Spatial memory deficits in maternal iron deficiency paradigms are associated with altered glucocorticoid levels

"The goal of this study was to examine the effect of maternal iron deficiency on the developing hippocampus in order to define a developmental window for this effect, and to see whether iron deficiency causes changes in glucocorticoid levels. The study was carried out using pre-natal, post-natal, and pre + post-natal iron deficiency paradigm. Iron deficient pregnant dams and their pups displayed elevated corticosterone which, in turn, differentially affected glucocorticoid receptor (GR) expression in the CA1 and the dentate gyrus. Brain Derived Neurotrophic Factor (BDNF) was reduced in the hippocampi of pups following elevated corticosterone levels. Reduced neurogenesis at P7 was seen in pups born to iron deficient mothers, and these pups had reduced numbers of hippocampal pyramidal and granule cells as adults. Hippocampal subdivision volumes also were altered. The structural and molecular defects in the pups were correlated with radial arm maze performance; reference memory function was especially affected. Pups from dams that were iron deficient throughout pregnancy and lactation displayed the complete spectrum of defects, while pups from dams that were iron deficient only during pregnancy or during lactation displayed subsets of defects. These findings show that maternal iron deficiency is associated with altered levels of corticosterone and GR expression, and with spatial memory deficits in their pups."     

Adipokine levels are altered by shiftwork: a preliminary study

Shiftwork is often associated with metabolic diseases, and in the past few years, several cytokines have been postulated to contribute to various diseases, including insulin resistance. The aim of this study was to compare the concentrations of adiponectin, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in samples of young adult men exposed to a fixed (i) night shift (n = 9), working from 22:00 to 06:00 h; (ii) early morning shift (n = 6), working from 06:00 to 14:00 h; and (iii) day shift (n = 7), working from 08:00 to 17:00 h. The fixed night-shift and early-morning-shift samples were considered collectively as a shiftworker group given their work times. Blood samples were collected during the regular working day at 4-h intervals over the course of 24 h, thus totaling six samples. Morphological and physical activity parameters did not differ between the three groups. Total energy intake was lowest on the early morning shifts (p 相似文献   

GABA concentration and GABAergic neuron populations in limbic areas are differentially altered by brain serotonin deficiency in Tph2 knockout mice

While tryptophan hydroxylase-2 (Tph2) null mutant (Tph2 ^?/?) mice are completely deficient in brain serotonin (5-HT) synthesis, the formation of serotonergic neurons and pathfinding of their projections are not impaired. However, 5-HT deficiency, during development and in the adult, might affect morphological and functional parameters of other neural systems. To assess the influence of 5-HT deficiency on γ-amino butyric acid (GABA) systems, we carried out measurements of GABA concentrations in limbic brain regions of adult male wildtype (wt), heterozygous (Tph2 ^+/?) and Tph2 ^?/? mice. In addition, unbiased stereological estimation of GABAergic interneuron numbers and density was performed in subregions of amygdala and hippocampus. Amygdala and prefrontal cortex displayed significantly increased and decreased GABA concentrations, respectively, exclusively in Tph2 ^+/? mice while no changes were detected between Tph2 ^?/? and wt mice. In contrast, in the hippocampus, increased GABA concentrations were found in Tph2 ^?/? mice. While total cell density in the anterior basolateral amygdala did not differ between genotypes, the number and density of the GABAergic interneurons were significantly decreased in Tph2 ^?/? mice, with the group of parvalbumin (PV)-immunoreactive (ir) interneurons contributing somewhat less to the decrease than that of non-PV-ir GABAergic interneurons. Major morphological changes were also absent in the dorsal hippocampus, and only a trend toward reduced density of PV-ir cells was observed in the CA3 region of Tph2 ^?/? mice. Our findings are the first to document that life-long reduction or complete lack of brain 5-HT transmission causes differential changes of GABA systems in limbic regions which are key players in emotional learning and memory processes. The changes likely reflect a combination of developmental alterations and functional adaptations of emotion circuits to balance the lack of 5-HT, and may underlie altered emotional behavior in 5-HT-deficient mice. Taken together, our findings provide further insight into the mechanisms how life-long 5-HT deficiency impacts the pathogenesis of anxiety- and fear-related disorders.     

