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8 Communications depuis 2020
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FEBS 2023 - the 47th FEBS Congress, 08-12 juillet, Tours, France
Allouche, R., Hafeez, Z., Dary, A., Genay, M., Miclo, L.
Streptococcus thermophilus is a dairy starter granted “Generally Recognized as Safe” by the FDA and “Qualified Presumption of Safety” by EFSA. A significant part of the world's population ingests this bacterium when consuming fermented products. Some strains of S. thermophilus, either in the live or heat-inactivated state, and peptides released after shaving and hydrolysis of the surface proteins of some strains of this bacterium displayed anti-inflammatory activity in vitro (Allouche et al.,2022). S. thermophilus cells could undergo lysis during their passage through the digestive tract. Consequently, its intracellular proteins could be hydrolysed by endogenous proteases leading to the release of peptides. We hypothesized that peptides generated from digestion of intracellular protein of S. thermophilus might also contribute to its overall anti-inflammatory effect. Therefore, intracellular proteins from S. thermophilus CNRZ-21N strain were recovered after sonication. After fractionation by size exclusion chromatography, the resulting 3-10 kDa protein fraction was hydrolysed by Corolase PP, a mixture of pancreatic proteases. MS-MS analysis showed that most of the identified peptides belonged to the ribosomal proteins. The hydrolysed fraction showed anti-inflammatory activity on macrophagelike THP-1 cells inflamed by LPS since their secretion of IL-8 and IL-1β cytokines and expression level of Pro-IL-1β were reduced. The results suggest that the peptides released from a fraction of intracellular proteins of S. thermophilus after digestion by Corolase PP may contribute to the anti-inflammatory activity of this bacterium and could be used as a functional ingredient to prevent lowgrade inflammation.
5th Edition of Innovations in Food Science and Human Nutrition (IFHN-2022), 20-21 septembre, Barcelone, Espagne
Allouche, R., Hafeez, Z., Dary-Mourot, A., Genay, M., Miclo, L.
23ème Colloque du Club des Bactéries Lactiques, 08-10 juin, Rennes, France
Allouche, R., Hafeez, Z., Papier, F., Dary-Mourot, A., Genay, M., Miclo, L.
61st Society Of Toxicology annual meeting & ToxExpo, 21-27 mars, San Diego, États-Unis
Morel, C., Emond, C., Duca, R., Debaugnies, F., Borde, P., Paoli, J., Hardy, E., Van Nieuwenhuyse, A., Schroeder, H., Grova, N.
Valproic acid-exposed rat is widely recognized as a validated model to assess Autism Spectrum disorders (ASD-VPA model). However, this model had never been studied for a co-exposure to pollutants like brominated flame retardants (e.g. α-hexabromocyclododecane, α-HBCDD). Both compounds interact on the same xenobiotic metabolism pathway resulting for VPA in the formation of delta-4 VPA, a reactive metabolite known to induce hepatic toxicity. Before assessing the role of α-HBCDD as a factor of susceptibility in the ASD-VPA model, it was essential to characterize VPA pharmacokinetic in α-HBCDD-co-exposure context. The aim of this work was thus to assess the pharmaco- and toxicokinetic involving the VPA/α-HBCDD co-exposure in rat. A sub-acute oral dose of α-HBCDD in oil (100 ng/kg/day) was administered in Wistar female rats for 12 days followed by a single intraperitoneal VPA dose (IP, 500 mg/kg bw) at D12 or a daily oral VPA dose for 3 days (PO, 500 mg/kg bw/day, D10-12). Sequential blood samplings were carried out from 20 min to 18 h after the last VPA administration. The results showed that α-HBCDD did not influence the VPA kinetic independently of the administration mode. The consecutive PO administration of VPA for 3 days did not allow to reach the IP Cmax and was 3.75 times lower than the IP one. In parallel, the toxicokinetic of α-HBCDD was carried out using the same sequential time points. Comparable Cmax values were observed for α-HBCDD only or α-HBCDD-VPA exposed rats by IP whereas a 3-fold increase in α-HBCDD Cmax was highlighted in rats administered with VPA PO. Such discrepancy could suggest an inhibition of CYP3A4 by the delta-4 VPA when VPA is administered for 3 days. A lag time seems therefore to be required to inhibit the metabolic pathway of α-HBCDD. A similar protocol was then carried out to demonstrate the efficiency of VPA/α-HBCDD co-exposure in pregnant rats. This preliminary study enabled to valid the usefulness of the VPA model in a context of α-HBCDD co-exposure, and pointed out, for the first time, the ability of VPA to enhance the internal effective dose of α-HBCDD.
