Early Low Protein Diet Aggravates Unbalance between Antioxidant Enzymes Leading to Islet Dysfunction

BACKGROUND:Islets from adult rat possess weak antioxidant defense leading to unbalance between superoxide dismutase (SOD) and hydrogen peroxide-inactivating enzymatic activities, catalase (CAT) and glutathione peroxidase (GPX) rending them susceptible to oxidative stress. We have shown that this vulnerability is influenced by maternal diet during gestation and lactation. METHODOLOGY/PRINCIPAL FINDINGS:The present study investigated if low antioxidant activity in islets is already observed at birth and if maternal protein restriction influences the development of islet antioxidant defenses. Rats were fed a control diet (C group) or a low protein diet during gestation (LP) or until weaning (LPT), after which offspring received the control diet. We found that antioxidant enzymatic activities varied with age. At birth and after weaning, normal islets possessed an efficient GPX activity. However, the antioxidant capacity decreased thereafter increasing the potential vulnerability to oxidative stress. Maternal protein malnutrition changed the antioxidant enzymatic activities in islets of the progeny. At 3 months, SOD activity was increased in LP and LPT islets with no concomitant activation of CAT and GPX. This unbalance could lead to higher hydrogen peroxide production, which may concur to oxidative stress causing defective insulin gene expression due to modification of critical factors that modulate the insulin promoter. We found indeed that insulin mRNA level was reduced in both groups of malnourished offspring compared to controls. Analyzing the expression of such critical factors, we found that c-Myc expression was strongly increased in islets from both protein-restricted groups compared to controls. CONCLUSION AND SIGNIFICANCE:Modification in antioxidant activity by maternal low protein diet could predispose to pancreatic islet dysfunction later in life and provide new insights to define a molecular mechanism responsible for intrauterine programming of endocrine pancreas

Clinical efficacy, safety, and immunogenicity of a live attenuated tetravalent dengue vaccine (CYD-TDV) in Children: a systematic review with meta-analysis

BACKGROUND Dengue hemorrhagic fever is the leading cause of hospitalization and death in children living in Asia and Latin America. There is an urgent need for an effective and safe dengue vaccine to reduce morbidity and mortality in this high-risk population given the lack of dengue specific treatment at present. This review aims to determine the efficacy, safety, and immunogenicity of CYD-TDV vaccine in children. METHODS This is a systematic review including meta-analysis of randomized controlled clinical trial data from Embase, Medline, the Cochrane Library, Web of Science, and ClinicalTrials.gov. Studies that assessed CYD-TDV vaccine efficacy [(1 - RR)*100], safety (RR), and immunogenicity (weighted mean difference) in children were included in this study. Random effects model was employed to analyze patient-level data extracted from primary studies. RESULTS The overall efficacy of CYD-TDV vaccine was 54% (40-64), while serotype-specific efficacy was 77% (66-85) for DENV4, 75% (65-82) for DENV3, 50% (36-61) for DENV1, and 34% (14-49) for DENV2. 15% (-174-74) vaccine efficacy was obtained for the unknown serotype. Meta-analysis of included studies with longer follow-up time (25 months) revealed that CYD-TDV vaccine significantly increased the risk of injection site reactions (RR = 1.1: 1.04-1.17; p-value = 0.001). Immunogenicity (expressed as geometric mean titers) in descending order was 439.7 (331.7-547.7), 323 (247 - 398.7), 144.1 (117.9-170.2), and 105 (88.7-122.8) for DENV3, DENV2, DENV1, and DENV4, respectively. CONCLUSION CYD-TDV vaccine is effective and immunogenic in children overall. Reduced efficacy of CYD-TDV vaccine against DENV2 notoriously known for causing severe dengue infection and dengue outbreaks cause for serious concern. Post hoc meta-analysis of long-term follow-up data (≥25 months) from children previously vaccinated with CYD-TDV vaccine is needed to make a conclusion regarding CYD-TDV vaccine safety in children. However, CYD-TDV vaccine should be considered for use in regions where DENV2 is not endemic as currently there is no specific treatment for dengue infection

‘It is not fair that you do not know we have problems’: Perceptual distance and the consequences of male leaders' conflict avoidance behaviours

