Les dommages au nerf optique (neuropathie optique) peuvent entraîner la perte permanente de la vision ou la cécité causée par la mort des cellules ganglionnaires de la rétine (CGR). Nous avons identifié qu’une surproduction de l'anion superoxyde constitue un événement moléculaire critique précédant la mort cellulaire induite par des lésions. Récemment, Suarez-Moreira et al (JACS 131:15078, 2009) ont démontré que la vitamine B12 peut capter l’anion superoxyde aussi efficacement que l’enzyme superoxyde dismutase. La carence en vitamine B12 peut conduire à une neuropathie optique causée par des mécanismes inconnus. Nous avons étudié la relation entre la captation de superoxyde par la cyanocobalamine (forme de vitamine B12 la plus abondante) et ses propriétés neuroprotectrices dans les cellules neuronales. La cyanocobalamine aux concentrations de 10 μM et 100 μM a réduit le taux de production de superoxyde respectivement par 34% et 79% dans les essais sans-cellule. Dans les cellules RGC-5 traités avec la ménadione, les concentrations de cyanocobalamine supérieures à 10 nM ont diminué l’anion superoxyde à des valeurs similaires à celles traitées par PEG-SOD. La cyanocobalamine aux concentrations de 100 μM et 1 μM a réduit la mort des cellules RGC-5 exposées à la ménadione par 20% et 32%, respectivement. Chez les rats avec section du nerf optique unilatérale, une dose intravitréenne de 667 μM de cyanocobalamine a réduit le nombre de CGRs exposées au superoxyde. Cette dose a également augmenté le taux de survie des CGRs comparativement aux rats injectés avec la solution témoin. Ces données suggèrent que la vitamine B12 peut être un neuroprotecteur important, et sa carence nutritionnelle pourrait causer la mort de CGRs. La vitamine B12 pourrait aussi potentiellement être utilisée comme une thérapie pour ralentir la progression de la mort CGR chez les patients avec les neuropathies optiques caractérisés par une surproduction de superoxyde. / Damage to the optic nerve (optic neuropathy) can result in permanent loss of vision or blindness through retinal ganglion cell (RGC) death. Our prior work identified a burst of superoxide anion as a critical molecular event in RGCs prior to injury-induced cell death. Recently, Suarez-Moreira et al (JACS 131:15078, 2009) demonstrated that vitamin B12 scavenges superoxide as effectively as superoxide dismutase. Vitamin B12 deficiency can lead to optic neuropathy through unknown mechanisms. We investigated the relationship between superoxide scavenging by cyanocobalamin, the most abundant vitamin B12¬¬ vitamer, and its neuroprotective properties in neuronal cells. Cyanocobalamin at concentrations of 10 μM and 100 μM reduced the rate of superoxide generation by 34% and 79% in cell free assays, respectively. In menadione-treated RGC-5 cells, cyanocobalamin concentrations above 10 nM scavenged superoxide anion similar to those treated with pegylated-SOD. Cyanocobalamin at concentrations of 100 μM and 1 mM reduced RGC-5 cell death from menadione by 20% and 32%, respectively. In rats with unilateral optic nerve transection, a single intravitreal dose of 667 μM cyanocobalamin significantly reduced the number of RGCs with superoxide. This dose also increased RGC survival rate compared to rats injected with saline control. These data suggest that vitamin B¬¬12 may be an important neuroprotectant, which could cause death of RGCs when depleted in nutritional deficiency. Vitamin B12 could also potentially be used as a therapy to slow progression of RGC death in patients with optic neuropathies characterized by overproduction of superoxide.