Basal and evoked levels of bioassayable growth hormone are altered by hindlimb unloading.

Bioassayable growth hormone (BGH) in rats is released in large quantities from the pituitary in response to the activation of large, proprioceptive afferent fibers from fast and mixed fiber-type hindlimb musculature. We hypothesized that hindlimb unloading (HU) of adult male rats would 1) reduce the basal levels of plasma BGH, and 2) abolish stimulus-induced BGH release. Rats were exposed to HU for 1, 4, or 8 wk. Plasma and pituitaries were collected under isoflurane anesthesia for hormone analyses. Additionally, at 4 and 8 wk, a subset of rats underwent an in situ electrical stimulation (Stim) of tibial nerve proprioceptive afferents. Basal plasma BGH levels were significantly reduced (-51 and -23%) after 1 and 8 wk of HU compared with ambulatory controls (Amb). Although Amb-Stim rats exhibited increased plasma BGH levels (88 and 143%) and decreased pituitary BGH levels (-27 and -22%) at 4 and 8 wk, respectively, stimulation in HU rats had the opposite effect, reducing plasma BGH (-25 and -33%) and increasing pituitary BGH levels (47 and 10%) relative to HU alone at 4 and 8 wk. The 22-kDa form of GH measured by immunoassay and the plasma corticosterone, T3, T4, and testosterone levels were unchanged by HU or Stim at all time points. These data suggest that BGH synthesis and release from the pituitary are sensitive both to chronically reduced neuromuscular loading and to acute changes in neuromuscular activation, independent of changes in other circulating hormones. Thus BGH may play a role in muscle, bone, and metabolic adaptations that occur in response to chronically unloaded states.     

Detection of genetically altered copper levels in Drosophila tissues by synchrotron x-ray fluorescence microscopy

Tissue-specific manipulation of known copper transport genes in Drosophila tissues results in phenotypes that are presumably due to an alteration in copper levels in the targeted cells. However direct confirmation of this has to date been technically challenging. Measures of cellular copper content such as expression levels of copper-responsive genes or cuproenzyme activity levels, while useful, are indirect. First-generation copper-sensitive fluorophores show promise but currently lack the sensitivity required to detect subtle changes in copper levels. Moreover such techniques do not provide information regarding other relevant biometals such as zinc or iron. Traditional techniques for measuring elemental composition such as inductively coupled plasma mass spectroscopy are not sensitive enough for use with the small tissue amounts available in Drosophila research. Here we present synchrotron x-ray fluorescence microscopy analysis of two different Drosophila tissues, the larval wing imaginal disc, and sectioned adult fly heads and show that this technique can be used to detect changes in tissue copper levels caused by targeted manipulation of known copper homeostasis genes.     

Precipitation of a selenium deficiency by high dietary levels of copper and zinc.

High mortality and a high incidence of exudative diathesis and muscular dystrophy were observed in chicks fed a diet supplemented with either 800 or 1600 ppm copper. Adding 0.5 ppm selenium to a basal diet containing 0.2 ppm prevented mortality and selenium deficiency signs. Dietary zinc levels of 2100 to 4100 ppm also resulted in high mortality, exudative diathesis, and muscular dystrophy. A selenium supplement of 0.5 ppm completely prevented the deficiency signs and markedly reduced mortality. The results demonstrate that both copper and zinc can induce a selenium deficiency in chicks when a diet relatively low in this element is fed.     