This study investigates perceptual distance in terms of managers' conflict avoidance behaviour and its consequences for subordinates. We argue that perceptual distance, or the disagreement between a manager's perception and that of his or her subordinates of his or her conflict avoidance, is a genuine phenomenon. We examine the extent to which the perceptual distance regarding managers' avoidance behaviour influences a team's justice climate as well as the role of gender. The data collected from three multinational companies in China show that the perceptual distance of a male manager's avoidance behaviour exists and that it is associated with a negative justice climate within the team. These findings provide evidence of gender's effect on leadership and highlight the benefits of female leadership

Recherche des gènes impliqués dans les phénomènes de prolifération/dédifférenciation des cellules b pancréatiques humaines (intérêt en thérapie cellulaire)

Le diabète de type 1, caractérisé par la destruction auto-immune des cellules b insulino-sécrétrices, est la forme la plus sévère de diabète. La capacité du pancréas à générer des cellules progénitrices a donné naissance à de nouvelles pistes de recherche sur la thérapie cellulaire du diabète de type 1. Nous avons montré que la prolifération des cellules b sur matrice extra-cellulaire en présence d'HGF entraînait une perte d'expression de marqueurs de différenciation tels que l'insuline et son facteur de transcription PDX-1/IPF-1. Après expansion (6 jours), nous avons essayé de ré-exprimer ces marqueurs par l'intermédiaire de composés connus pour leurs effets sur la prolifération et/ou la différenciation. Le butyrate de sodium nous a permis de réinduire le PDX-1/IPF-1 et l'insuline mais aussi de provoquer la sécrétion de gastrine, un facteur intervenant dans la néogenèse pancréatique. D'autres composés comme le TGF b, le calcitriol, le GLP-1 et l'activine A ont aussi eu des effets positifs sur la ré-expression de certains gènes. Ces premiers résultats indiquent qu'il est possible de réinduire une différenciation cellulaire après expansion de cellules b. Nous avons ensuite essayé d'identifier les gènes modifiés durant la culture à long-terme de cellules b purifiées par FACS. L'analyse de trois pancréas différents sur puces à ADN "maison" spécifiques du pancréas a mis en évidence que sur les 218 gènes étudiés, 49 étaient sous-exprimés (marqueurs de différenciation endocrine) et 76 surexprimés (marqueurs de cellules souches et de cellules exocrines). La transdifférenciation des cellules b montraient une surexpression de PBX-1, une protéine formant un hétérodimère avec PDX-1, et qui module l'activité transcriptionnelle de ce dernier. La neurogénine 3, un facteur clé dans la formation des cellules endocrines était lui aussi surexprimé. Ces résultats permettent d'obtenir une carte précise des gènes impliqués dans la prolifération des cellules b.Type 1 diabetes, caracterized by b cell destruction, is the most severe form of diabetes. The pancreatic capacity to generate progenitor cells have given new development in type 1 diabetes cell therapy. In vitro studies of beta cell proliferation on extracellular matrices plus growth factors (HGF) have highlighted a possible cell expansion technique which was however accompanied with loss of insulin secretion. Herein we showed that human islet cell proliferation was marked by a decreased expression of specific differentiation markers, particularly insulin and his transcription factor IPF-1. After a 6 day expansion period, we tried to reexpress the beta cell differentiation markers with compounds known for their differentiation and/or insulin-secreting properties. Sodium butyrate was a potent factor of IPF-1 and insulin, it also clearly induced secretion of gastrin, a known neogenic factor. Other compounds, namely TGF-b, calcitriol, GLP-1 and Activin A, efficiently enhanced the glucose sensor machinery. Our results indicate that specific beta cell gene expression may be induced after expansion and dedifferentiation. In a second time, we tried to identify genes modulated during long term culture of FACS purified b cells. Analysis of 3 differents pancreata were performed on "in-house" pancreas specific microarrays consisting of 218 genes. The expression of 49 of them was down-regulated (markers of endocrine differentiation), while 76 were induced by cell expansion. Their pattern argues for the transdifferentiation of beta cells into undifferentiated cells that overexpress both PBX1, a protein which can bind as a heterodimer with PDX1 and could switch the nature of the its transcriptional activity, and neurogenin 3, a key factor for the generation of endocrine islet cells. Our findings demonstrate that microarray-based technology provides a powerful tool for identifying genes involved in the regulation of pancreatic beta cell growth.LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Is taurine a functional nutrient?

