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Oxidative stress is often increased in several diseases such as age-related diseases (cardiovascular diseases, eye diseases (age-related macular degeneration (AMD) and cataracts), neurodegenerative diseases (Alzheimer's disease, multiple sclerosis), chronic inflammatory diseases (chronic inflammatory bowel disease (IBD)) as well as certain rare genetic diseases (Niemann Pick's disease, X-linked adrenoleukodystrophy (X-ALD)). Oxidative stress can oxidize various molecules, in particular the cholesterol present in lipid membranes, and lead to the formation of oxidized cholesterol derivatives: oxysterols. Some of them, such as 7-ketocholesterol (7KC), are toxic and may be the cause of a type of cell death, oxiapoptophagy, associating an increase in oxidative stress, activation of apoptosis and autophagic criteria. Using 158N murine oligodendrocytes, this work has allowed to better characterize the oxiapoptophagy induced by 7KC. The toxicity of 7KC on cellular organelles such as mitochondria and lysosome was confirmed. This work also shows that oxyapoptophagy is associated with topographic, morphological and functional modifications of the peroxisome. It has been shown that 7KC induces a decrease in the expression and activity of certain peroxisomal transporters (ABCD1, ABCD3) and peroxisomal enzymes (ACOX1, MFP2, catalase) and promotes an accumulation of very long-chain fatty acids (C24:0, C24:1 and C26:0, C26:1) degraded in the peroxisome. It has also been shown that certain lipids (α-tocopherol, α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), oleic acid (AO), Lorenzo's oil (oleic acid + erucic acid (4: 1)) and sulfo-N-succinimdyl oleate (SSO)) are cytoprotective and strongly attenuate 7KC-induced oxyaptophagy. This makes it possible to envisage the prevention or treatment of diseases associated with high levels of 7KC, in particular certain age-related diseases for which there are no effective treatments., Le stress oxydant est souvent augmenté dans plusieurs maladies comme des maladies liées à l’âge (maladies cardiovasculaires, maladies oculaires (dégénérescence maculaire liée à l’âge (DMLA) et cataracte), des maladies neurodégénératives (Maladie d’Alzheimer, sclérose en plaques), des maladies inflammatoires chroniques (maladies inflammatoires chroniques de l’intestin (MICI)) ainsi que certaines maladies génétiques rares (maladie de Niemann Pick, adrénoleucodystrophie liée à l’X (X-ALD)). Le stress oxydant peut oxyder différentes molécules, notamment le cholestérol présent dans les membranes lipidiques, et conduire à la formation de dérivés oxydés du cholestérol : les oxystérols. Certains d’entre eux, comme le 7-cétocholestérol (7KC), sont toxiques et peuvent être à l’origine d’un type de mort cellulaire, l’oxyapoptophagie, associant une élévation du stress oxydant, une activation de l’apoptose à des critères d’autophagie. En utilisant des oligodendrocytes murins 158N, ce travail a permis de mieux caractériser, l’oxyapoptophagie induite par le 7KC. La toxicité du 7KC sur les organites cellulaires comme la mitochondrie et le lysosome a été confirmée. Ce travail montre aussi que l’oxyapoptophagie est associée à des modifications topographiques, morphologiques et fonctionnelles du peroxysome. Il a été montré que le 7KC induit une diminution de l’expression et de l’activité de certains transporteurs peroxysomaux (ABCD1, ABCD3) et enzymes peroxysomales (ACOX1, MFP2, catalase) et favorise une accumulation d’acides gras à très longue chaine (C24:0, C24:1 et C26:0, C26:1) dégradés au niveau du peroxysome. Il a aussi été démontré que certains lipides (α-tocophérol, acide α-linolénique (ALA), acide éïcosapentaénoïque (EPA), acide docosahéxaénoïque (DHA), acide oléique (AO), huile de Lorenzo (acide oléique + acide érucique (4:1)) et le sulfo-N-succinimdyl oleate (SSO)) sont cytoprotecteurs et atténuent fortement l’oxyapoptophagie induite par le 7KC. Ceci permet d’envisager la prévention ou le traitement les maladies associées à des taux élevés de 7KC, en particulier certaines maladies liées à l’âge qui ne disposent pas de traitements efficaces.

