Moderate offspring exercise offsets the harmful effects of maternal protein deprivation on mitochondrial function and oxidative balance by modulating sirtuins.

BACKGROUND AND AIMS: It has been demonstrated that maternal low protein during development induces mitochondrial dysfunction and oxidative stress in the heart. Moderate-intensity exercise in early life, conversely, increases the overall cardiac health. Thus, we hypothesize that moderate-intensity exercise performed during young age could ameliorate the deleterious effect of maternal protein deprivation on cardiac bioenergetics. METHODS AND RESULTS: We used a rat model of maternal protein restriction during gestational and lactation period followed by an offspring treadmill moderate physical training. Pregnant rats were divided into two groups: normal nutrition receiving 17% of casein in the diet and undernutrition receiving a low-protein diet (8% casein). At 30 days of age, the male offspring were further subdivided into sedentary (NS and LS) or exercised (NT and LT) groups. Treadmill exercise was performed as follows: 4 weeks, 5 days/week, 60 min/day at 50% of maximal running capacity. Our results showed that a low-protein diet decreases oxidative metabolism and mitochondrial function associated with higher oxidative stress. In contrast, exercise rescues mitochondrial capacity and promotes a cellular resilience to oxidative stress. Up-regulation of cardiac sirtuin 1 and 3 decreased acetylation levels, redeeming from the deleterious effect of protein restriction. CONCLUSION: Our findings show that moderate daily exercise during a young age acts as a therapeutical intervention opposing the harmful effects of a maternal diet restricted in protein.

Neonatal treatment with fluoxetine improves mitochondrial respiration and reduces oxidative stress in liver of adult rats.

Recent studies have shown that exposure to fluoxetine treatment induces excessive production of ROS, and alters the antioxidant defense system in various tissues and cell types, mainly the liver. When fluoxetine is administered intraperitoneally, the drug rapidly reaches high concentrations in the liver, has potentially multiple toxic effects on energy metabolism in rat liver mitochondria. The aim of this study was to evaluate the effect of pharmacological treatment with fluoxetine during critical period for development on the mitochondrial bioenergetics and oxidative stress in liver of rat adult. To perform this study, the rat pups received Fx, or vehicle (Ct) from postnatal day 1 to postnatal day 21 (ie, during lactation period). We evaluated mitochondrial oxygen consumption, respiratory control ratio, ROS production, mitochondrial swelling by pore opening, oxidative stress biomarkers, and antioxidant defense in liver of rats at 60 days of age. Our studies have shown, that treatment with Fx during the lactation period resulted in reduced body mass gain, improvement of the mitochondrial respiratory capacity, induced higher mitochondrial resistance to calcium ion preventing the mitochondrial permeability transition pore opening, as well as decreased oxidative stress biomarkers, and increased the SH levels and enzymes antioxidant activities (SOD, CAT, GST) in liver of treated rats at 60 days of age. These findings suggest that pharmacological treatment with fluoxetine during critical period of development result in positive changes in liver of rats, as improvement of the mitochondrial bioenergetics and hepatic oxidative metabolism that persist in adulthood.

Oxidative injuries induced by maternal low-protein diet in female brainstem.

Many studies have shown that a maternal low-protein diet increases the susceptibility of offspring to cardiovascular disease in later-life. Moreover, a lower incidence of cardiovascular disease in females than in males is understood to be largely due to the protective effect of high levels of estrogens throughout a woman's reproductive life. However, to our knowledge, the role of estradiol in moderating the later-life susceptibility of offspring of nutrient-deprived mothers to cardiovascular disease is not fully understood. The present study is aimed at investigating whether oxidative stress in the brainstem caused by a maternal low-protein diet administered during a critical period of fetal/neonatal brain development (i.e during gestation and lactation) is affected by estradiol levels. Female Wistar rat offspring were divided into four groups according to their mothers' diets and to the serum estradiol levels of the offspring at the time of testing: (1) 22 days of age/control diet: (2) 22 days of age/low-protein diet; (3) 122 days of age/control diet: (4) 122 days of age/low-protein diet. Undernutrition in the context of low serum estradiol compared to undernutrition in a higher estradiol context resulted in increased levels of oxidative stress biomarkers and a reduction in enzymatic and non-enzymatic antioxidant defenses. Total global oxy-score showed oxidative damage in 22-day-old rats whose mothers had received a low-protein diet. In the 122-day-old group, we observed a decrease in oxidative stress biomarkers, increased enzymatic antioxidant activity, and a positive oxy-score when compared to control. We conclude from these results that following a protein deficiency in the maternal diet during early development of the offspring, estrogens present at high levels at reproductive age may confer resistance to the oxidative damage in the brainstem that is very apparent in pre-pubertal rats.

