Metastasis suppressor NM23 limits oxidative stress in mammals by preventing activation of stress-activated protein kinases/JNKs through its nucleoside diphosphate kinase activity.

NME1 (nonmetastatic expressed 1) gene, which encodes nucleoside diphosphate kinase (NDPK) A [also known as nonmetastatic clone 23 (NM23)-H1 in humans and NM23-M1 in mice], is a suppressor of metastasis, but several lines of evidence-mostly from plants-also implicate it in the regulation of the oxidative stress response. Here, our aim was to investigate the physiologic relevance of NDPK A with respect to the oxidative stress response in mammals and to study its molecular basis. NME1-knockout mice died sooner, suffered greater hepatocyte injury, and had lower superoxide dismutase activity than did wild-type (WT) mice in response to paraquat-induced acute oxidative stress. Deletion of NME1 reduced total NDPK activity and exacerbated activation of the stress-related MAPK, JNK, in the liver in response to paraquat. In a mouse transformed hepatocyte cell line and in primary cultures of normal human keratinocytes, MAPK activation in response to H2O2 and UVB, respectively, was dampened by expression of NM23-M1/NM23-H1, dependent on its NDPK catalytic activity. Furthermore, excess or depletion of NM23-M1/NM23-H1 NDPK activity did not affect the intracellular bulk concentration of nucleoside di- and triphosphates. NME1-deficient mouse embryo fibroblasts grew poorly in culture, were more sensitive to stress than WT fibroblasts, and did not immortalize, which suggested that they senesce earlier than do WT fibroblasts. Collectively, these results indicate that the NDPK activity of NM23-M1/NM23-H1 protects cells from acute oxidative stress by inhibiting activation of JNK in mammal models.-Peuchant, E., Bats, M.-L., Moranvillier, I., Lepoivre, M., Guitton, J., Wendum, D., Lacombe, M.-L., Moreau-Gaudry, F., Boissan, M., Dabernat, S. Metastasis suppressor NM23 limits oxidative stress in mammals by preventing activation of stress-activated protein kinases/JNKs through its nucleoside diphosphate kinase activity.

Relationship between diet and plasma long-chain n-3 PUFAs in older people: impact of apolipoprotein E genotype.

The main risk factors for Alzheimer's disease, age and the ε4 allele of the APOE gene (APOE4), might modify the metabolism of n-3 PUFAs and in turn, their impact on cognition. The aim of this study was to investigate the association between dietary fat and plasma concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in elderly persons, taking the APOE4 genotype into account. The sample was composed of 1,135 participants from the Three-City study aged 65 years and over, of whom 19% were APOE4 carriers. Mean plasma proportions of EPA [1.01%, standard deviation (SD) 0.60] and DHA (2.41%, SD 0.81) did not differ according to APOE4. In multivariate models, plasma EPA increased with frequency of fish consumption (P < 0.0001), alcohol intake (P = 0.0006), and female gender (P = 0.02), and decreased with intensive consumption of n-6 oils (P = 0.02). The positive association between fish consumption and plasma DHA was highly significant whatever the APOE genotype (P < 0.0001) but stronger in APOE4 noncarriers than in carriers (P = 0.06 for interaction). Plasma DHA increased significantly with age (P = 0.009) in APOE4 noncarriers only. These findings suggest that dietary habits, gender, and APOE4 genotype should be considered when designing interventions to increase n-3 PUFA blood levels in older people.

FGFR3 has tumor suppressor properties in cells with epithelial phenotype.

BACKGROUND: Due to frequent mutations in certain cancers, FGFR3 gene is considered as an oncogene. However, in some normal tissues, FGFR3 can limit cell growth and promote cell differentiation. Thus, FGFR3 action appears paradoxical. RESULTS: FGFR3 expression was forced in pancreatic cell lines. The receptor exerted dual effects: it suppressed tumor growth in pancreatic epithelial-like cells and had oncogenic properties in pancreatic mesenchymal-like cells. Distinct exclusive pathways were activated, STATs in epithelial-like cells and MAP Kinases in mesenchymal-like cells. Both FGFR3 splice variants had similar effects and used the same intracellular signaling. In human pancreatic carcinoma tissues, levels of FGFR3 dropped in tumors. CONCLUSION: In tumors from epithelial origin, FGFR3 signal can limit tumor growth, explaining why the 4p16.3 locus bearing FGFR3 is frequently lost and why activating mutations of FGFR3 in benign or low grade tumors of epithelial origin are associated with good prognosis. The new hypothesis that FGFR3 can harbor both tumor suppressive and oncogenic properties is crucial in the context of targeted therapies involving specific tyrosine kinase inhibitors (TKIs). TKIs against FGFR3 might result in adverse effects if used in the wrong cell context.

