Ethyl pyruvate (EP), a simple ester of pyruvic acid, has been shown to act as an anti-inflammatory molecule under various pathological conditions, such as, during cerebral ischemia and sepsis in animal models. Here, the authors investigated the novel molecular mechanism underlying the anti-oxidative effect of EP in primary astrocyte cultures, particularly with respect to nuclear factor E2-related factor 2 (Nrf2) activation and hemeoxygenase 1 (HO-1) induction. EP was found to induce Nrf2 translocation and the inductions of various genes downstream of Nrf2 and these resulted in the amelioration of the oxidative damage of H(2)O(2). Furthermore, EP dose-dependently suppressed H(2)O(2)-induced astrocyte cell death (12h preincubation with 5mM EP increased cell survival after 1h exposure to 100μM H(2)O(2) from 32.6±0.7% to 63±1.8%). HO-1 was markedly induced (4.9-fold) in EP-treated primary astrocyte cultures and Nrf2 was found to translocate from the cytosol to the nucleus and bind to the antioxidant response element (ARE) located on HO-1 promoter after EP treatment. siRNA-mediated HO-1 or Nrf2 knockdown and zinc protoporphyrin (ZnPP)-mediated inhibition of HO-1 activity showed that Nrf2 activation and HO-1 induction were responsible for the observed cytoprotective effect of EP, which was found to involve the ERK and Akt signaling pathways. Furthermore, EP-conditioned astrocyte culture media was found to have neuroprotective effects on primary neuronal cultures exposed to oxidative or excitotoxic stress, and this seemed to be mediated by glial cell line-derived neurotrophic factor (GDNF) and glutathione (GSH), which accumulated in EP-treated astrocyte culture media. Interestingly, we also found that in addition to HO-1, EP-induced Nrf2 activation increased the expressions of various anti-oxidant genes, including GST, NQO1, and GCLM. The study shows that EP-mediated Nrf2 activation and HO-1 induction in astrocytes act via autocrine and paracrine mechanisms to confer protective effects.

PURPOSE This study determined the seroprevalence of herpes virus 2 in gravidas and the differences between herpes virus 2-infected and healthy gravidas. The need to screen gravidas for herpes virus 2 was also evaluated. MATERIALS AND METHODS A retrospective analysis involving 500 gravidas who underwent herpes virus 2 serologic testing and delivery in our hospital between January 2009 and August 2010 was performed. All patients in the study group were classified as herpes simplex virus 2 (HSV2) positive, and all cases were analyzed with respect to the clinical course of the pregnancy, pregnancy outcome, obstetric complications, and neonatal outcomes. SPSS software (version 14.0) was used for statistical analysis. A chi-square test and Student's t-test were used for statistical analysis. RESULTS In the current study, the herpes virus 2 seroprevalence rate in gravidas was 17%. There was no significant difference in the rates of preterm delivery, premature rupture of membranes, preterm labor, and intrauterine growth restriction between the herpes virus 2-infected gravidas and the healthy control group. The rates of spontaneous abortion and sexually transmitted disease were higher in the herpes virus 2 infection group than the healthy control group. CONCLUSION After educating gravidas on genital herpes and, if gravidas thereafter consent to herpes virus 2 screening, the risk of neonatal herpes virus 2 infections can be reduced. In addition, examination of gravidas for sexually transmitted diseases would increase as would appropriate treatment.

High mobility group box 1 (HMGB1) is an endogenous danger signal molecule. In a previous report, we showed that HMGB1 is massively released during NMDA-induced acute damaging process in the postischemic brain and triggers inflammatory processes, like microglial activation. siRNA-mediated HMGB1 knockdown markedly reduced infarct volumes, confirming the crucial role played by HMGB1 in the postischemic brain. In the present study, we showed neuroprotective effects of glycyrrhizin (GL) in the postischemic rat brain after middle cerebral artery occlusion (MCAO). GL, a triterpene present in the roots and rhizomes of licorice, Glycyrrhiza glabra, has been shown to have anti-inflammatory and anti-viral effects. It has been reported that GL binds directly to HMGB1, and inhibits its chemoattractant and mitogenic activities. The administration of GL (10mg/kg) intravenously at 3 or 6h after MCAO reduced infarct volumes to 12.9±4.2% and 46.2±9.9%, respectively, of untreated control. This neuroprotective effect was accompanied by improvements in motor impairment and neurological deficits and suppressions of microglia activation and proinflammatory cytokine induction. Interestingly, GL almost completely blocked HMGB1 secretion in the postischemic brain and in lipopolysaccharide (LPS)-treated microglia cells. Furthermore, HMGB1 phosphorylation, which is the initial step for HMGB1 secretion, and the interaction between HMGB1 and protein kinase C (PKC) or calcium/calmodulin-dependent protein kinase IV (CaMKIV) were suppressed dose-dependently by GL. Here, we hypothesized that the blockage for the putative phosphorylation sites in HMGB1 by GL might be attributed to this suppression. In addition to the anti-inflammatory effects, we found that GL has anti-excitotoxic and anti-oxidative effects in neurons. Together these results indicate that GL has neuroprotective efficacy in the postischemic brain via its anti-inflammatory, anti-excitotoxic, and anti-oxidative effects and in particular, it exerts anti-inflammatory effect, at least in part, by inhibiting HMGB1 secretion.