Background Colorectal cancer (CRC) is the second most common malignancy in developed countries. The mortality is high, with nearly half of patients dying from the disease. The primary treatment of CRC is surgery, and decisions about additional treatment with chemotherapy are based mainly on tumor stage. Novel prognostic markers that identify patients at high risk of recurrence and cancer-related death are needed. The development of CRC has been described in terms of two different pathways; the microsatellite instability (MSI) and chromosomal instability (microsatellite stable, MSS) pathway. More recently, the CpG island methylator phenotype (CIMP), characterized by frequent DNA hypermethylation, has been described as an alternative pathway of tumorigenesis. The event of DNA methylation is dependent on one-carbon metabolism, in which folate and vitamin B12 have essential functions. The purpose of this thesis was to study CIMP in CRC. The specific aims were to investigate the potential role of components of one-carbon metabolism as risk factors for this subgroup of tumors, and the prognostic importance of CIMP status, taking into consideration important confounding factors, such as MSI and tumor-infiltrating T cells. Methods CRC cases and referents included in the Northern Sweden Health and Disease Study (NSHDS, 226 cases and 437 referents) and CRC cases in the Colorectal Cancer in Umeå Study (CRUMS, n=490) were studied. Prediagnostic plasma concentrations of folate and vitamin B12 were analyzed in NSHDS. In both study groups, CIMP status was determined in archival tumor tissue by real-time quantitative PCR using an eight-gene panel (CDKN2A, MLH1, CACNA1G, NEUROG1, RUNX3, SOCS1, IGF2 and CRABP1). MSI screening status and the density of tumor-infiltrating T cells were determined by immunohistochemistry.  Results An inverse association was found between plasma concentrations of vitamin B12 and rectal, but not colon, cancer risk. We also found a reduced risk of CIMP-high and CIMP-low CRC in study subjects with the lowest levels of plasma folate. We found that patients with CIMP-low tumors in both NSHDS and CRUMS had a poorer prognosis compared with CIMP-negative, regardless of MSI screening status. We also found that MSS CIMP-high patients had a poorer prognosis compared with MSS CIMP-negative. The density of tumor-infiltrating T cells and CIMP status were both found to be independent predictors of CRC patient prognosis. A particularly poor prognosis was found in patients with CIMP-low tumors poorly infiltrated by T cells. In addition, the density of T cells appeared to be more important than MSI screening status for predicting CRC patient prognosis. Conclusion Rather than being one disease, CRC is a heterogeneous set of diseases with respect to clinico-pathological and molecular characteristics. We found that the association between risk and plasma concentration of vitamin B12 and folate depends on tumor site and CIMP status, respectively. Patient prognosis was found to be different depending on CIMP and MSI screening status, and the density of tumor-infiltrating T cells.

Made available in DSpace on 2014-08-20T13:32:50Z (GMT). No. of bitstreams: 1 tese_vinicius_coitinho_tabeleao.pdf: 864855 bytes, checksum: 84b7f4f2dc9f4bc7025094cdcd06be5f (MD5) Previous issue date: 2014-02-28 / Dairy cows are expected to perform maximum of their productive capacity, especially during the transition period (three weeks before and up to three weeks after calving). This period is characterized by intense changes in metabolism which cause a negative energy balance. This fact generates a period of typical weight loss, which has been correlated with insulin resistance, once the available glucose is destined for lactose synthesis, which in turn is responsible, in part, for milk production levels. Moreover, during lactation there are several managements that impairs animals health. If not executed properly, can cause trauma and predisposition for infections, especially of the mammary gland, because this gland is heavily manipulated and has contact with potentially infectious agents. From a entrance doorway, these agents can infect the gland and cause mastitis, which may be clinical (with clinical signs) or subclinical (without clinical signs). In situations of metabolic disorders or in cases of mastitis, the milk production may be affected. Therefore, there is a constant search for technologies that can minimize these disorders and assist the production systems. Our objective was to investigate the effects of combining butaphosphan and