High concentrations of plasma n3 fatty acids are associated with decreased risk for late age-related macular degeneration.

High dietary intakes of n3 (ω3) polyunsaturated fatty acids (PUFA) and fish have been consistently associated with a decreased risk for age-related macular degeneration (AMD). We assessed the associations of late AMD with plasma n3 PUFA, a nutritional biomarker of n3 PUFA status. The Antioxydants Lipides Essentiels Nutrition et Maladies Occulaires (Alienor) Study is a prospective, population-based study on nutrition and age-related eye diseases performed in 963 residents of Bordeaux (France) aged ≥73 y. Participants had a first eye examination in 2006-2008 and were followed for 31 mo on average. Plasma fatty acids were measured by GC from fasting blood samples collected in 1999-2001. AMD was graded from non-mydriatic color retinal photographs at all examinations and spectral domain optical coherence tomography at follow-up. After adjustment for age, gender, smoking, education, physical activity, plasma HDL-cholesterol, plasma triglycerides, CFH Y402H, apoE4, and ARMS2 A69S polymorphisms, and follow-up time, high plasma total n3 PUFA was associated with a reduced risk for late AMD [OR = 0.62 for 1-SD increase (95% CI: 0.44-0.88); P = 0.008]. Associations were similar for plasma 18:3n3 [OR = 0.62 (95% CI: 0.43-0.88); P = 0.008] and n3 long-chain PUFA [OR = 0.65 (95% CI: 0.46-0.92); P = 0.01]. This study gives further support to the potential role of n3 PUFAs in the prevention of late AMD and highlights the necessity of randomized clinical trials to determine more accurately the value of n3 PUFAs as a means of reducing AMD incidence.

In vivo gene transfer targeting in pancreatic adenocarcinoma with cell surface antigens.

BACKGROUND: Pancreatic ductal adenocarcinoma is a deadly malignancy resistant to current therapies. It is critical to test new strategies, including tumor-targeted delivery of therapeutic agents. This study tested the possibility to target the transfer of a suicide gene in tumor cells using an oncotropic lentiviral vector. RESULTS: Three cell surface markers were evaluated to target the transduction of cells by lentiviruses pseudotyped with a modified glycoprotein from Sindbis virus. Only Mucin-4 and the Claudin-18 proteins were found efficient for targeted lentivirus transductions in vitro. In subcutaneous xenografts of human pancreatic cancer cells models, Claudin-18 failed to achieve efficient gene transfer but Mucin-4 was found very potent. Human pancreatic tumor cells were modified to express a fluorescent protein detectable in live animals by bioimaging, to perform a direct non invasive and costless follow up of the tumor growth. Targeted gene transfer of a bicistronic transgene bearing a luciferase gene and the herpes simplex virus thymidine kinase gene into orthotopic grafts was carried out with Mucin-4 oncotropic lentiviruses. By contrast to the broad tropism VSV-G carrying lentivirus, this oncotropic lentivirus was found to transduce specifically tumor cells, sparing normal pancreatic cells in vivo. Transduced cells disappeared after ganciclovir treatment while the orthotopic tumor growth was slowed down. CONCLUSION: This work considered for the first time three aspect of pancreatic adenocarcinoma targeted therapy. First, lentiviral transduction of human pancreatic tumor cells was possible when cells were grafted orthotopically. Second, we used a system targeting the tumor cells with cell surface antigens and sparing the normal cells. Finally, the TK/GCV anticancer system showed promising results in vivo. Importantly, the approach presented here appeared to be a safer, much more specific and an as efficient way to perform gene delivery in pancreatic tumors, in comparison with a broad tropism lentivirus. This study will be useful in future designing of targeted therapies for pancreatic cancer.