Protein kinase and cyclic AMP levels in differentiating myoblasts are altered by extracellular calcium

Protein kinase specific activities and cyclic AMP levels show a similar pattern of response, when the Ca²⁺ concentration is altered in the culture medium of differentiating chick skeletal muscle cells; an increase at intermediate Ca²⁺ concentrations (0.05–0.2mM), followed by a decrease at higher concentrations (2mM). Effects of Ca²⁺ on protein kinase appear to be on cyclic AMP-independent enzymes in both nucleus and cytoplasm, and are quite the reverse of Ca²⁺ effects on the muscle-specific enzyme, creatine kinase.     

Plant morphology and root hydraulics are altered by nutrient deficiency in Pistacia lentiscus (L.)

The plants in arid and semiarid areas are often limited by water and nutrients. Morpho-functional adjustments to improve nutrient capture may have important implications on plant water balance, and on plant capacity to withstand drought. Several studies have shown that N and P deficiencies may decrease plant hydraulic conductance. Surprisingly, studies on the implications of nutrient limitations on water use in xerophytes are scarce. We have evaluated the effects of strong reductions in nitrogen and phosphorus availability on morphological traits and hydraulic conductance in seedlings of a common Mediterranean shrub, Pistacia lentiscus L.. Nitrogen deficiency resulted in a decrease in aboveground biomass accumulation, but it did not affect belowground biomass accumulation or root morphology. Phosphorus-deficient plants showed a decrease in leaf area, but no changes in aboveground biomass. Root length, root surface area, and specific root length were higher in phosphorus-deficient plants than in control plants. Nitrogen and phosphorus deficiency reduced both root hydraulic conductance and root hydraulic conductance scaled by total root surface area. On the other hand, nutrient limitations did not significantly affect root conductance per unit of foliar surface area. Thus, adaptation to low nutrient availability did not affect seedling capacity for maintaining water supply to leaves. The implications for drought resistance and survival during seedling establishment in semi-arid environments are discussed.     

Steroid levels in crinoid echinoderms are altered by exposure to model endocrine disruptors

Sexual steroids (testosterone and estradiol) were measured in the whole body of wild specimens of the crinoid Antedon mediterranea collected from the Tyrrhenian Sea (Italy). Testosterone levels (274-1,488 pg/g wet weight (w.w.)) were higher than those of estradiol (60-442 pg/g w.w.) and no significant differences between males and females were observed. No clear seasonal trend was either detected - individuals from February, June and October 2004 analyzed - apart from a peak of estradiol in males in autumn. Nonetheless, dramatic changes on tissue steroid levels were observed when individuals were exposed to model androgenic and anti-androgenic compounds for 2 and 4 weeks. The selected compounds were 17 alpha-methyltestosterone (17 alpha-MT), triphenyltin (TPT), fenarimol (FEN), cyproterone acetate (CPA), and p,p'-DDE. Endogenous testosterone levels were significantly increased after exposure to 17 alpha-MT, TPT and FEN, while different responses were observed for estradiol; 17 alpha-MT and FEN increased endogenous estradiol (up to seven-fold), and TPT lead to a significant decrease. Concerning the anti-androgenic compounds, CPA significantly reduced testosterone in a dose-dependent manner without altering estradiol levels, whereas specimens exposed to p,p'-DDE at a low dose (24 ng/L) for 4 weeks showed a four-fold increase in T levels. Overall, the data show the ability of the selected compounds to alter endogenous steroid concentrations in A. mediterranea, and suggest the existence in this echinoderm species of vertebrate-like mechanisms that can be affected by exposure to androgenic and anti-androgenic chemicals.     

A study of copper treatment and tissue copper levels in the murine congenital copper deficiency, mottled.

The injection of copper chloride overcomes the lethality and pigment deficiency in the brindled ($\text{Mo}$^br) mouse mutant but copper levels remain depressed in the liver and brain, and a further accumulation occurs in the kidney. The copper-dependent synthesis of brain noradrenaline returns to normal but the activity of brain cytochrome c oxidase, although increased, remains depressed. Significant changes in tissue copper content of female brindled heterozygotes are reported and in each case, the changes exceed those expected on the basis of X-inactivation. The significance of these results to the development of a satisfactory treatment regime for this disease is discussed.     

