Search

It is widely accepted that glutamate is the most important excitatory neurotransmitter in the central nervous system (CNS). However, there is also a large amount of glutamate in the blood. Generally, the concentration gradient of glutamate between intraparenchymal and blood environments is stable. However, this gradient is dramatically disrupted under a variety of pathological conditions, resulting in an amplifying cascade that causes a series of pathological reactions in the CNS and peripheral organs. This eventually seriously worsens a patient's prognosis. These two "isolated" systems are rarely considered as a whole even though they mutually influence each other. In this review, we summarize what is currently known regarding the maintenance, imbalance and regulatory mechanisms that control the intraparenchymalblood glutamate concentration gradient, discuss the interrelationships between these systems and further explore their significance in clinical practice. [ABSTRACT FROM AUTHOR]

Background: H19 is a paternally imprinted gene that has been shown to be highly expressed in the trophoblast tissue. Results from previous studies have initiated a debate as to whether noncoding RNA H19 acts as a tumor suppressor or as a tumor promotor in trophoblast tissue. In the present study, we developed lentiviral vectors expressing H19-specific small interfering RNA (siRNA) to specifically block the expression of H19 in the human choriocarcinoma cell line JAR. Using this approach, we investigated the impact of the H19 gene on the proliferation, invasion and apoptosis of JAR cells. Moreover, we examined the effect of H19 knockdown on the expression of insulin-like growth factor 2 (IGF2), hairy and enhancer of split homologue-1 (HES-1) and dual-specific phosphatase 5 (DUSP5) genes. Results: H19 knockdown inhibited apoptosis and proliferation of JAR cells, but had no significant impact on cell invasion. In addition, H19 knockdown resulted in significant upregulation of HES-1 and DUSP5 expression, but not IGF2 expression in JAR cells. Conclusions: The finding that H19 downregulation could simultaneously inhibit proliferation and apoptosis of JAR cells highlights a putative dual function for H19 in choriocarcinoma and may explain the debate on whether H19 acts as a tumor suppressor or a tumor promotor in trophoblast tissue. Furthermore, upregulation of HES-1 and DUSP5 may mediate H19 downregulation-induced suppression of proliferation and apoptosis of JAR cells. [ABSTRACT FROM AUTHOR]

Background/Aim: Both peroxisome proliferator-activated receptor (PPAR) δ and Ski are reported to be involved in skin wound repair. However, their link is unclear. Our aim is to investigate the interaction of PPARδ and Ski and this interaction-associated effect in wound healing. Methods: Effect of PPARδ activation on Ski expression was detected in rat skin fibroblasts by real-time PCR and western blot. Luciferase assay, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay were performed to identify the binding site of PPARδ in the promoter region of rat Ski gene. And the functional activity of PPARδ regulation to Ski was detected in fibroblast proliferation and rat skin wound healing model. Results: PPARδ agonist GW501516 upregulated Ski expression in a dose-dependent manner. Direct repeat-1 (DR1) response element locating at -865~-853 in Ski promoter region was identified to mediate PPARδ binding to Ski and associated induction of Ski. Furthermore, PPARδ upregulated Ski to promote fibroblasts proliferation and rat skin wound repair, which could be largely blocked by pre-treated with Ski RNA interference. Conclusion: This study demonstrates that Ski is a novel target gene for PPARδ and upregulation of Ski to promote fibroblast proliferation is implicated in the PPARδ-mediated wound healing. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 113, 1536–1544. Adenosine A2A receptors (A2ARs) in bone marrow-derived cells (BMDCs) are involved in regulation of inflammation and outcome in several CNS injuries; however their relative contribution to traumatic brain injury (TBI) is unknown. In this study, we created a mouse cortical impact model, and BMDC A2ARs were selectively inactivated in wild-type (WT) mice or reconstituted in global A2AR knockout (KO) mice (i.e. inactivation of non-BMDC A2ARs) by bone marrow transplantation. When compared with WT mice, selective inactivation of BMDC A2ARs significantly attenuated the neurological deficits, brain water content and cell apoptosis at 24 h post-TBI as global A2AR KO did. However, compared with the A2AR KO mice, selective reconstitution of BMDC A2ARs failed to reinstate brain injury, indicating the contribution of the non-BMDC A2AR to TBI. Furthermore, the protective outcome by selective inactivation of BMDC A2AR or broad inactivation of non-BMDC A2ARs was accompanied with reduced CSF glutamate level and suppression of the inflammatory cytokines interleukin-1, or interleukin-1 and tumor necrosis factor-α. These findings demonstrate that inactivation of A2ARs in either BMDCs or non-BMDCs is sufficient to confer the protective effect as global A2AR KO against TBI, indicating the A2AR involvement in TBI by multiple cellular mechanisms of A2AR involvement including inhibition of glutamate release and inflammatory cytokine expressions. [ABSTRACT FROM AUTHOR]