Safflower (Carthamus tinctorius L.) oil during pregnancy and lactation influences brain excitability and cortex oxidative status in the rat offspring.

OBJECTIVES: To evaluate how safflower oil (SFO) influences brain electrophysiology and cortical oxidative status in the offspring, mothers received a diet with SFO during brain development period. METHODS: Beginning on the 14th day of gestation and throughout lactation, rats received safflower (safflower group - SG) or soybean oil (control group - CG) in their diet. At 65 days old, cortical spreading depression (CSD) and cortex oxidative status were analyzed in the offspring. RESULTS: SG presented reduction of the CSD velocity as compared to the CG (SG: 3.24 ± 0.09; CG: 3.37 ± 0.07 mm/min). SFO reduced levels of lipid peroxidation by 39.4%. SG showed the following increases: glutathione-S-transferase, 40.8% and reduced glutathione, 34.3%. However, SFO decreased superoxide dismutase by 40.4% and catalase by 64.1%. To control for interhemispheric effects, since CSD was recorded only in the right cortex, we evaluated the oxidative status in both sides of the cortex; no differences were observed. DISCUSSION: Data show that when SFO is consumed by the female rats during pregnancy and lactation, the offspring present long-term effects on brain electrophysiology and cortical oxidative state. The present study highlights the relevance of understanding the SFO intake of pregnant and lactating mammals.

Maternal protein restriction induced-hypertension is associated to oxidative disruption at transcriptional and functional levels in the medulla oblongata.

Maternal protein restriction during pregnancy and lactation predisposes the adult offspring to sympathetic overactivity and arterial hypertension. Although the underlying mechanisms are poorly understood, dysregulation of the oxidative balance has been proposed as a putative trigger of neural-induced hypertension. The aim of the study was to evaluate the association between the oxidative status at transcriptional and functional levels in the medulla oblongata and maternal protein restriction induced-hypertension. Wistar rat dams were fed a control (normal protein; 17% protein) or a low protein ((Lp); 8% protein) diet during pregnancy and lactation, and male offspring was studied at 90 days of age. Direct measurements of baseline arterial blood pressure (ABP) and heart rate (HR) were recorded in awakened offspring. In addition, quantitative RT-PCR was used to assess the mRNA expression of superoxide dismutase 1 (SOD1) and 2 (SOD2), catalase (CAT), glutathione peroxidase (GPx), Glutamatergic receptors (Grin1, Gria1 and Grm1) and GABA(A)-receptor-associated protein like 1 (Gabarapl1). Malondialdehyde (MDA) levels, CAT and SOD activities were examined in ventral and dorsal medulla. Lp rats exhibited higher ABP. The mRNA expression levels of SOD2, GPx and Gabarapl1 were down regulated in medullary tissue of Lp rats (P<.05, t test). In addition, we observed that higher MDA levels were associated to decreased SOD (approximately 45%) and CAT (approximately 50%) activities in ventral medulla. Taken together, our data suggest that maternal protein restriction induced-hypertension is associated with medullary oxidative dysfunction at transcriptional level and with impaired antioxidant capacity in the ventral medulla.

The deleterious effects of maternal protein deprivation on the brainstem are minimized with moderate physical activity by offspring during early life.

