113 research outputs found

    The Association between Vitamin D Receptor Expression and Prolonged Overall Survival in Breast Cancer.

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    Summary In this study, we analyzed vitamin D receptor (VDR) expression and survival in a breast cancer patient cohort of 82 breast cancer patients. Immunohistochemical analysis was possible in 91.5% of the patients (75/82). Staining was evaluated using the semi-quantitative assay according to Remmele and Stegner (immunoreactivity score [IRS]). IRS 0–1 was negative/very low, IRS 2–4 was moderate to high, and IRS 6–12 was high. Statistical analysis was performed by Spearman’s correlation test (p<0.05 significant). Overall survival was analyzed using Kaplan-Meier estimations. Only 6 patients had a negative IRS. Moderate IRS values were present in 20 patients. Most of the patients had a high IRS (49). For survival analysis, data were dichotomized (IRS 0–4: negative to moderate and IRS 6–12: high VDR expression). In univariate analysis, VDR expression showed significant differences in progression-free survival (PFS) and overall survival (OS). Patients with high IRS scores showed significantly better PFS and OS than patients with moderate/negative IRS scores for VDR expression. Tumor size was significantly correlated to PFS. When analyzed separately, the three different IRS groups showed significant differences in VDR expression. The present data suggest that VDR expression in breast cancer tissue may be of clinical significance, and the results provide evidence that VDR may be a factor with prognostic relevance. (J Histochem Cytochem 60:121–129, 2012). Keywords: breast cancer, vitamin D receptor, immunohistochemistry, prognosi

    Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

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    The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions

    Neurosteroid Dehydroepiandrosterone Interacts with Nerve Growth Factor (NGF) Receptors, Preventing Neuronal Apoptosis

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    The neurosteroid dehydroepiandrosterone (DHEA), produced by neurons and glia, affects multiple processes in the brain, including neuronal survival and neurogenesis during development and in aging. We provide evidence that DHEA interacts with pro-survival TrkA and pro-death p75NTR membrane receptors of neurotrophin nerve growth factor (NGF), acting as a neurotrophic factor: (1) the anti-apoptotic effects of DHEA were reversed by siRNA against TrkA or by a specific TrkA inhibitor; (2) [3H]-DHEA binding assays showed that it bound to membranes isolated from HEK293 cells transfected with the cDNAs of TrkA and p75NTR receptors (KD: 7.4±1.75 nM and 5.6±0.55 nM, respectively); (3) immobilized DHEA pulled down recombinant and naturally expressed TrkA and p75NTR receptors; (4) DHEA induced TrkA phosphorylation and NGF receptor-mediated signaling; Shc, Akt, and ERK1/2 kinases down-stream to TrkA receptors and TRAF6, RIP2, and RhoGDI interactors of p75NTR receptors; and (5) DHEA rescued from apoptosis TrkA receptor positive sensory neurons of dorsal root ganglia in NGF null embryos and compensated NGF in rescuing from apoptosis NGF receptor positive sympathetic neurons of embryonic superior cervical ganglia. Phylogenetic findings on the evolution of neurotrophins, their receptors, and CYP17, the enzyme responsible for DHEA biosynthesis, combined with our data support the hypothesis that DHEA served as a phylogenetically ancient neurotrophic factor

    Hypoxia induced amoeboid microglial cell activation in postnatal rat brain is mediated by ATP receptor P2X4

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    <p>Abstract</p> <p>Background</p> <p>Activation of amoeboid microglial cells (AMC) and its related inflammatory response have been linked to the periventricular white matter damage after hypoxia in neonatal brain. Hypoxia increases free ATP in the brain and then induces various effects through ATP receptors. The present study explored the possible mechanism in ATP induced AMC activation in hypoxia.</p> <p>Results</p> <p>We first examined the immunoexpression of P2X4, P2X7 and P2Y12 in the corpus callosum (CC) and subependyma associated with the lateral ventricles where both areas are rich in AMC. Among the three purinergic receptors, P2X4 was most intensely expressed. By double immunofluorescence, P2X4 was specifically localized in AMC (from P0 to P7) but the immunofluorescence in AMC was progressively diminished with advancing age (P14). It was further shown that P2X4 expression was noticeably enhanced in P0 day rats subjected to hypoxia and killed at 4, 24, 72 h and 7 d versus their matching controls by double labeling and western blotting analysis. P2X4 expression was most intense at 7 d whence the inflammatory response was drastic after hypoxia. We then studied the association of P2X4 with cytokine release in AMC after hypoxic exposure. In primary microglial cells exposed to hypoxia, IL-1β and TNF-α protein levels were up-regulated. Blockade of P2X4 receptor with 2', 3'-0-(2, 4, 6-Trinitrophenyl) adenosine 5'-triphosphate, a selective P2X1-7 blocker resulted in partial suppression of IL-1β (24% <it>vs </it>hypoxic group) and TNF-α expression (40% <it>vs </it>hypoxic group). However, pyridoxal phosphate-6-azo (benzene-2, 4-disulfonic acid) tetrasodium salt hydrate, a selective P2X1-3, 5-7 blocker did not exert any significant effect on the cytokine expression.</p> <p>Conclusions</p> <p>It is concluded that P2X4 which is constitutively expressed by AMC in postnatal rats was enhanced in hypoxia. Hypoxia induced increase in IL-1β and TNF-α expression was reversed by 2', 3'-0-(2, 4, 6-Trinitrophenyl) adenosine 5'-triphosphate suggesting that P2X4 mediates ATP induced AMC activation and its production of proinflammatory cytokines.</p