Early and advanced glycation end-products are increased in dietary copper deficiency

The hypothesis that nonenzymatic glycosylation of proteins (glycation) contributes to damage associated with dietary copper deficiency has depended largely on indirect evidence. Thus far, the observation of an elevated percentage of glycated hemoglobin in copper-deficient rats has provided the only direct evidence of an increase in glycation. We sought further direct evidence of increased glycation in copper deficiency. Male weanling rats were fed a copper-adequate (CuA, 6.4 mg Cu/kg diet) or copper-deficient diet (CuD, 0.4 mg Cu/kg diet) for 5 weeks. Rats fed the CuD diet were copper deficient as judged by depressed organ copper concentrations and a variety of indirect indices. Measurements of hemoglobin A(1) and serum fructosamine (both early glycation end-products) as well as serum pentosidine (an advanced glycation end-product) indicated that all three compounds were elevated in CuD rats relative to CuA rats. This finding further supports the view that glycation is enhanced and thus may contribute to defects associated with dietary copper deficiency.     

Cardiolipin biosynthesis and remodeling enzymes are altered during development of heart failure

Cardiolipin (CL) is responsible for modulation of activities of various enzymes involved in oxidative phosphorylation. Although energy production decreases in heart failure (HF), regulation of cardiolipin during HF development is unknown. Enzymes involved in cardiac cardiolipin synthesis and remodeling were studied in spontaneously hypertensive HF (SHHF) rats, explanted hearts from human HF patients, and nonfailing Sprague Dawley (SD) rats. The biosynthetic enzymes cytidinediphosphatediacylglycerol synthetase (CDS), phosphatidylglycerolphosphate synthase (PGPS) and cardiolipin synthase (CLS) were investigated. Mitochondrial CDS activity and CDS-1 mRNA increased in HF whereas CDS-2 mRNA in SHHF and humans, not in SD rats, decreased. PGPS activity, but not mRNA, increased in SHHF. CLS activity and mRNA decreased in SHHF, but mRNA was not significantly altered in humans. Cardiolipin remodeling enzymes, monolysocardiolipin acyltransferase (MLCL AT) and tafazzin, showed variable changes during HF. MLCL AT activity increased in SHHF. Tafazzin mRNA decreased in SHHF and human HF, but not in SD rats. The gene expression of acyl-CoA: lysocardiolipin acyltransferase-1, an endoplasmic reticulum MLCL AT, remained unaltered in SHHF rats. The results provide mechanisms whereby both cardiolipin biosynthesis and remodeling are altered during HF. Increases in CDS-1, PGPS, and MLCL AT suggest compensatory mechanisms during the development of HF. Human and SD data imply that similar trends may occur in human HF, but not during nonpathological aging, consistent with previous cardiolipin studies.     

Animal models of CRH excess and CRH receptor deficiency display altered adaptations to stress

This review highlights new information gained from studies using recently developed animal models that harbor specific alterations in corticotropin-releasing hormone (CRH) pathways. We discuss features of a transgenic mouse model of chronic CRH overexpression and two mouse models that lack either CRH receptor type 1 (CRH-R1) or type 2 (CRH-R2). Together these models provide new insights into the role of CRH pathways in promoting stability through adaptive changes, a process known as allostasis.     

Effect of interferon-alpha on tyrosine hydroxylase and catecholamine levels in the brain of rats

We investigated the effect of interferon on tyrosine hydroxylase (TH) and catecholamine levels in the brains of 12-week-old male Wistar rats. Interferon-alpha (300,000 IU/kg/day, s.c.) was administered to rats for 7 days. Locomotor activity of interferon-alpha-treated rats was significantly lower than that of control rats. Norepinephrine and dopamine levels and TH activities in the cerebral cortex, hypothalamus and medulla oblongata of interferon-alpha-treated rats were significantly higher than those of control rats. Norepinephrine and dopamine levels and TH activities in the thalamus and hippocampus were not different between interferon-alpha treated and control rats. These results suggest that interferon-alpha-induced depression may be related to change in the catecholamine synthetic pathway in the central nervous system.     