Adherence to a Mediterranean diet and plasma fatty acids: data from the Bordeaux sample of the Three-City study.

Higher adherence to a Mediterranean diet (MeDi) and n-3 PUFA may both contribute to decreased dementia risk, but the association between MeDi adherence and lipid status is unclear. The aim of the present study was to analyse the relationship between plasma fatty acids and MeDi adherence in French elderly community dwellers. The study population (mean age 75·9 years) consisted of 1050 subjects from Bordeaux (France) included in the Three-City cohort. Adherence to the MeDi (scored as 0-9) was computed from a FFQ and 24 h recall. The proportion of each plasma fatty acid was determined. Cross-sectional analysis of the association between plasma fatty acids and MeDi adherence was performed by multi-linear regression. After adjusting for age, sex, energy intake, physical activity, smoking status, BMI, plasma TAG and apoE-ɛ4 genotype, plasma palmitoleic acid was significantly inversely associated with MeDi adherence, whereas plasma DHA, the EPA+DHA index and total n-3 PUFA were positively associated with MeDi adherence. The n-6:n-3 PUFA, arachidonic acid (AA):EPA, AA:DHA and AA:(EPA+DHA) ratios were significantly inversely associated with MeDi adherence. Plasma EPA was positively associated with MeDi adherence only in apoE-ɛ4 non-carriers. There was no association between MeDi adherence and SFA and total MUFA. The present results suggest that the protective effect of the MeDi on cognitive functions might be mediated by higher plasma DHA and lower n-6:n-3 PUFA ratios.

Plasma retinol and association with socio-demographic and dietary characteristics of free-living older persons: the Bordeaux sample of the three-city study.

The objective was to describe retinol plasma concentration and its association with socio-demographic characteristics and dietary habits in French older persons. The study population consisted of 1664 subjects aged 65 + from Bordeaux (France), included in the Three-City cohort. Retinol plasma concentration was determined in fasting blood samples. Dietary assessment was performed by a food frequency questionnaire allowing estimation of weekly intake of dietary sources of vitamin A or provitamin A. The weekly number of glasses of alcohol was also recorded. Age, sex, marital status, educational and income levels, body-mass index (BMI), and smoking were registered. Cross-sectional analysis of the association between plasma retinol and socio-demographic characteristics and dietary habits was performed by multilinear regression. Mean plasma retinol was close to the homeostatically regulated concentration of 2.0 micromol/L but ranged from 0.35 to 6.77 micromol/L. It was higher in women and divorced or separated individuals, and increased with income but not with age or educational level. Plasma retinol was positively and independently associated with the frequency of offal consumption and to the number of glasses of alcohol consumed per week. These results allow targeting older individuals who are at risk of either excessive or deficient vitamin A status and who should benefit from dietary counseling.

The mammalian Nm23/NDPK family: from metastasis control to cilia movement.

Nucleoside diphosphate kinases (NDPK) are encoded by the NME genes, also called NM23. They catalyze the transfer of gamma-phosphate from nucleoside triphosphates to nucleoside diphosphates by a ping-pong mechanism involving the formation of a high energy phospho-histidine intermediate [1, 2]. Besides their known functions in the control of intracellular nucleotide homeostasis, they are involved in multiple physiological and pathological cellular processes such as differentiation, development, metastastic dissemination or cilia functions. Over the past 15 years, ten human genes have been discovered encoding partial, full length, and/or tandemly repeated Nm23/NDPK domains, with or without N-or C-terminal extensions and/or additional domains. These genes encode proteins exhibiting different functions at various tissular and subcellular localizations. Most of these genes appear late in evolution with the emergence of the vertebrate lineage. This review summarizes the present knowledge on these multitalented proteins.

[Method validation of a critical parameter in human embryos culture: culture media pH]. / Validation de la mesure d'un paramètre critique en culture d'embryons humains : le pH.