Maternal protein malnutrition during developmental periods might impair the redox state and the brain's excitatory/inhibitory neural network, increasing central sympathetic tone. Conversely, moderate physical exercise at an early age reduces the risk of chronic diseases. Thus, we hypothesized that a moderate training protocol could reduce the harmful effects of a low-protein maternal diet on the brainstem of young male offspring. We used a rat model of maternal protein restriction during the gestational and lactation period followed by an offspring's continuous treadmill exercise. Pregnant rats were divided into two groups according to the protein content in the diet: normoprotein (NP), receiving 17% of casein, and low protein (LP), receiving 8% of casein until the end of lactation. At 30 days of age, the male offspring were further subdivided into sedentary (NP-Sed and LP-Sed) or exercised (NP-Ex and LP-Ex) groups. Treadmill exercise was performed as follows: 4 weeks, 5 days/week, 60 min/day at 50% of maximal running capacity. The trained animals performed a treadmill exercise at 50% of the maximal running capacity, 60 min/day, 5 days/week, for 4 weeks. Our results indicate that a low-protein diet promotes deficits in the antioxidant system and a likely mitochondrial uncoupling. On the other hand, physical exercise restores the redox balance, which leads to decreased oxidative stress caused by the diet. In addition, it also promotes benefits to GABAergic inhibitory signaling. We conclude that regular moderate physical exercise performed in youthhood protects the brainstem against changes induced by maternal protein restriction.

Overweight during development dysregulates cellular metabolism and critical genes that control food intake in the prefrontal cortex.

BACKGROUNDS AND AIMS: Childhood obesity is increasing substantially across the world. The World Obesity Federation (WOF) and World Health Organization (WHO) predicted that in 2030 > 1 billion people will be obese, and by 2035 over 4 billion will reach obesity worldwide. According to WHO, the world soon cannot afford the economic cost of obesity, and we need to act to stop obesity acceleration now. Data in the literature supports that the first 1000 days of life are essential in preventing obesity and related adversities. Therefore, using basic research, the present a study that focuses on the immediate effect of overnutrition and serotonin modulation during the lactation period. METHODS: Using a neonatal overfeeding model, male Wistar rats were divided into four groups based on nutrition or serotonin modulation by pharmacological treatment up to 22 days of life. Cellular and mitochondrial function markers, oxidative stress biomarkers and mRNA levels of hedonic and homeostatic genes were evaluated. RESULTS: Our data showed that overfeeding during lactation decrease NAD/NADH ratio, citrate synthase activity, and increase ROS production. Lipid and protein oxidation were increased in overfed animals, with a decrease in antioxidant defenses, we also observe a differential expression of mRNA levels of homeostatic and hedonic genes. On the contrary, serotonin modulation with selective serotonin reuptake inhibitors treatment reduces harmful effects caused by overnutrition. CONCLUSION: Early effects of overnutrition significantly affect the prefrontal cortex at molecular and cellular level, which could mediate obesity-related neurodegenerative dysfunction.

The immediate effect of overnutrition and fluoxetine treatment during the critical period of development on the hippocampus.

It is well known that overnutrition, overweight, and obesity in children can modulate brain mechanisms of plasticity, monoaminergic systems, and mitochondrial function. The immediate effect of overnutrition during the developmental period has not been thoroughly examined in rats until the present. This study sought to evaluate the impact on adult rats of early life overfeeding and fluoxetine treatment from post-natal day 1 (PND1) to post-natal day 21 (PND21) relative to mitochondrial function, oxidative balance, and expression of specific monoaminergic genes in the hippocampus. The following were evaluated: mitochondrial function markers, oxidative stress biomarkers, dopamine-and serotonin-related genes, and BDNF mRNA levels. Overfeeding during the lactation period deregulates cellular metabolism and the monoaminergic systems in the hippocampus. Strikingly, serotonin modulation by fluoxetine treatment protected against some of the effects of early overnutrition. We conclude that overfeeding during brain development induce detrimental effects in mitochondria and in the genes that regulate homeostatic status that can be the molecular mechanisms related to neurological diseases.

Effects of fluoxetine withdrawal in the brainstem and hypothalamus of overnourished rats: Chronic modulation on oxidative stress levels.