cyanocobalamin on the glycemic metabolism in healthy dairy cows in the postpartum period and their effects on the mammary gland recovery in dairy cows after clinical mastitis treatment. Thus, our study was stratified into two assumptions: 1) the use of the association of butaphosphan and cyanocobalamin enhances peripheral insulin resistance in dairy cows, providing greater amounts of glucose for milk production, 2) the supplementation with butaphosphan and cyanocobalamin facilitates mammary gland recovery in dairy cows affected by mastitis. In experiment 1, animals receiving repeated doses of butaphosphan and cyanocobalamin had greater weight loss and increased (P<0.05) of the activities of the enzymes aspartate aminotransferase and creatine kinase. Moreover, at end of treatment had an increase (P<0.05) in glucose concentration in treated animals when compared to the beginning of study. In experiment 2, the comparative analyzes between mild and moderate mastitis did not differ (P>0.05) in any parameters. The animals treated with butaphosphan and cyanocobalamin had lower (P<0.05) somatic cell count after the third application. However, the concentrations of glucose, albumin, TPP, NEFA and the chemical and physical components of milk did not differ (P>0.05) among groups. In concusion, the combination of butaphosphan and cyanocobalamin shows promising results as a source of nutrient that allows intensify physiological reactions mainly dependent phosphorylation. / As vacas leiteiras são desafiadas a desempenhar o máximo da sua capacidade produtiva, principalmente, durante o período de transição (três semanas anteriores e três semanas posteriores ao parto). Este período é caracterizado por intensas mudanças no metabolismo que causam um balanço energético negativo. Este fato gera uma perda de peso característica do período, que tem sido correlacionada com a resistência periférica à insulina, haja vista, que a glicose disponível esta sendo destinada para síntese de lactose, que por sua vez é responsável, parcialmente, pelo volume de leite produzido. Além disso, durante a lactação há vários manejos que podem oferecer risco à saúde dos animais, caso não sejam executados adequadamente, causando traumas e predispondo o animal a infecções, especialmente, da glândula mamária, já que ela é intensamente manipulada e tem contato com vários agentes potencialmente infecciosos. A partir de uma porta de entrada estes agentes podem infectar a glândula causando a mastite, que pode se apresentar na forma clínica (com presença de sinais clínicos), ou subclínica (sem sinais clínicos). Nas situações de desequilíbrio metabólico, ou em casos de mastite, a produção de leite pode ser prejudicada. Diante disso, há uma busca constante por tecnologias que possam minimizar estes transtornos e auxiliar os sistema de produção. Nosso objetivo foi verificar o efeito da associação de butafosfan e cianocobalamina sobre o metabolismo glicêmico de vacas leiteiras saudáveis no período pós-parto, além dos seus efeitos sobre a recuperação da glândula mamária em vacas leiteiras após o tratamento de mastite clínica. Para tanto, nosso estudo foi estratificado em dois trabalhos com as seguintes hipóteses: 1) a utilização da associação de butafosfan e cianocobalamina pode intensificar a resistência à insulina periférica, disponibilizando maior quantidade de glicose para a produção de leite em vacas leiteiras; 2) a suplementação da associação de butafosfan e cianocobalamina pode auxiliar na recuperação da glândula mamária de vacas leiteiras, após o tratamento da mastite clínica. No experimento 1, os animais que receberam sucessivas doses de butafosfan e cianocobalamina tiveram maior perda de peso e aumento (P<0,05) das atividades das enzimas aspartato amino transferase e creatinoquinase. Além disso, ao final do tratamento houve aumento (P<0,05) dos níveis glicêmicos nos animais tratados, quando comparados ao inicio. No experimento 2, as análises comparativas entre as mastites, leve e moderada, não diferiram em nenhum dos parâmetros (P>0,05). Os animais tratados com butafosfan e cianocobalamina apresentaram menor (P<0,05) contagem de células somáticas após a terceira aplicação. Entretanto, os níveis de glicose, albumina, PPT, AGNES e os componentes químicos e físicos do leite não diferiram (P>0,05) entre os grupos. Nessas condições de estudo, podemos concluir que a associação de butafosfan e cianocobalamina apresenta resultados promissores como fonte de nutriente que permite intensificar as reações fisiológicas, principalmente, as dependentes de fosforilação.