In vitro human embryos culture depends largely on the atmospheric conditions within the incubators of the laboratory. The pH of culture media, an indirect reflection of the CO2 content inside these incubators, is a critical parameter. Collaboration between the biochemistry and reproductive biology departments enabled the automated measurement of the pH in the culture medium on a blood gas analyzer. This method has been validated and evaluated. It is applicable in all laboratories whatever the medium and the conditions of culture. It allows strict monitoring of this parameter for the optimization of the culture conditions necessary to improve the results of in vitro fertilization attempts.

Pravastatin in HIV-infected patients treated with protease inhibitors: a placebo-controlled randomized study.

PURPOSE: The objectives of the study were to assess the effects of pravastatin on plasma HIV RNA, lipid parameters, and protease inhibitor (PI) concentrations in patients treated with PI-containing regimens and with total cholesterol (TC) > or = 5.5 mmol/L. METHOD: A clinical trial including patients randomized to receive pravastatin or matching placebo for 12 weeks was implemented. RESULTS: Twelve patients were included in the pravastatin group and 9 in the placebo group. At week 12 (W12), no patient had experienced virological failure. Between week 0 (W0) and W12, the median differences for TC were -1.4 mmol/L in the pravastatin group and +0.2 mmol/L in the placebo group (p = .005); for LDL, they were -1.0 mmol/L and +0.3 (p = .007), respectively. A significant decrease of the PI concentration (12 hours after administration) ratio W12 - W0/W0 was noticed in the pravastatin group (-0.2 [interquartile range, -0.3 to -0.1] as compared with the placebo group (0.1 [IQR, 0.0 to 0.3]) (p = .03). When the study was restricted to patients treated with lopinavir/ritonavir, a decrease from 3.8 microg/mL at baseline to 2.9 mug/mL at W12 was noticed in the pravastatin arm (p = .04) but not in the control arm (p = 1.00). No clinical adverse event reached a severity of grade 3. CONCLUSION: We observed in this study that the use of pravastatin in PI-treated patients was not associated with major change in the plasma HIV RNA on 12 weeks of follow-up. However, we found a trend of decrease of the trough PI concentration at W12, suggesting a possible drug-drug interaction of pravastatin on PI metabolism.

Moderate dietary intake of myristic and alpha-linolenic acids increases lecithin-cholesterol acyltransferase activity in humans.

Cholesterol removal from tissues into HDL depends on the activity of lecithin-cholesterol acyltransferase (LCAT; E.C. 2.3.1.43) that is associated with lower cardiovascular diseases risk. HDL cholesterol concentration and LCAT activity can be modulated by dietary fatty acids. Original data with substrate models have shown a positive effect of myristic acid (MA) on the esterification rate of cholesterol. The purpose of this study was to examine the effect of moderate intakes of MA associated with recommended intake of alpha-linolenic acid (ALA) on LCAT activity in humans. Two experimental diets were tested for 3 months each. Diet 1-MA 1.2% of total energy (TE) and ALA 0.9% TE, diet 2-MA 1.8% and ALA 0.9% TE; a control diet (MA 1.2% and ALA 0.4% TE) was given 3 months before diet 1 and diet 2. The endogenous activity of LCAT was determined at completion of each diet. Compared with the control diet (13.2 +/- 3.1 micromol CE/(L x h)), LCAT activity increased significantly (P < 0.001) with diet 1 (24.2 +/- 3.6 micromol CE/(L x h)) and diet 2 (33.3 +/- 7.4 micromol CE/(L x h)); the increase observed with diet 2 was significantly (P < 0.001) greater than that due to diet 1. These results suggest that ALA (from rapeseed oil, mainly in sn-2 position) and MA (from dairy fat, mainly in sn-2 position) favor LCAT activity, by respective increases of 83 and 38%. When they are supplied together, a complementary effect was observed (average increase of 152%). Moreover, these observations were associated with a decrease of the ratio of total to HDL-cholesterol. In conclusion, our results suggest that moderate supply of MA (1.8% TE) associated with the recommended intake of ALA (0.9% TE) contributes to improve LCAT activity.

Plasma fatty acid biomarkers are associated with gait speed in community-dwelling older adults: The Three-City-Bordeaux study.