Poor nutritional quality in the early stages of development is associated with neurological diseases in adulthood. Studies showed that obesity-induced oxidative stress contributes to the genesis of neurological diseases through dysregulation of the brainstem and hypothalamus. Fluoxetine (Fx) is an antidepressant member in the family of selective serotonin reuptake inhibitors (SSRI) that can induce positive effects by reducing oxidative damage in brain tissues. We aimed to evaluate the late effect of Fx in the brainstem and hypothalamus of overnourished rats during development. Male Wistar rats, after birth, were randomly divided into the normal-nourished group (N, n = 9) and the overnourished group (O, n = 3). On the 39th day of life, the groups were subdivided into normofed, and the overnourished group treated or not with fluoxetine (10 mg/kg daily) (NF, NV, OF, and OV). All groups were treated from the 39th to the 59th day of life, and within 90 days, the tissues were collected for oxidative stress analysis. Briefly, our results showed that Fx treatment induced a tissue-dependent long-lasting effect in overfed animals, increasing the enzymatic defense (i.e., CAT and GST activity) in the hypothalamus, but more intensive, increasing the non-enzymatic defense (i.e., Total Thiols and GSH levels) in the brainstem. Overall, our study suggests that serotonin modulation at the final stage of brain development causes a long-lasting impact on brain structures in overfed rats at a different mode.

Sex differences in the phosphorylation of mitochondrial proteins result in reduced production of reactive oxygen species and cardioprotection in females.

RATIONALE: Although premenopausal females have a lower risk for cardiovascular disease, the mechanism(s) are poorly understood. OBJECTIVE: We tested the hypothesis that cardioprotection in females is mediated by altered mitochondrial protein levels and/or posttranslational modifications. METHODS AND RESULTS: Using both an in vivo and an isolated heart model of ischemia and reperfusion (I/R), we found that females had less injury than males. Using proteomic methods we found that female hearts had increased phosphorylation and activity of aldehyde dehydrogenase (ALDH)2, an enzyme that detoxifies reactive oxygen species (ROS)-generated aldehyde adducts, and that an activator of ALDH2 reduced I/R injury in males but had no significant effect in females. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, blocked the protection and the increased phosphorylation of ALDH2 in females, but had no effect in males. Furthermore, we found an increase in phosphorylation of alpha-ketoglutarate dehydrogenase (alphaKGDH) in female hearts. alphaKGDH is a major source of ROS generation particularly with a high NADH/NAD ratio which occurs during I/R. We found decreased ROS generation in permeabilized female mitochondria given alphaKGDH substrates and NADH, suggesting that increased phosphorylation of alphaKGDH might reduce ROS generation by alphaKGDH. In support of this hypothesis, we found that protein kinase C-dependent phosphorylation of purified alphaKGDH reduced ROS generation. Additionally, myocytes from female hearts had less ROS generation following I/R than males and addition of wortmannin increased ROS generation in females to the same levels as in males. CONCLUSIONS: These data suggest that posttranslational modifications can modify ROS handling and play an important role in female cardioprotection.

Maternal safflower oil consumption improve reflex maturation, memory and reduces hippocampal oxidative stress in the offspring rats treated during pregnancy and lactation.

OBJECTIVE: Evaluate the influence of maternal consumption of safflower oil on reflex maturation, memory and offspring hippocampal oxidative stress. METHODOLOGY: Two groups were formed: control group (C), whose mothers received a standard diet, and Safflower group (SF), whose mothers received a normolipidic diet with safflower oil as lipid source. Treatment was given from the 14th day of gestation and throughout lactation. To evaluate newborn development, the reflex ontogeny indicators between the 1st and the 21st days of life were evaluated; to assess memory, from the 42nd day of life on these animals were examined on open field habituation and novel object recognition test. Following behavioral analysis, the animals were anesthetized and decapitated. Hippocampus was rapidly dissected. In the hippocampal tissues, we evaluated the levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione S transferase (GST) and reduced glutathione (GSH). RESULTS: SF offspring showed delayed maturation of reflexes and improvement of novel object recognition in short-term and long-term (p < 0.05). Safflower oil decreases lipid peroxidation evaluated by MDA levels (p < 0.001) and increases antioxidant defenses as shown by SOD, CAT, GST and GSH levels (p < 0.05). In our study, the composition of flavonoids present in the oil was not evaluated. Furthermore, in a future study, the effect of maternal consumption on female offspring should be verified. CONCLUSION: Maternal intake of safflower oil could: (1) change neonate reflex parameters, (2) promote improvement of cognitive development in adolescence (3) improve antioxidant enzymatic and non-enzymatic defenses in the hippocampus.