PURPOSE OF REVIEW: Taurine, a free amino acid, is found in millimolar concentrations in most mammalian tissues. Mammals are able to synthesize taurine endogenously, but some species such as humans are more dependent on dietary sources of taurine. A growing body of evidence suggests that taurine plays a preponderant role in many physiological processes, which will be summarized in this review. RECENT FINDINGS: Evidence for the requirement of taurine in the human diet has been obtained in many studies involving animal models and a few clinical trials. Recent and past studies suggested that taurine might be a pertinent candidate for use as a nutritional supplement to protect against oxidative stress, neurodegenerative diseases or atherosclerosis. Taurine has demonstrated promising actions in vitro, and as a result clinical trials have begun to investigate its effects on various diseases. SUMMARY: Taurine appears to have multiple functions and plays an important role in many physiological processes, such as osmoregulation, immunomodulation and bile salt formation. Taurine analogues/derivatives have recently been reported to have a marked activity on various disorders. Taken together, these observations actualize the old story of taurine

Implication of nitric oxide in the increased islet-cells vulnerability of adult progeny from protein-restricted mothers and its prevention by taurine.

An increased vulnerability of adult beta-cell seems to be programmed in early life as adult islets from the progeny of dams fed a low protein diet exhibited an increased apoptotic rate after cytokines stimulation. This was prevented by maternal taurine supplementation. Here, we investigated the mechanisms implicated in such an increased vulnerability and how taurine exerts its protective role. Along gestation and lactation, Wistar rats were fed a 20% (Control [C group]) or an isocaloric 8% protein diet (Recovery [R group]) supplemented or not with taurine (CT and RT groups respectively). Offspring received a 20% protein diet after weaning. Islets from 3 month-old females were isolated and cultured for 48h before being incubated with or without cytokines for 24h. In unstimulated islets, apoptotic rate and NO. secretion were higher in R than in C. Both GADD153mRNA and protein were increased, whereas mRNA of mitochondrial gene ATPase6 was down-regulated in R group compared to C. In the RT group, taurine protected from apoptosis and restored a normal NO. production, GADD153 as well as ATPase6 mRNA expression. After cytokines-induction, apoptosis and NO. secretion were still increased in R compared to C but both parameters were normalized in RT group. In conclusion, maternal low protein diet programmes a different pattern of gene expression in islet-cells of adult progeny. Higher NO. production by these islets could be an important actor in the subsequent cell death. The prevention of these events by maternal taurine supplementation emphasises the importance of taurine during endocrine pancreas development

Maternal low protein diet alters pancreatic islet mitochondrial function in a sex-specific manner in the adult rat.

Mitochondrial dysfunction may be a long-term consequence to poor nutritional environment during early life. Our aim was to investigate whether maternal low protein diet may program mitochondrial dysfunction in islets of adult progeny before glucose intolerance ensues. To address this, pregnant Wistar rats were fed isocaloric diets containing either 20% protein (C) or 8% protein (LP) throughout gestation. From birth, offspring received the control diet. The mitochondrial function was analyzed in islets of 3 month-old offspring. Related to their basal insulin release, cultured islets from both male and female LP offspring presented a lower response to glucose challenge and a blunted ATP production compared to C offspring. The expression of malate deshydrogenase as well as the subunit 6 of the ATP synthase encoded by mitochondrial genome (mtDNA) was lower in these islets, reducing the capacity of ATP production through the Krebs cycle and oxidative phosphorylation. However, mtDNA content was unchanged in LP islets compared to C. Several consequences of protein restriction during fetal life were more marked in male offspring. Only LP males showed an increased ROS production associated to a higher expression of mitochondrial subunits of the electron transport chain ND4L, an overexpression of PPARgamma and UCP-2 and a strongly reduced beta-cell mass. In conclusion, mitochondrial function is clearly altered in islets from LP adult offspring in a sex-specific manner. That may provide a cellular explanation for the earlier development of glucose intolerance in male than in female offspring of dams fed a LP diet. Key words: Developmental programming, Islets, Low protein diet, mitochondria