The aim of this thesis was to study the biomarker homocysteine and other novel potential vascular risk factors for dementia. In an out-patient based study of a cohort of 926 consecutive subjects referred to our Memory Unit during 1996―2000, serum-folate was lower and total plasma homocysteine (tHcy) and serum methyl malonate were higher in subjects being prescribed with B12. In the subgroup diagnosed with dementia and with a positive family history of dementia, tHcy was higher than in the subgroup diagnosed as non-demented. It is necessary to supplement subjects with vitamin B12 deficiency with B12, but our results indicate that it is not sufficient with B12 alone because this gives rise to intracellular folate deficiency. We also found indications of a genetic component in dementia because tHcy was higher in the group with a positive family history of dementia. These findings prompted further studies of homocysteine metabolism. The frequency of mutations in the gene for folate receptor-α (FOLR-1), and the fibrinolytic pattern in dementia and non-dementia were studied in the two cohorts DGM (n=300) and AS (n=389). The DGM cohort is a consecutive series of subjects attending our Memory Care Unit for investigation of suspected cognitive problems or dementia between 2003 - 2007. The AS (= active seniors) cohort comprises retired, apparently healthy subjects from central Sweden, actively participating in study circles. A rare haplotype in the FOLR-1, with mutations in two nearby loci, was discovered, possibly associated with lower serum-folate and higher tHcy concentrations and was more frequent in the DGM group. The transport of folate to the CSF was studied in the DGM-cohort. Dementia with a vascular component was associated with a lower CSF to serum folate ratio indicative of reduced transport of folate to the CSF and further to the brain. The vascular endothelial derived fibrinolytic markers tPA, tPA/PAI-1-complex, and vWF were not only higher in vascular dementia (VaD) but also in Alzheimer’s Disease (AD) when compared to the AS group. The impaired fibrinolytic activity in both vascular dementia and in AD is a novel finding, signifying a vascular component in the development of dementia. In conclusion we found that both hereditary and nutritional background factors were linked to dementia and furthermore that a dysregulated fibrinolysis was linked to both VaD and AD.

Cells must regulate their metabolism in order to grow, adapt to changes in nutrient availability and maintain homeostasis. Flux, or the turnover of metabolites, through the metabolic network can be regulated at the allosteric and transcriptional levels. While study of allosteric regulation is limited to biochemical examination of individual proteins, transcriptional control of metabolism can be explored at a systems level. We endeavored to elucidate transcriptional mechanisms of metabolic flux regulation in the model organism Caenorhabditis elegans (C. elegans). We also worked to create a visual tool to explore metabolic pathways that will support future efforts in the research of metabolic gene regulation. C. elegans is a small, free-living nematode that feeds on bacteria and experiences a high level of diversity in nutrient level and composition. Previously, we identified a mechanism by which the essential cofactor, vitamin B12, regulates the expression of genes involved in the degradation of propionate, referred to as B12‑mechanism‑I. This mechanism functions to prevent the toxic accumulation of propionate and requires the TFs NHR-10 and NHR-68. Using genetic screens as well as transcriptomic and metabolomic approaches, we discover a second mechanism by which vitamin B12 regulates metabolic gene expression: B12-mechanism-II. Unlike B12-mechanism-I, B12-mechanism-II is independent of propionate, requires the transcription factor NHR-114 and functions to maintain the metabolic activity of the Methionine/S-adenosylmethionine cycle in a tightly regulated regime. We also present WormPaths, an online resource that allows visualization of C. elegans metabolic pathways and enables metabolic pathway enrichment of user-uploaded transcriptomic data.