Stress and circulating cell-free mitochondrial DNA: A systematic review of human studies, physiological considerations, and technical recommendations.

Cell-free mitochondrial DNA (cf-mtDNA) is a marker of inflammatory disease and a predictor of mortality, but little is known about cf-mtDNA in relation to psychobiology. A systematic review of the literature reveals that blood cf-mtDNA varies in response to common real-world stressors including psychopathology, acute psychological stress, and exercise. Moreover, cf-mtDNA is inducible within minutes and exhibits high intra-individual day-to-day variation, highlighting the dynamic regulation of cf-mtDNA levels. We discuss current knowledge on the mechanisms of cf-mtDNA release, its forms of transport ("cell-free" does not mean "membrane-free"), potential physiological functions, putative cellular and neuroendocrine triggers, and factors that may contribute to cf-mtDNA removal from the circulation. A review of in vitro, pre-clinical, and clinical studies shows conflicting results around the dogma that physiological forms of cf-mtDNA are pro-inflammatory, opening the possibility of other physiological functions, including the cell-to-cell transfer of whole mitochondria. Finally, to enhance the reproducibility and biological interpretation of human cf-mtDNA research, we propose guidelines for blood collection, cf-mtDNA isolation, quantification, and reporting standards, which can promote concerted advances by the community. Defining the mechanistic basis for cf-mtDNA signaling is an opportunity to elucidate the role of mitochondria in brain-body interactions and psychopathology.

Effects of glutamine supplementation on kidney of diabetic rat.

Glutamine is the most important donor of NH(3) in kidney playing an important role in acid-base buffering system. Besides this effect, glutamine presents many other relevant functions in the whole body, such as a precursor of arginine in adult and neonates. In addition to these effects, some studies have shown that glutamine can potentiate renal disease. In the present study, the effect of short-term treatment (15 days) with glutamine on control and diabetic rats was investigated. Using biochemical, histological and molecular biology analysis from control and diabetic rats we verified that glutamine supplementation increase in pro-inflammatory interleukins (IL)-1beta and IL-6 content in renal cortex and induce alteration in glomerular characteristics. This study showed that short-term treatment with glutamine in association with increased glucose levels could cause important alterations in glomerular morphology that may result in fast progression of kidney failure.

A maternal low-protein diet and neonatal overnutrition result in similar changes to glomerular morphology and renal cortical oxidative stress measures in male Wistar rats.

There is a strong correlation between inadequate gestational and postpartum nutrition and the occurrence of cardiovascular diseases. The present study investigated the effects of a maternal low-protein diet and neonatal overfeeding on the oxidative balance and morphology of the renal cortex of male Wistar rats. Two independent protocols were used. First, pregnant Wistar rats received diets containing either 17% (normal protein) or 8% (low protein) casein throughout pregnancy and lactation. Second, the litter size was reduced by one-third on the third postnatal day to induce overnourishment in offspring. At 30 days, the oxidative balance and morphology of the renal cortex were analyzed. There was a small but significant increase in renal corpuscle area in the low protein (LP, 5%) and overnutrition (ON, 8%) groups. Glomerular tuft area also increased in LP (6%) and ON (9%), as did glomerular cellularity (LP, +11%; ON, +12%). In the oxidative stress analyses, both nutritional insults significantly elevated lipid peroxidation (LP, +18%; ON, +135%) and protein oxidation (LP, +40%; ON, +65%) while significantly reducing nonenzymatic antioxidant defenses, measured as reduced glutathione (LP, -32%; ON, -45%) and total thiol content (LP, -28%; ON, -24%). We also observed a decrease in superoxide dismutase (LP, -78%; ON, -51%), catalase (LP, -18%; ON, -61%), and glutathione S-transferase (only in ON, -44%) activities. Our results demonstrate that nutritional insults, even those of a very different nature, during perinatal development can result in similar changes in oxidative parameters and glomerular morphology in the renal cortex.