BACKGROUND & AIMS: Nutritional factors, such as fatty acids (FA), could modulate physical performance in the elderly. In particular, the opposite properties of long-chain n-3 and n-6 polyunsaturated FAs (LC PUFAs) could impact muscle function. We aimed to assess the cross-sectional association between plasma FAs and gait speed in French elderly community-dwellers. METHODS: Elderly participants from the Bordeaux centre of the Three-City Study were included. The proportion of 12 FAs, and gait speed (m/s) were measured concomitantly at enrollment. Low gait speed (LGS) was defined as below the first quartile of gait speed. FA patterns were derived from the 12 individual FAs using principal component analysis. Multivariate logistic regression models were used and odds-ratios (OR) were expressed per one additional standard-deviation unit of each plasma FA or per one additional unit of pattern score. RESULTS: Among 982 participants, 239 (24.3%) had a low gait speed (<0.63 m/s) at baseline. Regarding individually each FA, a higher proportion of eicosapentaenoic acid (EPA) and of docosahexaenoic acid (DHA) were associated with lower odds of LGS (OR = 0.76; 95% CI: 0.63-0.93 and OR = 0.79; 95% CI: 0.67-0.95 respectively). Conversely, a higher arachidonic acid (AA):(EPA + DHA) ratio was associated with higher odds of LGS. Three main FA patterns were identified. A higher score on the FA pattern characterized by higher proportions of LC n-3 PUFAs was associated with lower odds of LGS (OR = 0.78; 95% CI: 0.67-0.90). CONCLUSIONS: A FA pattern mainly driven by high plasma concentrations of LC n-3 PUFAs is cross-sectionally associated with higher gait speed in community-dwelling older adults, while a higher AA:(EPA + DHA) ratio is associated with lower gait speed. These findings suggest a potential protective effect of n-3 PUFA on physical performance decline.

Resveratrol and capsaicin used together as food complements reduce tumor growth and rescue full efficiency of low dose gemcitabine in a pancreatic cancer model.

Pancreatic adenocarcinoma, highly resistant to all current anti-cancer treatments, necessitates new approaches promoting cell death. We hypothesized that combined actions of several Bioactive Food Components (BFCs) might provide specific lethal effect towards tumor cells, sparing healthy cells. Human tumor pancreatic cell lines were tested in vitro for sensitivity to resveratrol, capsaicin, piceatannol, and sulforaphane cytotoxic effects. Combination of two or three components showed striking synergetic effect with gemcitabine in vitro. Each BFC used alone did not affect pancreatic tumor growth in a preclinical in vivo model, whereas couples of BFCs had anti-tumor activity. In addition, tumor toxicity was similar using gemcitabine alone or a combination of BFCs and two thirds of gemcitabine dose. Moreover, BFCs enhanced fibrotic response as compared to gemcitabine treatment alone. Reactive oxygen species (ROS) and apoptosis increases were observed, while cell cycle was very mildly affected. This study raises the possibility to use BFCs as beneficial food complements in the therapy of pancreatic adenocarcinoma, especially for patients unable to receive full doses of chemotherapy.

Acute oxidative stress is associated with cell proliferation in the mouse liver.

Oxidative stress is known to produce tissue injury and to activate various signaling pathways. To investigate the molecular events linked to acute oxidative stress in mouse liver, we injected a toxic dose of paraquat. Liver necrosis was first observed, followed by histological marks of cell proliferation. Concomitantly, activation of the MAP kinase pathway and increased levels of the anti-apoptotic protein Bcl-XL were observed. Gene expression profiles revealed that the differentially expressed genes were potentially involved in cell proliferation. These data suggest that paraquat-induced acute oxidative stress triggers the activation of regeneration-related events in the liver.

Moderate intake of myristic acid in sn-2 position has beneficial lipidic effects and enhances DHA of cholesteryl esters in an interventional study.