    Effects of dietary vegetable oil on atlantic salmon hepatocyte fatty acid desaturation and liver fatty acid compositions

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    Fatty acyl desaturase activities, involved in the conversion of the C18 EFA, 18:2n-6 and 18:3n-3, to the highly unsaturated fatty acids (HUFA) 20:4n-6, 20:5n-3 and 22:6n-3, are known to be under nutritional regulation. Specifically, the activity of the desaturation/elongation pathway is depressed when animals, including fish, are fed fish oils rich in n-3HUFA compared to animals fed vegetable oils rich in C18 EFA. The primary aims of the present study were a) to establish the relative importance of product inhibition (n-3HUFA) versus increased substrate concentration (C18 EFA) and, b) to determine whether 18:2n-6 and 18:3n-3 differ in their effects, on the hepatic fatty acyl desaturation/elongation pathway in Atlantic salmon (Salmo salar). Smolts were fed ten experimental diets containing blends of two vegetable oils, linseed (LO) and rapeseed oil (RO), and fish oil (FO) in a triangular mixture design for 50 weeks. Fish were sampled after 32 and 50 weeks, lipid and fatty acid composition of liver determined, fatty acyl desaturation/elongation activity estimated in hepatocytes using [1-14C]18:3n-3 as substrate, and the data subjected to regression analyses. Dietary 18:2n-6 was positively correlated, and n-3HUFA negatively correlated, with lipid content of liver. Dietary 20:5n-3 and 22:6n-3 were positively correlated with liver fatty acids with a slope greater than unity suggesting relative retention and deposition of these HUFA. In contrast, dietary 18:2n-6 and 18:3n-3 were positively correlated with liver fatty acids with a slope of less than unity suggesting metabolism via β-oxidation and/or desaturation/elongation. Consistent with this, fatty acyl desaturation/elongation in hepatocytes was significantly increased by feeding diets containing vegetable oils. Dietary 20:5n-3 and 22:6n-3 levels were negatively correlated with hepatocyte fatty acyl desaturation. At 32 weeks, 18:2n-6 but not 18:3n-3, was positively correlated with hepatocyte fatty acyl desaturation activity whereas the reverse was true at 50 weeks. The data indicate that both feedback inhibition through increased n-3HUFA and decreased C18 fatty acyl substrate concentration are probably important in determining hepatocyte fatty acyl desaturation activities, and that 18:2n-6 and 18:3n-3 may differ in their effects on this pathway

    Vascular β-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAβ mice

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    Cerebrovascular lesions related to congophilic amyloid angiopathy (CAA) often accompany deposition of β-amyloid (Aβ) in Alzheimer’s disease (AD), leading to disturbed cerebral blood flow and cognitive dysfunction, posing the question how cerebrovascular pathology contributes to the pathology of AD. To address this question, we characterised the morphology, biochemistry and functionality of brain blood vessels in transgenic arctic β-amyloid (arcAβ) mice expressing human amyloid precursor protein (APP) with both the familial AD-causing Swedish and Arctic mutations; these mice are characterised by strong CAA pathology. Mice were analysed at early, mid and late-stage pathology. Expression of the glucose transporter GLUT1 at the blood–brain barrier (BBB) was significantly decreased and paralleled by impaired in vivo blood-to-brain glucose transport and reduced cerebral lactate release during neuronal activation from mid-stage pathology onwards. Reductions in astrocytic GLUT1 and lactate transporters, as well as retraction of astrocyte endfeet and swelling consistent with neurovascular uncoupling, preceded wide-spread β-amyloid plaque pathology. We show that CAA at later disease stages is accompanied by severe morphological alterations of brain blood vessels including stenoses, BBB leakages and the loss of vascular smooth muscle cells (SMCs). Together, our data establish that cerebrovascular and astrocytic pathology are paralleled by impaired cerebral metabolism in arcAβ mice, and that astrocyte alterations occur already at premature stages of pathology, suggesting that astrocyte dysfunction can contribute to early behavioural and cognitive impairments seen in these mice

    Chemical Behavior and Reaction Kinetics of Sulfur and Nitrogen Half-Mustard and Iprit Carbonate Analogues

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    Sulfur and nitrogen mustards are very toxic, yet versatile organic molecules with numerous applications. Herein, we report on a synthesis of a new class of green compounds, i.e., half-mustard and iprit carbonates, that result in new, unexplored, and safe molecules. Their chemical behavior with several nucleophiles and their reaction kinetics have been investigated

    Molecular and functional properties of P2X receptors—recent progress and persisting challenges

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