Oxidative stress is often increased in several diseases such as age-related diseases (cardiovascular diseases, eye diseases (age-related macular degeneration (AMD) and cataracts), neurodegenerative diseases (Alzheimer's disease, multiple sclerosis), chronic inflammatory diseases (chronic inflammatory bowel disease (IBD)) as well as certain rare genetic diseases (Niemann Pick's disease, X-linked adrenoleukodystrophy (X-ALD)). Oxidative stress can oxidize various molecules, in particular the cholesterol present in lipid membranes, and lead to the formation of oxidized cholesterol derivatives: oxysterols. Some of them, such as 7-ketocholesterol (7KC), are toxic and may be the cause of a type of cell death, oxiapoptophagy, associating an increase in oxidative stress, activation of apoptosis and autophagic criteria. Using 158N murine oligodendrocytes, this work has allowed to better characterize the oxiapoptophagy induced by 7KC. The toxicity of 7KC on cellular organelles such as mitochondria and lysosome was confirmed. This work also shows that oxyapoptophagy is associated with topographic, morphological and functional modifications of the peroxisome. It has been shown that 7KC induces a decrease in the expression and activity of certain peroxisomal transporters (ABCD1, ABCD3) and peroxisomal enzymes (ACOX1, MFP2, catalase) and promotes an accumulation of very long-chain fatty acids (C24:0, C24:1 and C26:0, C26:1) degraded in the peroxisome. It has also been shown that certain lipids (α-tocopherol, α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), oleic acid (AO), Lorenzo's oil (oleic acid + erucic acid (4: 1)) and sulfo-N-succinimdyl oleate (SSO)) are cytoprotective and strongly attenuate 7KC-induced oxyaptophagy. This makes it possible to envisage the prevention or treatment of diseases associated with high levels of 7KC, in particular certain age-related diseases for which there are no effective treatments., Le stress oxydant est souvent augmenté dans plusieurs maladies comme des maladies liées à l’âge (maladies cardiovasculaires, maladies oculaires (dégénérescence maculaire liée à l’âge (DMLA) et cataracte), des maladies neurodégénératives (Maladie d’Alzheimer, sclérose en plaques), des maladies inflammatoires chroniques (maladies inflammatoires chroniques de l’intestin (MICI)) ainsi que certaines maladies génétiques rares (maladie de Niemann Pick, adrénoleucodystrophie liée à l’X (X-ALD)). Le stress oxydant peut oxyder différentes molécules, notamment le cholestérol présent dans les membranes lipidiques, et conduire à la formation de dérivés oxydés du cholestérol : les oxystérols. Certains d’entre eux, comme le 7-cétocholestérol (7KC), sont toxiques et peuvent être à l’origine d’un type de mort cellulaire, l’oxyapoptophagie, associant une élévation du stress oxydant, une activation de l’apoptose à des critères d’autophagie. En utilisant des oligodendrocytes murins 158N, ce travail a permis de mieux caractériser, l’oxyapoptophagie induite par le 7KC. La toxicité du 7KC sur les organites cellulaires comme la mitochondrie et le lysosome a été confirmée. Ce travail montre aussi que l’oxyapoptophagie est associée à des modifications topographiques, morphologiques et fonctionnelles du peroxysome. Il a été montré que le 7KC induit une diminution de l’expression et de l’activité de certains transporteurs peroxysomaux (ABCD1, ABCD3) et enzymes peroxysomales (ACOX1, MFP2, catalase) et favorise une accumulation d’acides gras à très longue chaine (C24:0, C24:1 et C26:0, C26:1) dégradés au niveau du peroxysome. Il a aussi été démontré que certains lipides (α-tocophérol, acide α-linolénique (ALA), acide éïcosapentaénoïque (EPA), acide docosahéxaénoïque (DHA), acide oléique (AO), huile de Lorenzo (acide oléique + acide érucique (4:1)) et le sulfo-N-succinimdyl oleate (SSO)) sont cytoprotecteurs et atténuent fortement l’oxyapoptophagie induite par le 7KC. Ceci permet d’envisager la prévention ou le traitement les maladies associées à des taux élevés de 7KC, en particulier certaines maladies liées à l’âge qui ne disposent pas de traitements efficaces.

In addition to its role in erythropoiesis, erythropoietin (Epo) plays a role in tissue protection, which includes cardioprotective, nephroprotective and neuroprotective effects. The presence of Epo and its receptor (Epo-R) in pulmonary tissue also suggests a cytoprotective effect of Epo in the lung. Our project aims to document this role in a murine model under-expressing Epo. The obtained results will lead to a better understanding of the cytoprotective effects of Epo and will also give an appreciation of its beneficial effects in cases of lung injury.