Among the saturated fatty acids (SFA), myristic acid is known to be one of the most atherogenic when consumed at high levels. Our purpose was to compare the effects of two moderate intakes of myristic acid on plasma lipids in an interventional study. Twenty-five male monks without dyslipidemia were given two isocaloric diets for 5 weeks each. In diet 1, 30% of the calories came from fat (8% SFA, 0.6% myristic acid) and provided 200 mg cholesterol/day. Calories of diet 2 were 34% fat (11% SFA, 1.2% myristic acid) with the same levels of oleate, linoleate, alpha-linolenate and cholesterol. A baseline diet was provided before each diet. In comparison with baseline, diets 1 and 2 induced a decrease in total cholesterol, LDL-cholesterol and triglycerides (P<.001); HDL-cholesterol was not modified and the apo A-I/apo B ratio increased (P<.001). Plasma triglycerides were lower after diet 2 than after diet 1 whereas HDL-cholesterol was higher (P<.05). In phospholipids, myristic acid, oleic acid, linoleic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) increased after diet 2 vs. baseline (P<.01) and diet 1 (P<.05). Both diets were associated with an increase in alpha-linolenate of cholesteryl esters (P<.05), but only diet 2 was associated with an increase in DHA of cholesteryl esters (P<.05). In diet 2, myristic acid intake was positively correlated with myristic acid of phospholipids, and alpha-linolenic acid intake was correlated with alpha-linolenic acid of cholesteryl esters. Moderate intake (1.2% of total calories) of myristic acid has beneficial lipidic effects and enhances DHA of cholesteryl esters.

Oxidative and antioxidative status in pregnant women with either gestational or type 1 diabetes.

OBJECTIVES: To evaluate oxidative and antioxidative status in pregnant diabetic women between 26 and 32 weeks of gestation. DESIGN AND METHODS: Free and total malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPX), and vitamins A and E were determined in plasma and erythrocytes of 54 pregnant women. Among these, 27 were diabetics with either gestational diabetes mellitus (GDM), sub-group I, or previous insulin-dependent diabetes mellitus (type 1 diabetes), sub-group II. The other 27 patients were controls. Fasting plasma glucose and HbA(1c) levels were determined in all women. RESULTS: HbA(1c) levels, plasma-, and erythrocyte-free MDA levels were significantly higher in all diabetic women and in both sub-groups than in controls. Plasma vitamin E and erythrocyte vitamin A levels were significantly lower in all diabetic women than in controls. Moreover, GPX and SOD activities were significantly reduced in all diabetic women, GPX in both sub-groups and SOD only in type 1 diabetes. CONCLUSIONS: The increased oxidative stress we demonstrated in pregnant women with previous type 1 diabetes or with GDM should be monitored by strictly controlling blood glucose during pregnancy with stringent recommendations and perhaps antioxidant supplementation.

Plasma long-chain omega-3 fatty acids and atrophy of the medial temporal lobe.

OBJECTIVE: The long-chain ω-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are potential candidates for interventions to delay Alzheimer disease (AD), but evidence from clinical studies is mixed. We aimed at determining whether plasma levels of EPA or DHA predict atrophy of medial temporal lobe (MTL) gray matter regions in older subjects. METHODS: A total of 281 community dwellers from the Three-City Study, aged 65 years or older, had plasma fatty acid measurements at baseline and underwent MRI examinations at baseline and at 4 years. We studied the association between plasma EPA and DHA and MTL gray matter volume change at 4 years. RESULTS: Higher plasma EPA, but not DHA, was associated with lower gray matter atrophy of the right hippocampal/parahippocampal area and of the right amygdala (p < 0.05, familywise error corrected). Based on a mean right amygdala volume loss of 6.0 mm(3)/y (0.6%), a 1 SD higher plasma EPA (+0.64% of total plasma fatty acids) at baseline was related to a 1.3 mm(3) smaller gray matter loss per year in the right amygdala. Higher atrophy of the right amygdala was associated with greater 4-year decline in semantic memory performances and more depressive symptoms. CONCLUSION: The amygdala, which develops neuropathology in the early stage of AD and is involved in the pathogenesis of depression, may be an important brain structure involved in the association between EPA and cognitive decline and depressive symptoms.

The anti-metastatic nm23-1 gene is needed for the final step of mammary duct maturation of the mouse nipple.