Maternal Protein Restriction in Two Successive Generations Impairs Mitochondrial Electron Coupling in the Progeny's Brainstem of Wistar Rats From Both Sexes.

Maternal protein deficiency during the critical development period of the progeny disturbs mitochondrial metabolism in the brainstem, which increases the risk of developing cardiovascular diseases in the first-generation (F1) offspring, but is unknown if this effect persists in the second-generation (F2) offspring. The study tested whether mitochondrial health and oxidative balance will be restored in F2 rats. Male and female rats were divided into six groups according to the diet fed to their mothers throughout gestation and lactation periods. These groups were: (1) normoprotein (NP) and (2) low-protein (LP) rats of the first filial generation (F1-NP and F1-LP, respectively) and (3) NP and (4) LP rats of the second filial generation (F2-NP and F2-LP, respectively). After weaning, all groups received commercial chow and a portion of each group was sacrificed on the 30th day of life for determination of mitochondrial and oxidative parameters. The remaining portion of the F1 group was mated at adulthood and fed an NP or LP diet during the periods of gestation and lactation, to produce progeny belonging to (5) F2R-NP and (6) F2R-LP group, respectively. Our results demonstrated that male F1-LP rats suffered mitochondrial impairment associated with an 89% higher production of reactive species (RS) and 137% higher oxidative stress biomarkers, but that the oxidative stress was blunted in female F1-LP animals despite the antioxidant impairment. In the second generation following F0 malnutrition, brainstem antioxidant defenses were restored in the F2-LP group of both sexes. However, F2R-LP offspring, exposed to LP in the diets of the two preceding generations displayed a RS overproduction with a concomitant decrease in mitochondrial bioenergetics. Our findings demonstrate that nutritional stress during the reproductive life of the mother can negatively affect mitochondrial metabolism and oxidative balance in the brainstem of F1 progeny, but that restoration of a normal diet during the reproductive life of those individuals leads toward a mitochondrial recovery in their own (F2) progeny. Otherwise, if protein deprivation is continued from the F0 generation and into the F1 generation, the F2 progeny will exhibit no recovery, but instead will remain vulnerable to further oxidative damage.

Glutamine enhances glucose-induced mesangial cell proliferation.

The proliferation of mesangial cells (MC) in the presence of glutamine (0-20 mM) was determined in both low (5 mM) and high (25 mM) glucose-containing medium. Glutamine in a high glucose (HG) environment increased cell proliferation in a dose-dependent manner. Inhibition of glutamine:fructose 6-phosphate amidotransferase (GFAT) and of phosphodiesterase significantly reduced glutamine-induced proliferation. Supraphysiologic levels of glutamine increase MC proliferation in a HG milieu via GFAT and cAMP-dependent pathways, suggesting that glutamine could pose a risk for diabetic nephropathy.

Protective effects of estrogen against cardiovascular disease mediated via oxidative stress in the brain.

During their reproductive years women produce significant levels of estrogens, predominantly in the form of estradiol, that are thought to play an important role in cardioprotection. Mechanisms underlying this action include both estrogen-mediated changes in gene expression, and post-transcriptional activation of protein signaling cascades in the heart and in neural centers controlling cardiovascular function, in particular, in the brainstem. There, specific neurons, especially those of the bulbar region play an important role in the neuronal control of the cardiovascular system because they control the outflow of sympathetic activity and parasympathetic activity as well as the reception of chemical and mechanical signals. In the present review, we discuss how estrogens exert their cardioprotective effect in part by modulating the actions of internally generated products of cellular oxidation such as reactive oxygen species (ROS) in brain stem neurons. The significance of this review is in integrating the literature of oxidative damage in the brain with the literature of neuroprotection by estrogen in order to better understand both the benefits and limitations of using this hormone to prevent cardiovascular disease.

Fish oil supplementation reverses behavioral and neurochemical alterations induced by swimming exercise in rats.