The effect of copper deficiency on heart microsomal phosphatidylcholine biosynthesis and concentration

The effect of dietary copper deficiency on phosphatidylcholine biosynthetic enzymes, phosphatidylethanolamine methyltransferase, phosphatidyldimethyltransferase and choline phosphotransferase of heart microsomes was measured in rats. The data indicated that dietary copper deficiency can alter phosphatidylcholine biosynthesis and concentration in microsomal membranes of the heart. There was a significant decrease in the specific activity of choline phosphotransferase. There was a significant decrease in the concentration of total phospholipid-P, phosphatidylcholine-P, phosphatidylethanolamine-P, phosphatidylinositol-P, sphingomyelin-P and cardiolipin-P in the microsomes of the copper deficient animals. There was a significant decrease in the concentration of copper in microsomes of heart and liver in the copper deficient animals.     

Changes in copper and zinc status and response to dietary copper deficiency in metallothionein-overexpressing transgenic mouse heart

Previous studies have shown that cardiac-specific overexpression of metallothionein (MT) inhibits progression of dietary copper restriction-induced cardiac hypertrophy. Because copper and zinc are critically involved in myocardial response to dietary copper restriction, the present study was undertaken to understand the effect of MT on the status of copper and zinc in the heart and the subsequent response to dietary copper restriction. Dams of cardiac-specific MT-transgenic (MT-TG) mouse pups and wild-type (WT) littermates were fed copper-adequate (CuA) or copper-deficient (CuD) diet starting on the fourth day post delivery, and the weanling mice were continued on the same diet until they were sacrificed. Zinc and copper concentrations were significantly elevated in MT-TG mouse heart, but the extent of zinc elevation was much more than that of copper. Dietary copper restriction significantly decreased copper concentrations to the same extent in both MT-TG and WT mouse hearts, and decreased zinc concentrations along with a decrease in MT concentrations in the MT-TG mouse heart. Copper deficiency-induced heart hypertrophy was significantly inhibited, but copper deficiency-induced suppression of serum ceruloplasmin or hepatic Cu,Zn-SOD activities was not inhibited in the MT-TG mice. These results suggest that elevation in zinc but not in copper in the heart may be involved in the MT inhibition of copper deficiency-induced cardiac hypertrophy.     

Deciphering phenotypic variance in different models of DNA-PKcs deficiency

DNA-PKcs deficiency has been studied in numerous animal models and cell culture systems. In previous studies of kinase inactivating mutations in cell culture systems, ablation of DNA-PK's catalytic activity results in a cell phenotype that is virtually indistinguishable from that ascribed to complete loss of the enzyme. However, a recent compelling study demonstrates a remarkably more severe phenotype in mice harboring a targeted disruption of DNA-PK's ATP binding site as compared to DNA-PKcs deficient mice. Here we investigate the mechanism for these divergent results. We find that kinase inactivating DNA-PKcs mutants markedly radiosensitize immortalized DNA-PKcs deficient cells, but have no substantial effects on transformed DNA-PKcs deficient cells. Since the non-homologous end joining mechanism likely functions similarly in all of these cell strains, it seems unlikely that kinase inactive DNA-PK could impair the end joining mechanism in some cell types, but not in others. In fact, we observed no significant differences in either episomal or chromosomal end joining assays in cells expressing kinase inactivated DNA-PKcs versus no DNA-PKcs. Several potential explanations could explain these data including a non-catalytic role for DNA-PKcs in promoting cell death, or alteration of gene expression by loss of DNA-PKcs as opposed to inhibition of its catalytic activity.Finally, controversy exists as to whether DNA-PKcs autophosphorylates or is the target of other PIKKs; we present data demonstrating that DNA-PK primarily autophosphorylates.