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Bakgrund: Akne är en av de vanligaste dermatologiska sjukdomarna och drabbar nästan alla människor under puberteten. Sjukdomen kan även fortsätta eller utvecklas i vuxen ålder där prevalensen av akne är högre bland kvinnor. Vid måttlig till svår akne förekommer inflammatoriska lesioner i ansikte och på övre bål som ofta lämnar ärr vid läkning. Isotretinoin (Iso) är det mest effektiva läkemedlet mot akne men kommer med många besvärliga och allvarliga biverkningar. Utifrån två fallpresentationer verkar Iso kunna påverka kroppens folatstatus negativt. Folat är ett essentiellt vitamin som har en viktig roll i DNA-syntesen och metabolismen av aminosyror. Syfte: Syftet med litteraturstudien var att undersöka om behandling med Iso har negativ effekt på kroppens folatstatus. Vid undersökning av detta söktes följande frågor att besvaras: Sänker Iso kroppens folatstatus? Ökar Iso homocysteinnivåerna i plasma? Sänker Iso kroppens B12-status? Metod: Arbetet har utförts genom systematisk litteratursökning i Pubmed och Scopus under januari och februari 2021. I båda databaserna har fyra olika fritextsökningar genomförts med isotretinoin som bestående sökord vidare tillsammans med folic acid, folate, homocysteine och vitamin B12. Elva artiklar har inkluderats för analys. Resultat: Effekten av Iso på kroppens folatstatus undersöktes i tio studier och i sex av dessa studier observerades signifikant minskade serumfolatnivåer. Homocysteinnivåer undersöktes i tio studier och i åtta av dessa observerades ökade homocysteinnivåer efter behandling med Iso. Åtta studier undersökte förändringar i serumkoncentrationen av B12 vid behandling med Iso och i tre av dessa studier observerades signifikant minskande B12-nivåer. Slutsats: Utifrån resultatet går det att tolka att omsättningen av folat och B12 kan ha ökat vid stigande homocysteinnivåer. Tillskott av folsyra och B12 kan vara att rekommendera till patienter med akne som behandlas med Iso och där homocysteinnivåerna i plasma stiger. Studier med längre behandlingsperiod bör utföras för att kunna avgöra hur en fullständig behandling med Iso påverkar vitaminstatusen för folat och B12. / Background: Acne is one of the most common dermatological diseases generally affecting people going through puberty. The prevalence of adult acne is increasing and especially among women. Clinical symptoms of acne in moderate and severe cases are inflammatory lesions located in the face and upper body that can often cause scarring. Isotretinoin (Iso) is the most effective therapeutic drug against acne but has many side-effects. Iso appears to adversely affect the body's folate status according to two case presentations. Folate is an essential vitamin and has an important role in DNA synthesis and amino acid metabolism. Aim: The aim of the literature study was to examine if treatment with Iso has a negative effect on the body's folate status. Following questions were searched to be answered: Does Iso lower the body's folate status? Dose Iso increase plasma homocysteine levels? Does Iso lower the body's vitamin B12 status?Method: Eleven articles examining the effect of Iso treatment on folate status, homocysteine and B12 levels were collected from a literature search in Pubmed and Scopus during January and February 2021. Four different free text searches were carried out with isotretinoin as the consisting key word together with folic acid, folate, homocysteine ​​and vitamin B12. Results: The effect of Iso on the body's folate status was examined by ten studies and in six of these studies significantly reduced serum folate levels were observed. Homocysteine levels were examined in ten studies and in eight of these were increased homocysteine levels observed after treatment with Iso. Eight studies examined changes in the serum concentration of B12 and in three of these studies significantly decreased B12 levels were observed after treatment with Iso. Conclusion: The results give an indication that the turnover of folate and B12 may have increased with rising homocysteine plasma levels. Supplements of folic acid and B12 may be recommended for patients undergoing treatment with Iso if plasma homocysteine levels are rising during treatment. Studies with a longer treatment period with Iso need to be done to determine how a complete treatment with Iso affects folate and B12 status.