Lifestyle modifications, especially weight loss, are efficient on NASH liver injury, however rarely followed in clinical practice. The target population of pharmacologic treatments is represented by patients with NASH and fibrosis. Out of histological improvement, efficacy of treatments should be assessed through liver morbi-mortality benefit, but also on extrahepatic events, such as cardiovascular. Among anti-diabetic treatments, glitazones et GLP-1 agonists have shown efficacy on histological liver injury. Vitamin E is efficient on liver injury but at the cost of prostate cancer and stroke over risk. About 60 new molecules are under investigation in NASH and have 4 different types of mechanism of action: metabolic, oxidative stress/apoptosis, anti inflammatory and anti fibrotic. A phase 3 trial evaluating obeticholic acid have shown a 72 weeks duration treatment improved significantly fibrosis.

International audience; Diabetes is characterized by chronic hyperglycemia. Type 2 diabetes, which represents 90% of diabetes cases, is the consequence of an insulin resistance and pancreatic beta cell dysfunction combination. Since the beta cells are the only cells of the organism to synthesize and to secrete insulin, it is essential to maintain and to protect their function and survival. It is currently proposed that an ideal and innovative treatment of type 2 diabetes should be based on an approach targeting pancreatic beta-cell dysfunction and death. It is now well described that chronic hyperglycemia is critically involved in the development of beta-cell dysfunction and apoptotic death (Glucotoxicity). Reducing the chronic hyperglycemia is a key objective in the treatment of type 2 diabetes, to attenuate not only the development of micro and macrovascular complications, but also the deleterious effects exerted on the pancreatic beta cells.; Le diabète est une affection du métabolisme caractérisée par un taux élevé de sucre dans le sang (hyperglycémie). Le diabète de type 2, qui représente 90 % des cas de diabète, résulte de la combinaison d'un défaut partiel de sécrétion d'insuline et d'un degré variable de résistance à l'insuline. Les cellules bêta pancréatiques sont les seules cellules de l'organisme capables de produire et de sécréter l'insuline, il est indispensable de maintenir leur fonction et leur nombre. L'hyperglycémie chronique est maintenant connue comme un élément déterminant de la réduction de la fonction des cellules bêta et de leur mort par apoptose. Réduire cette hyperglycémie se révèle comme un objectif majeur dans la prise en charge et le traitement du diabète de type 2, afin de ralentir non seulement le développement de complications micro- et macro-vasculaires, mais également d'atténuer ses effets délétères sur les cellules bêta pancréatiques.

Calcitriol and analogs inhibit renin-angiotensin system, which has a pivotal role in glomerular and tubulo-interstitial damages and proteinuria, and inhibit NF-κB activation which is known to play an important role in renal diseases by promoting inflammation and fibrogenesis. Vitamin D presents interesting pleiotropic effects for the CKD patient (reduction of mortality, antiproteinuric effect and anti-inflammatory properties). "Native" vitamin D (cholecalciferol or ergocalciferol) administration in these patients also decrease parathyroid hormone levels. Native vitamin D administration in CKD patients is safe and does not lead to increased risk of vascular calcification, despite the known hypercalcemic and hyperphosphoremic properties of the molecule in its active form. Native vitamin D administration is not associated with an increased risk of renal stones, at pharmacological doses and without important concomitant administration of calcium salts. In the field of renal transplantation, experimental studies show that vitamin D analogs have a protective role against acute rejection but clinical studies remain mainly observational.

Spermatozoa leave the testis in an immature functional state and are devoid of self defense mechanisms. They will become motile and ready to fertilize only after their descent and their progressive maturation within the epididymal tubule. The epididymis also ensures the survival and the protection of male gametes while they go through the epididymis and during their storage in between two ejaculations. Amongst common stresses that concern spermatozoa, oxidative stress occupies a peculiar and dual position. While the events of epididymal sperm maturation necessitate a given level of oxidation, spermatozoa are particularly sensitive to oxidative damage. A fine balance between beneficial oxidation versus detrimental oxidative damage has to be maintained in the epididymal environment. Antioxidant enzymes of the glutathione peroxidase family play a key role in controling such a situation in the epididymis.