Colloque annuel de la Société Cerveau et Maladies Cérébrovasculaires 2021, 28 mai, Dématérialisé
Morel, C., Maguin Gaté, K., Christophe, A., Jubreaux, J., Paoli, J., Degiorgio, C., Bouillaud-Kremarik, P., Grova, N., Schroeder, H.
Introduction: Evidence is now growing that exposure to environmental pollutants during the critical period of early-life brain development may be a strong risk factor, contributing to the emergence of neurobehavioral disorders later in life. The present study aims at evaluating the developmental neurotoxicity of an early exposure to an environmental chemical of high concern for human health, hexabromocyclododecane (HBCDD), a persistent organobromine flame retardant, in comparison with VPA, a common anti-epileptic drug known to induce developmental disorders including teratogenicity and neurobehavioral disturbances. HBCDD is a brominated flame retardant added to foam materials as a technical mixture of 3 isomers with the α-one to be of most concern for human health. Nowadays, little is known about the neurotoxicity of this isomer. A previous study (Maurice et al., Toxicol. Teratol., 2015) highlighted that a daily exposure of rat pups to α-HBCDD during gestation and lactation (66 ng/kg/day) induced early disturbances in locomotor maturation, exploratory activity and level of anxiety later in life.
Material et Methods: In order to assess neurobehavioral impairments induced by a perinatal exposure to HBCDD or VPA in the F1 generation at different postnatal ages from PND1 to PND122, pregnant Wistar rats were divided into three groups: Control, VPA, and HBCDD. HBCDD-exposed rats were administered daily p.o. during gestation and lactation (GD0 to PND21) with 100 ng/kg/day of α-HBCDD isomer in oil, whereas the two other groups received the vehicle only. At GD12, VPA-treated rats received a single i.p. injection of VPA at a dose of 600 mg/kg whereas the two other groups were injected with the vehicle only. Pups were tested for their early behavioral development from PND3 to PND21 using a standardized test battery. Anxiety and social behavior were assessed at two time points (juvenile PND 41 and adult age PND 122) by using the elevated-plus-maze and the social recognition test.
Results: The present results point out the ability of both compounds to induce subtle behavioral disturbances that may be quite different between the two chemicals.
Conclusion: The results of the social recognition test associated with the measurements of the cytochrome oxydase activity and epigenetic changes in various brain regions, currently under progress, should provide us additional information on the impact of an early exposure to HBCDD or VPA on behavioral impairments later in life.
Séminaire de l'école doctorale SIReNa, 26 mars, Dématérialisé
Morel, C., Christophe, A., Maguin-Gaté, K., Jubreaux, J., Degiorgio, C., Bouillaud-Kremarik, P., Grova, N., Schroeder, H.