Nm23/NDP kinases are multifunctional enzymes involved in the general homeostasis of triphosphate nucleosides. Numerous studies have shown that NDPKs also serve as regulatory factors of various cell activities, not always connected to nucleotide phosphorylation. In particular, the nme-1 gene, encoding the NM23-1/NDPKA protein, has been reported as a metastasis suppressor gene. This activity was validated in hepatocellular tumors induced in nm23-1 deficient mice. Yet, data describing the primary physiological functions of nm23-1/NDPKA is still scarce. We have characterized in depth the phenotype of nm23-1 deletion in the mammary gland in mice carrying whole body nm23-M1 invalidation. We also asked why the nm23-M1⁻/⁻ mutant females displayed severe nursing disability. We found that the growth retardation of mutant virgin glands was due to reduced proliferation and apoptosis of the epithelial cells within the terminal end buds. The balance of pro/anti-apoptotic factors was impaired in comparison with wild type glands. In the lactating glands, the reduced proliferation rate persisted, but the apoptotic factors were unchanged. However, those defects did not seem to affect the gland maturation since the glands lacking nm23-1/NDPKA appeared morphologically normal. Thorough examination of all the functional aspects of the mammary glands revealed that lack of nm23-1/NDPKA does not impact the production or the ejection of milk in the lumen of lobuloalveolae. Interestingly, an epithelial plug was found to obstruct the extremity of the unique lactiferous duct delivering the milk out of the nipple. These cells, normally disappearing after lactation takes place, persisted in the mutant nipples. This work provides a rare instance of nm23-1/NDPKA physiological functions in the mammary glands and reveals its implication as a modulator factor of proliferation and apoptosis in this tissue.

ω-3 fatty acids and cognitive decline: modulation by ApoEε4 allele and depression.

Long-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may slow cognitive decline. The ε4 allele of the ApolipoproteinE (ApoE), the main genetic risk factor for Alzheimer's disease, and depressive symptoms, which are frequently associated with cognitive impairment in older persons, may modify this relationship. We estimated the associations between EPA and DHA plasma levels and subsequent cognitive decline over 7 years, taking into account ApoE-ε4 status and depressive symptoms, in a prospective population-based cohort. Participants (≥ 65 years, n = 1,228 nondemented at baseline) were evaluated at least once over three follow-up visits using four cognitive tests. Plasma EPA was associated with slower decline on Benton Visual Retention Test (BVRT) performances in ApoE-ε4 carriers, or in subjects with high depressive symptoms at baseline. Plasma DHA was associated with slower decline on BVRT performances in ApoE-ε4 carriers only. EPA and DHA may contribute to delaying decline in visual working memory in ApoE-ε4 carriers. In older depressed subjects, EPA, but not DHA, may slow cognitive decline.

Plasma eicosapentaenoic acid is inversely associated with severity of depressive symptomatology in the elderly: data from the Bordeaux sample of the Three-City Study.

BACKGROUND: Depressive symptoms are commonly observed in elderly people, and nutritional factors such as polyunsaturated fatty acids (PUFAs) have been proposed as potential protective determinants of depressive disorders. OBJECTIVE: The objective was to analyze the relation between plasma fatty acids and severity of depressive symptomatology (DS) in French elderly community dwellers. DESIGN: The study population (mean age: 74.6 y) consisted of 1390 subjects from Bordeaux (France) included in the Three-City Study cohort. DS was evaluated by using the Center for Epidemiologic Studies Depression scale. The use of antidepressant drugs was recorded. The proportion of each plasma fatty acid was determined. Cross-sectional analysis of the association between plasma fatty acids and severity of DS was performed by multilinear regression. RESULTS: Compared with control subjects, subjects with DS were older, were more often women, were more often widowed or single, were of lower income, were receiving antidepressant treatment more frequently, had a lower incidence of hypercholesterolemia, and had lower Mini-Mental State Examination scores (mean: -1.1 point; P < 0.0001). Plasma eicosapentaenoic acid (EPA) was lower in the subjects with DS than in the control subjects (0.85% compared with 1.01%; P = 0.001). There were no significant differences in any other fatty acid. When adjusted for potential confounders, such as sociodemographic characteristics and health indicators, plasma EPA was inversely associated with the severity of DS (beta = -0.170, P = 0.040) in subjects taking antidepressants. CONCLUSION: Higher plasma EPA was associated with a lower severity of DS in elderly subjects, especially those taking antidepressants.