Airways are continually exposed to multiple inhaled oxidants and protect themselves with cellular and extracellular antioxidants throughout the epithelial lining fluid and tissues. Oxidative stress, resulting from the increased oxidative burden and decreased level of antioxidant proteins, is involved in cellular and tissue damage related to the pathogenesis of many acute and chronic respiratory diseases. Evidence suggested that nuclear factor erythroid-2-related factor 2 (Nrf2), a transcription factor that controls antioxidant response element (ARE)-regulated antioxidant and cytoprotective genes has an essential protective role in the lungs against oxidative airway diseases. Therefore, Nrf2 promises to be an attractive therapeutic target for intervention and prevention strategies in respiratory diseases. We have reviewed major findings on the mechanisms of lung protection against oxidative stress by Nrf2 and the current literature suggesting that Nrf2 is a valuable therapeutic target.

Levodopa has been the mainstay of treatment for Parkinson's disease since the 1960s, but the dyskinesias it induces are a major drawback. High-frequency deep brain stimulation offers a safe, reversible alternative. Targets include the thalamus, pallidum, subthalamic nucleus and, more recently, the pedunculopntine nucleus, which requires low-frequency excitation. The subthalamic nucleus is the preferred target in Parkinson's disease. Other treatments such as gene therapy are in the pipeline.

Obesity is a state of chronic low-grade inflammation that predisposes people to several diseases and that is increasingly prevalent. Rheumatoid arthritis (RA) is marked by the presence of proinflammatory cytokines and, in general, the presence of high levels of inflammatory markers is associated with a severe disease course and joint damage.To assess the impact of obesity on disease activity, quality of life and articular damage in patients with established RA.Between July 2009 to December 2009, 119 RA patients were included and divided in two groups according to the body mass index (obeses and controls). RA activity was assessed by the Disease Activity Score (DAS) 28, quality of life by the Health Assessment Questionnaire (HAQ) and radiographic joint damage by the modified Sharp score.Obesity was not correlated with worsen RA activity (p=0.71) nor quality of life impairment (p=0.51). The obese group had a lower modified Sharp score than the control group (64.97versus113.64; p0.032) and this association remained significant after adjustment for age, sex, disease activity, extraarticular manifestations, comorbidities, presence of rheumatoid factor, and disease duration.Obesity does not have an impact on disease activity nor changes in quality of life, but it has a protective effect on the amount of joint destruction in established rheumatoid arthritis.

During more than a half of century, numerous compounds have been tested in different models against radiation-induced cataract. In this report, we will review the radioprotectors that have been already tested for non-human crystalline lens protection. We will focus on the most important published studies in this topic and the mechanisms of cytoprotection reported in vitro and in vivo from animals. The most frequent mechanisms incriminated in the cytoprotective effect are: free radical scavenging, limitation of lipid peroxidation, modulation of cycle progression increase of intracellular reduced glutathion pool, reduction of DNA strand breaks and limitation of apoptotic cell death. Amifostine (or Ethyol) and anethole dithiolethione (or Sulfarlem), already used clinically as chemo- and radioprotectants, could be further tested for ocular radioprotection particularly for radiation-induced cataract.

Cyclin-dependent kinases (CDKs) are widely involved in regulating the cell division cycle. The discovery of numerous alterations of CDKs, cyclins, their regulators and their substrates in many human tumours has strongly stimulated the search for chemical inhibitors of CDKs. The potential use of these potent and selective kinase inhibitors in cancer therapy is presently under investigation. Recently a group from Glaxo Wellcome unexpectedly discovered a potential new application of these CDK inhibitors to prevent chemotherapy-induced alopecia. These cyto-protective properties might also be extended to other tissues damaged during chemotherapy.

The cardiomyocyte capacity to regulate ATP production to face any change in energy demand is a major determinant of cardiac function. This process is based on a balanced fatty acid (FA) metabolism, because FA is the main fuel of the heart, although the most expensive one in oxygen. The pathway is, however, weakly controlled by the cardiac myocyte which can well regulate FA mitochondrial entry but not cell FA uptake. For this reason, several pathological situations often result from either harmful accumulation of FA and derivatives or excess FA-oxidation. Control of the FA/glucose balance by decreased energy production from FA would thus offer an alternative strategy in the treatment of ischaemia, providing the cardiomyocytes weak ability in handling the non-metabolised FA is controlled. The initiation and the regulation of cardiac contraction both result from membrane activity; the other major role of lipids in the heart is their contribution to membrane homeostasis through phospholipid synthesis pathways and phospholipases. The anti-anginal activity of Trimetazidine, reported as a cytoprotective effect without a haemo-dynamic component; is associated with reduced use of FA for energy. However, accumulation of FA and derivatives has never been observed. Trimetazidine is reported to increase significantly the synthesis of phospholipids without influencing the other lipid classes, thus increasing the incorporation of FA in membrane structures. This cytoprotection appears to be based on the redirection of the use of FA to phospholipid synthesis, which would decrease their availability for energy production. This class of compounds, with the same properties as Trimetazidine, offers a metabolic approach to the treatment of ischaemia.