Evidence is now growing that early-life environmental pollutant exposure during the critical period of brain development may be an important risk factor, contributing to the emergence of neurobehavioral disorders later in life (Grova et al., 2019). In this context, our team previously highlighted that a daily exposure of rat pups to the α isomer of HBCDD, a brominated flame retardant largely added to polystyrene building materials, during gestation and lactation (66 ng/kg/day) induced disturbances in locomotor maturation, exploratory activity and level of anxiety over the first 6 weeks of postnatal life (Maurice et al., 2015). The present study therefore aims at evaluating the developmental neurotoxicity of an early exposure to this chemical that is considered as a compound of high concern for human health, in comparison with valproic acid (VPA), a common anti-epileptic drug known to induce developmental disorders and contribute to the emergence of autism spectrum disorders. HBCDD-exposed dams were administered daily p.o. from GD0 to PND21 with 100 ng/kg/day of α-HBCDD isomer in oil, whereas the two other groups received the vehicle only. At GD12, VPA-treated rats received a single i.p. injection of VPA at a dose of 600 mg/kg whereas the two other groups were injected with the vehicle only. Pups were tested for their early behavioral development from PND3 to PND21 using a standardized test battery. At PND21, brains were collected and cortex removed for further analysis. The results pointed out the ability of both compounds to induce subtle significant behavioral changes during the neurodevelopment with the reduction in the time spent to grasp a rotating grid in VPA-exposed pups at PND9-11 and the increase in the time to move back in the neogative geotaxis task in the HBCDD-treated rats at PND8-10. No significant modification in the olfactory discriminative test (PN9-PND11) has been observed among groups. Cortical protein expression was analyzed for the neuroinflammation and synaptic plasticity, demonstrating a significant increase in the level of glial fibrillary acidic protein (GFAP) associated with a diminution of synaptophysin in the VPA-treated pups whereas HBCDD-exposed rats showed only an increasing level of expression of GFAP. In conclusion, both results suggest the ability of both compounds to impair slightly the brain and behavior development of rat pups in a different way according to the chemicals. The measurements of the cytochrome oxydase activity in various brain regions, currently under progress, should provide us additional information on the impact of an early exposure to HBCDD or VPA on behavioral impairments later in life.
Journée doctorale virtuelle franco-allemande et transfrontalière : Biotechnologies et Sciences de la Vie, 10 novembre, dématérialisée
Allouche, R., Hafeez, Z., Dary-Mourot, A., Genay, M., Miclo, L.
Séminaire de l'École Doctorale SIReNa, 13 février, Nancy, France
Allouche, R., Hafeez, Z., Dary, A., Genay, M., Miclo, L.
Streptococcus thermophilus is widely used as a starter culture in the dairy industry and has been awarded generally recognized as safe status (GRAS) by the American Food and Drug Administration. Some strains of S. thermophilus display an anti-inflammatory activity in vitro (Junjua et al., 2016). Inflammation is a part of the regular host reaction to injury or infection caused by pathogens, damaged cells, irritants and allergens. However, the mechanism of action by which this bacterium modulates inflammatory response remains unclear. It has been shown that the hydrolysis of food proteins or endogenous proteins by some digestive proteases releases peptides with various biological activities. Such peptides can also be generated by the surface proteolytic system of Lactic Acid Bacteria (Hafeez et al., 2014) as S. thermophilus, which produces bioactive peptides from bovine caseins (Miclo et al., 2012). These peptides are inactive within the sequence of the parent protein and display their activity after a hydrolysis step. Thus, the assumption that peptides generated in the gastro-intestinal tract from hydrolysis of S. thermophilus surface or intracellular proteins could display an anti?inflammatory activity and contribute to the overall anti-inflammatory effect of the bacterium can be made. Therefore, it is interesting to explore the role of such peptides in the modulation of inflammation. In a first approach, this study aims to investigate the anti-inflammatory properties of hydrolysates genrated after hydrolysis by gastrointestinal enzymes of surface proteins of S. thermophilus. The method involves the recovery of bacterial surface polypeptides by shaving with pepsin. Supernatant obtained after shaving was analysed by RP-HPLC and showed the release of peptides. The next challenge constitutes evaluation in in vitro cell model of anti-inflammatory activity of the peptides obtained and the characterisation of these peptides by mass spectrometry. This study will lead to novel insights into the modulation of host inflammatory response through probable action of peptides obtained from S. thermophilus.