During brain injury, extracellular adenosine and glutamate levels increase rapidly and dramatically. We hypothesized that local glutamate levels in the brain dictates the adenosine-adenosine A2A receptor (A2AR) effects on neuroinflammation and brain damage outcome. Here, we showed that, in the presence of low concentrations of glutamate, the A2AR agonist 3-[4-[2-[[6-amino-9-[(2R,3R,4S,5S)-5- (ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]purin-2-yl]amino]ethyl]phenyl]propanoic acid (CGS21680) inhibited lipopolysaccharide (LPS)-induced nitric oxide synthase (NOS) activity of cultured microglial cells, an effect that was dependent on the protein kinaseA(PKA) pathway. However, in high concentrations of glutamate, CGS21680 increased LPS-induced NOS activity in a protein kinase C (PKC)-dependent manner. Thus, increasing the local level of glutamate redirects A2AR signaling from the PKA to the PKC pathway, resulting in a switch in A2AR effects from antiinflammatory to proinflammatory. In a cortical impact model of traumatic brain injury (TBI) in mice, brain water contents, behavioral deficits, and expression of tumor necrosis factor-α, interleukin-1 mRNAs, and inducible NOS were attenuated by administering CGS21680 at post-TBI time when brain glutamate levels were low, or by administering the A2AR antagonist ZM241385 [4-(2-{[5-amino-2-(2-furyl)[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yl]amino}ethyl)phenol] at post-TBI time when brain glutamate levels were elevated. Furthermore, pre-TBI treatment with the glutamate release inhibitor (S)-4C3HPG [(S)-4-carboxy-3- hydroxyphenylglycine] converted the debilitating effect of CGS21680 administered at post-TBI time with high glutamate level to a neuroprotective effect. This further indicates that the switch in the effect of A2AR activation in intact animals from antiinflammatory to proinflammatory is dependent on glutamate concentration. These findings identify a novel role for glutamate in modulation of neuroinflammation and brain injury via the adenosine-A2AR system. [ABSTRACT FROM AUTHOR]

Heat shock protein 90 (Hsp90), encoded by hsp84 and hsp86 in mice, has been confirmed to modulate glucocorticoid receptor (GR) function; however, the contribution of Hsp90 in glucocorticoid (GC) sensibility/resistance has received less attention. Previously, we found that genetic variations of Hsp84 are related to differences in the in vivo GC-GR responses between BALB/c and C57BL/6 mice suffering from traumatic injury. To evaluate the modulation of Hsp84 polymorphisms on the GC response, we used a cellular heat-stress injury (HSI) model combined with a transgene-plasmid infection approach and assessed HSI-induced cellular damage and GR nuclear translocation, with or without dexamethasone pretreatment. We demonstrated that after HSI, fibroblasts from the C57BL/6 line exhibit higher cellular survival, higher nuclear GR levels and lower lactate dehydrogenase activity compared to those from the BALB/c line. We showed that dexamethasone-rescued HSI-induced damage is accompanied by increasing nuclear GR levels in both lines. Importantly, this protection against HSI was greater in C57BL/6 fibroblasts and was resistant to geldanamycin, a selective inhibitor of Hsp90. Importantly, transfection of the hsp84-transgene from C57BL/6 mice increased the nuclear GR levels and lessened HSI-induced damage in BALB/c fibroblasts. Our data thereby demonstrate that Hsp84 from C57BL/6 mice modulates higher cellular GC-GR responsiveness. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]