Human milk as well as the milk of several mammalian species contains, beside major nutrients and anti-infectious and immunocompetent substances, a group of biologically active substances called "milk-borne trophic factors" or "growth modulators". Milk-borne trophic can be classified into three groups: hormones and trophic peptides; nucleotides, nucleosides and derived substances; and polyamines, especially spermine and spermidine. Certain hormones and peptides such as growth hormone, insulin, insulin like-growth factor I (IGF-I), epidermal growth factor (EGF), prolactin and growth hormone releasing factor (GHRF) can influence directly newborn's metabolism after intestinal absorption and promote growth and differentiation of several organs and target tissues. They could exert a cytoprotective effect against toxins and toxic substances and reduce the potential risk of necrotizing enterocolitis. Nucleotides are present in human milk at high levels, and are precursors of nucleic acids, which implies that they can enhance growth and differentiation of several organs and tissues, especially the liver. Nucleotides from milk enhance lipid metabolism, lipoprotein synthesis and liver cell function and regeneration. In addition, they have a determinant action on the development of the gut associated lymphoid tissue (GALT). Lastly, polyamines, mainly spermine and spermidine, are polycationic substances virtually present in all cells, whose concentration in human milk is about ten times higher than in infant formulae. In addition, spermine and spermidine levels increase markedly during the first 3 days of lactation reaching, after 1 week, plateau levels which are respectively 12 and eight times higher than the levels measured at day 0. Although several experimental studies have shown that polyamines from the milk of lactating mammals determine important mitogenic, metabolic and immunological effects promoting growth and differentiation of the immature gastrointestinal tract of the offspring, their beneficial effects on growth and differentiation of the gastrointestinal tract in humans remain hypothetical. As a consequence, enrichment of milk formulae in one or in several trophic factors is an important but complex goal. Its practical realization is not realistic today because of a too great number of incertitudes. The most important is related to potential beneficial or adverse effects emerging at short or at long term and to the individual interactions of these substances which could be agonist and antagonist because they are naturally present in milk as a "complex cocktail" whose composition changes during the lactation period.

E. coli k99+ infection in calves : protective effect of smectite In new-born calves, E. coli infection causes gastroenteritis. Twelve hours after inoculation of an enterotoxinogenic strain of E. coli diarrhea occurs followed by dehydratation. Ultrastructural observation under electron microscopy confirms the pathogenic effect of E. coli which is shown as the elongation of the intestinal villi and damage of the enterocytes. If calves receive smectite at a dose of 500 mg/kg/4 days, at the same time as the inoculum, the signs of diarrhea are reduced and dehydratation does not occur. These results are confirmed by determinations of plasma concentrations of Na+, K+ ions and of lactic. Furthermore, from the ultrastructural viewpoint the intestinal villi retain their normal appearance. To conclude, smectite, a colloidal clays, as a result of its absorption of E. coli and its effects on the mucus, protects the ileal mucosa from the pathogenic effects of enterotoxinogenic E. coli., Chez les veaux nouveau-nés, l’infection colibacillaire est responsable de gastro-entérite. Douze heures après l’inoculation d’une souche d’E. coli entérotoxinogène apparaît la diarrhée puis la déshydratation. L’observation ultra-structurale en microscopie électronique à balayage confirme l’effet pathogène du colibacille qui se manifeste par un allongement des villosités intestinales et une altération des entérocytes. Si les veaux reçoivent en même temps que l’inoculum de la smectite à la dose de 500 mg/kg/4 jours, les signes diarrhéiques sont réduits et sans déshydratation. Ces résultats sont confirmés par les mesures de concentrations plasmatiques des ions Na+, K+, et de l’acide lactique. Par ailleurs, d’un point de vue ultrastructural, les villosités intestinales gardent un aspect normal. En conclusion, la smectite, argile colloïdale, par ses propriétés d’adsorption du colibacille et ses effets sur le mucus protège la muqueuse iléale des effets pathogènes des colibacilles entérotoxinogènes., Navetat Hervé, Droy Marie-Thérèse, Espinasse J. Infection expérimentale du veau par le colibacille K 99+ : effet protecteur de la smectite. In: Bulletin de l'Académie Vétérinaire de France tome 141 n°3, 1988. pp. 365-375.