<p>Prema podacima iz 2011 godine, u Srbiji je približno 630 000 ljudi (8,6%) obolelo od dijabetes melitus-a, a procenjuje se da će taj broj porasti na 730 000 (10,2%) do 2030 godine. Preko 90% obolelih ima tip 2 dijabetes melitus (T2DM). Prva linija medikamentne terapije predstavljaju bigvanidi čiji je najznačajniji predstavnik metformin. Prema literaturnim podacima, u oko 10-30% sluĉajeva, kontinuirana upotreba metformina ima za posledicu smanjenu intestinalnu apsorpciju vitamina B12. Tačan patofiziolo&scaron;ki mehanizam koji dovodi do metforminom indukovane malapsorpcije vitamina B12 nije u potpunosti ispitan i poznat i postoji nekoliko aktuelnih teorija s ciljem obja&scaron;njenja ovog kompleksnog problema. Cilj rada je bio utvrđivanje nivoa, dinamike, trenda i učestalosti promena vitamina B12, holotranskobalamina (B12 aktiv), homocisteina i folne kiseline tokom kontinuirane primene metformina tokom godinu dana. Studija praćenja je sprovedena u Centru za laboratorijsku medicinu a u saradnji sa Klinikom za endokrinologiju, dijabetes i bolesti metabolizma, Kliničkog centra Vojvodine. Ovom studijom je obuhvaćeno 50 ispitanika obolelih od T2DM a u momentu uvođenja metformina. Svim ispitanicima je određivana koncentracija vitamina B12, B12 aktiva, homocisteina i folne kiseline, u momentu uvođenja terapije kao i nakon 4, 8 i 12 meseci primene metformina. Za dvanaest meseci kontinuirane primene metformina, utvrđen je kontinuirani pad i redukcija vrednosti ukupnog vitamina B12 za 25.29 %, odnosno vrednosti B12 aktiva za 23.26 %. U toku ispitivanja, utvrđen je kontinuirani trend porasta vrednosti homocisteina u krvi, s statistički značajnim porastom vrednosti homocisteina nakon osam meseci primene metformina. Po&scaron;av&scaron;i od predpostavki da metformin istovremeno blokira apsorpciju vitamina B12 u gastrointestinalnom traktu kao i raspoloživost iz postojećih, tkivnih rezervi, zatečene količine ovog vitamina u ciljnim ćelijama se postepeno redukuju i tro&scaron;e, rezultujući krajnjem snižavanju nivoa metabolički aktivnih oblika kobalamina, te posledičnoj akumulaciji homocisteina kako u ćelijskom, tako i u vanćelijskom prostoru. Na osnovu dobijenih rezultata ispitivanja može se predložiti opservacija nivoa ukupnog vitamina B12 i homocisteina u krvi pre uvođenja metformina u terapiju tipa 2 dijabetes melitusa kao i dvanaest meseci nakon toga. Na osnovu nivoa jednogodi&scaron;njeg pada koncentracija ukupnog vitamina B12, porasta koncentracija homocisteina, kao i drugih kliničkih i laboratorijskih parametara, može se razmatrati opcija uvođenja supstitucione terapije vitaminom B12 ili dalja opservacija nivoa vitamin B12 u krvi i ćelijskom prostoru.</p> / <p>According to data from 2011, in Serbia, approximately 630.000 people (8.6%) were diagnosed with diabetes mellitus, and it is estimated that this number will increase to 730.000 (10.2%) by 2030. Over 90% are type 2 diabetes mellitus (T2DM) patients. The first line of medication therapy is metformin. According to the literature data, in about 10-30% of cases, continuous use of metformin causes impared intestinal absorption of vitamin B12. The exact pathophysiological mechanism leading to metformin induced malabsorption of vitamin B12 has not been fully known, and there are several current theories to explain this complex problem. The aim of this study was to determine the level, dynamics, trend and frequency of changes in blood levels of total vitamin B12, holotranscobalamin (B12 active), homocysteine and folic acid during continuous application of metformin, over a year. The study was carried out at the Center of Laboratory Medicine in cooperation with the Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Vojvodina. This study included 50 T2DM patients at the time of the introduction of metformin therapy. Levels of vitamin B12, holotranscobalamin, homocysteine and folic acid are determined before and after 4, 8 and 12 months of metformin administration, to all subjects. After a year of metformin use, the level of total vitamin B12 has been reduced by 25.29%, as well as holotranskobalamin by 23.26%. During the study, a continuous elevation of homocysteine levels was determined, with statistically significant increase in homocysteine values after eight months of metformin administration. Starting