Diet and exercise are known to affect learning and memory. However, the effects of these interventions in the brain under development remains to be better investigated as the effects of high-intensity exercise. Moreover, it is still unclear how long the influence of diet and exercise lasts after the interventions are ceased. To investigate this, juvenile Wistar rats (30 days old) were supplemented with fish oil rich in polyunsaturated fatty acids (PUFAs) and performed swimming training for 50 days, 45 min per day, 5 times/week. The animals were assessed for locomotor activity with the open field test and for spatial memory with the object location task. To investigate neurochemical parameters such as fatty acids incorporation within the plasma membrane and brain-derived neurotrophic factor (BDNF) levels, the animals were euthanized, and the hippocampus dissected. These investigations were made at the end of the supplementation and exercise protocols and 21 days after the protocol has ended. Results indicate that high-intensity exercise impaired the spatial memory and decreased the levels of BDNF. Although supplementation led to PUFAs incorporation in plasma membrane, it did not prevent the harmful effect of exercise on memory. After 21 days of interruption, we observed that the supplementation reversed not only the deleterious effect of exercise on memory but also increased the BDNF levels. These results point to a complex influence of diet and exercise on spatial memory of juvenile rats, persisting after 21 days of interruption.

LipoCardium: endothelium-directed cyclopentenone prostaglandin-based liposome formulation that completely reverses atherosclerotic lesions.

Atherosclerosis is a multifactorial inflammatory disease of blood vessels which decimates one in every three people in industrialized world. Despite the important newest clinical approaches, currently available strategies (e.g. nutritional, pharmacological and surgical) may only restrain the worsening of vascular disease. Since antiproliferative cyclopentenone prostaglandins (CP-PGs) are powerful anti-inflammatory agents, we developed a negatively charged liposome-based pharmaceutical formulation (LipoCardium) that specifically direct CP-PGs towards the injured arterial wall cells of atherosclerotic mice. In the blood stream, LipoCardium delivers its CP-PG contents only into activated arterial wall lining cells due to the presence of antibodies raised against vascular cell adhesion molecule-1 (VCAM-1), which is strongly expressed upon inflammation by endothelial cells and macrophage-foam cells as well. After 4 months in a high-lipid diet, all low-density lipoprotein receptor-deficient adult control mice died from myocardium infarction or stroke in less than 2 weeks, whereas LipoCardium-treated (2 weeks) animals (still under high-lipid diet) completely recovered from vascular injuries. In vitro studies using macrophage-foam cells suggested a tetravalent pattern for LipoCardium action: anti-inflammatory, antiproliferative (and pro-apoptotic only to foam cells), antilipogenic and cytoprotector (via heat-shock protein induction). These astonishing cellular effects were accompanied by a marked reduction in arterial wall thickness, neointimal hyperplasia and lipid accumulation, while guaranteed lifespan to be extended to the elderly age. Our findings suggest that LipoCardium may be safely tested in humans in a near future and may have conceptual implications in atherosclerosis therapy.

[Molecular bases of diabetic nephropathy]. / Bases moleculares da glomerulopatia diabética.

The determinant of the diabetic nephropathy is hyperglycemia, but hypertension and other genetic factors are also involved. Glomerulus is the focus of the injury, where mesangial cell proliferation and extracellular matrix occur because of the increase of the intra- and extracellular glucose concentration and overexpression of GLUT1. Sequentially, there are increases in the flow by the poliol pathway, oxidative stress, increased intracellular production of advanced glycation end products (AGEs), activation of the PKC pathway, increase of the activity of the hexosamine pathway, and activation of TGF-beta1. High glucose concentrations also increase angiotensin II (AII) levels. Therefore, glucose and AII exert similar effects in inducing extracellular matrix formation in the mesangial cells, using similar transductional signal, which increases TGF-beta1 levels. In this review we focus in the effect of glucose and AII in the mesangial cells in causing the events related to the genesis of diabetic nephropathy. The alterations in the signal pathways discussed in this review give support to the observational studies and clinical assays, where metabolic and antihypertensive controls obtained with angiotensin-converting inhibitors have shown important and additive effect in the prevention of the beginning and progression of diabetic nephropathy. New therapeutic strategies directed to the described intracellular events may give future additional benefits.