflect dysregulation of liver lipid homeostasis.Since similar profiles of genes were affected by either LSR heterozygosity or by high-fat diet, this would suggest that LSR is a key receptor in regulating hepatic lipid homeostasis, and whose downregulation combined with a Western-type diet may increase predisposition to diet-induced obesity
Improved Neuroprotection Provided by Drug Combination in Neurons Exposed to Cell-Derived Soluble Amyloid-beta Peptide
International audienceOligomeric amyloid-beta (A beta) peptide contributes to impaired synaptic connections and neurodegenerative processes, and as such, represents a primary therapeutic target for Alzheimer's disease (AD)-modifying approaches. However, the lack of efficacy of drugs that inhibit production of A beta demonstrates the need for a better characterization of its toxic effects, both on synaptic and neuronal function. Here, we used conditioned medium obtained from recombinant HEK-A beta PP cells expressing the human amyloid-beta protein precursor (A beta-CM), to investigate A beta-induced neurotoxic and synaptotoxic effects. Characterization of A beta-CM revealed that it contained picomolar amounts of cell-secreted A beta in its soluble form. Incubation of primary cortical neurons with A beta-CM led to significant decreases in synaptic protein levels as compared to controls. This effect was no longer observed in neurons incubated with conditioned medium obtained from HEK-A beta PP cells grown in presence of the B-secretase inhibitor, Semagacestat or LY450139 (LY-CM). However, neurotoxic and pro-apoptotic effects of A beta-CM were only partially prevented using LY-CM, which could be explained by other deleterious compounds related to chronic oxidative stress that were released by HEK-A beta PP cells. Indeed, full neuroprotection was observed in cells exposed to LY-CM by additional treatment with the antioxidant resveratrol, or with the pluripotent n-3 polyunsaturated fatty acid docosahexaenoic acid. Inhibition of A beta production appeared necessary but insufficient to prevent neurodegenerative effects associated with AD due to other neurotoxic compounds that could exert additional deleterious effects on neuronal function and survival. Therefore, association of various types of protective agents needs to be considered when developing strategies for AD treatment
Maintenance of membrane organization in the aging mouse brain as the determining factor for preventing receptor dysfunction and for improving response to anti-Alzheimer treatments.
Although a major risk factor for Alzheimer's disease (AD), the "aging" parameter is not systematically considered in preclinical validation of anti-AD drugs. To explore how aging affects neuronal reactivity to anti-AD agents, the ciliary neurotrophic factor (CNTF)-associated pathway was chosen as a model. Comparison of the neuroprotective properties of CNTF in 6- and 18-month old mice revealed that CNTF resistance in the older animals is associated with the exclusion of the CNTF-receptor subunits from rafts and their subsequent dispersion to non-raft cortical membrane domains. This age-dependent membrane remodeling prevented both the formation of active CNTF-receptor complexes and the activation of prosurvival STAT3 and ERK1/2 pathways, demonstrating that age-altered membranes impaired the reactivity of potential therapeutic targets. CNTF-receptor distribution and CNTF signaling responses were improved in older mice receiving dietary docosahexaenoic acid, with CNTF-receptor functionality being similar to those of younger mice, pointing toward dietary intervention as a promising adjuvant strategy to maintain functional neuronal membranes, thus allowing the associated receptors to respond appropriately to anti-AD agents
Inhibitory action of benzo[α]pyrene on hepatic lipoprotein receptors in vitro and on liver lipid homeostasis in mice.
Dyslipidemia associated with obesity often manifests as increased plasma LDL and triglyceride-rich lipoprotein levels suggesting changes in hepatic lipoprotein receptor status. Persistent organic pollutants have been recently postulated to contribute to the obesity etiology by increasing adipogenesis, but little information is available on their potential effect on hepatic lipoprotein metabolism.The objective of this study was to investigate the effect of the common environmental pollutant, benzo[α]pyrene (B[α]P) on two lipoprotein receptors, the LDL-receptor and the lipolysis-stimulated lipoprotein receptor (LSR) as well as the ATP-binding cassette transporter A1 (ABCA1) using cell and animal models.LSR, LDL-receptor as well as ABCA1 protein levels were significantly decreased by 26-48% in Hepa1-6 cells incubated (<2 h) in the presence of B[α]P (≤1 µM). Real-time PCR analysis and lactacystin studies revealed that this effect was due primarily to increased proteasome, and not lysosomal-mediated degradation rather than decreased transcription. Furthermore, ligand blots revealed that lipoproteins exposed to 1 or 5 µM B[α]P displayed markedly decreased (42-86%) binding to LSR or LDL-receptor. B[α]P-treated (0.5 mg/kg/48 h, i.p. 15 days) C57BL/6J mice displayed higher weight gain, associated with significant increases in plasma cholesterol, triglycerides, and liver cholesterol content, and decreased hepatic LDL-receptor and ABCA1 levels. Furthermore, correlational analysis revealed that B[α]P abolished the positive association observed in control mice between the LSR and LDL-receptor. Interestingly, levels of other proteins involved in liver cholesterol metabolism, ATP-binding cassette transporter G1 and scavenger receptor-BI, were decreased, while those of acyl-CoA:cholesterol acyltransferase 1 and 2 were increased in B[α]P-treated mice.B[α]P demonstrates inhibitory action on LSR and LDL-R, as well as ABCA1, which we propose leads to modified lipid status in B[α]P-treated mice, thus providing new insight into mechanisms underlying the involvement of pollutants in the disruption of lipid homeostasis, potentially contributing to dyslipidemia associated with obesity