from the assumption that metformin blocks the absorption of vitamin B12 in the gastrointestinal tract as well as the availability of existing tissue reserves, the amount of this vitamin in the target cells is gradually reduced, resulting in an extremely low level of metabolically active forms of this vitamin and the consequent accumulation of homocysteine in intracellular and extracellular space. On the basis of the obtained test results, it may suggest observation of the level of total vitamin B12 and homocysteine prior to the introduction of metformin in T2DM therapy and after one year thereafter. Based on the level of one-year decline of total vitamin B12 and the increase of homocysteine concentrations, as well as other clinical and laboratory parameters, substitution therapy with vitamin B12 or further monitoring of laboratory parameters of vitamin B12 metabolism may be proposed.</p>

L’enzyme méthionine synthase (MTR) catalyse la reméthylation de l’homocystéine en méthionine, le précurseur du donneur universel de groupe méthyle S-Adenosylmethionine (SAM), impliqué dans des mécanismes de régulations épigénétiques. Des polymorphismes de MTR sont associés à des défauts métaboliques et des défauts de développement embryonnaire. Afin d’étudier les conséquences d’une déficience en MTR, nous avons généré des modèles murins d’invalidation conditionnelle du gène MTR de manière constitutive ou inductible dans le foie et dans le cerveau. L’invalidation constitutive ou inductible ciblée dans le foie pendant l’embryogenèse n’est pas viable, suggérant un rôle limitant de la méthionine synthase sur le développement précoce et l’organogenèse en lien probable avec les conséquences sur la prolifération cellulaire. Dans les périodes post-natales, nous avons utilisé le modèle inductible complété par une hépatectomie pour étudier les altérations de la régénération hépatique liée aux effets sur le stress cellulaire ainsi que l’expression et l’activation des cyclines. Le KO dans le cerveau induit principalement une perte des fonctions de mémorisation de l’apprentissage hippocampo-dépendant. Au total, nos résultats illustrent les effets différents de l’invalidation de MTR en fonction de l’organe considéré. Le foie est un organe très plastique avec une capacité de régénération très importante. Les effets sur les étapes de l’organogénèse et sur l’inhibition de la régénération confirment l’hypothèse du rôle majeur et limitant de la méthionine synthase dans la régulation du cycle cellulaire. Le modèle d’invalidation au niveau du cerveau confirme le rôle très important de la voie de reméthylation de l’homocystéine catalysée par la méthionine synthase, rôle qui a déjà été illustré par d’autres travaux sur les rats carencés en donneur de méthyle et sur la souris transgénique KO cd320 / The enzyme methionine synthase (MTR) catalyzes the remethylation of homocysteine to methionine, the precursor of the methyl donor S-universal Adenosylmethionine (SAM), involved in epigenetic regulation mechanisms. We generated mouse models with conditional invalidation of the mtr gene in a constitutive or inducible manner to delete the gene expression specifically in the liver and brain. Constitutive invalidation during embryonic life is not sustainable when targeted to the liver, suggesting a limiting role of methionine synthase in early organogenesis and probably on cell proliferation. We performed hepatectomy to study regeneration-related effects on the cellular stress and found dramatic effects on cell proliferation through altered expression and activation of cyclins. The constitutive model in brain highlighted the behavioral anomalies related to a loss of learning and memory. This suggested major effects in the hippocampus. Overall, our findings highlighted the specific effects of the invalidation of methionine synthase in both organs. The liver is a plastic member with a very high regenerative capacity. The effects on organogenesis and inhibition of regeneration confirm the hypothesis for a major role of methionine synthase in cell cycle regulation. The invalidation model in the brain confirms the important role of the remethylation pathway catalysed by methionine synthase, a role which has been shown by other studies in rats deprived in methyl donors and in cd320 KO transgenic mice