Noninvasive intranasal drug administration has been noted to allow direct delivery of drugs to the brain. In the present study, the therapeutic efficacy of intranasal small interfering RNA (siRNA) delivery was investigated in the postischemic rat brain. Fluorescein isothiocyanate (FITC)-labeled control siRNA was delivered intranasally in normal adult rats using e-PAM-R, a biodegradable PAMAM dendrimer, as gene carrier. Florescence-tagged siRNA was found in the cytoplasm and processes of neurons and of glial cells in many brain regions, including the hypothalamus, amygdala, cerebral cortex, and striatum, in 1 hour after infusion, and the FITC-fluorescence was continuously detected for at least 12 hours. When siRNA for high mobility group box 1 (HMGB1), which functions as an endogenous danger molecule and aggravates inflammation, was delivered intranasally, the target gene was significantly depleted in many brain regions, including the prefrontal cortex and striatum. More importantly, intranasal delivery of HMGB1 siRNA markedly suppressed infarct volume in the postischemic rat brain (maximal reduction to 42.8 ± 5.6% at 48 hours after 60 minutes middle cerebral artery occlusion (MCAO)) and this protective effect was manifested by recoveries from neurological and behavioral deficits. These results indicate that the intranasal delivery of HMGB1 siRNA offers an efficient means of gene knockdown-mediated therapy in the ischemic brain.

The preparation of two-dimensional monolayers of polymer particles over a large area was demonstrated via a facile solution process. Polymer microspheres were continuously self-assembled into a close-packed monolayer from a colloidal solution confined between two plates such that the top plate was carefully dragged at a constant velocity in the direction opposite that of the monolayer growth. In situ direct observation of the particle movement during the coating process confirmed that particle transport was directed toward the contact line of the solution meniscus by evaporation-induced convective flow. Sliding of the top plate apparently effectively counterbalanced the convective flow to provide the particles with a contact line for growth of a monolayer particle array. The influence of particle concentration, sliding speed of the top plate, and surface wettability of the bottom substrate were investigated and optimized. Monolayer particle arrays were successfully demonstrated as a template for the preparation of ZnO films with ordered hollow hemispherical structures. This approach is applicable to the fabrication of ordered structures of monodispersed particles composed of various materials over large areas.

Hollow thin walled NiO tubes functionalized by catalytic Pt were synthesized via nanofiber templating and multilayered sputter-coating of Pt and NiO thin overlayers followed by heat-treatment at 600 °C. Sandwich Pt-NiO-Pt tube networks exhibited superior C(2)H(5)OH sensing response and remarkable selectivity against CO and H(2) gases.

The activation of p38 mitogen-activated protein kinases (MAPKs) has been implicated in many cellular processes, such as, inflammation, cell death, and survival. In mammals, four distinct genes encode the four known members of p38 MAPKs, p38α, p38β, p38γ, and p38δ. Despite the fact that p38α and p38β MAPKs share over 75% homology sequences, they have distinct, perhaps even opposite roles under stress conditions. In our previous report, we showed that p38β MAPK is induced in activated astrocytes in the penumbra of the postischemic brain, wherein it was co-localized with αB-crystallin and MAPKAPK-2. To investigate the functional significance of p38β MAPK in astrocytes, a C6 astroglioma cell line stably over-expressing p38β MAPK was generated. In these cells, hydrogen peroxide-induced apoptosis was reduced to 44.3% of that obtained from normal C6 cells. Interestingly, we found that expression of a small heat shock protein, αB-crystallin, was significantly increased in these cells, but that the expressions of HSP27 and HSP70 were not. Repression of αB-crystallin expression by αB-crystallin siRNA transfection suppressed the protective effect and recovered caspase 3 activity, indicating that αB-crystallin induction plays a crucial role in the protection against H₂O₂-induced apoptosis observed in p38β-overexpressing C6 astroglioma cells. We found that the binding between αB-crystallin and partially processed caspase-3 (a p24 intermediate) was significantly increased in p38β-overexpressing cells, which might result in suppression of caspase 3 activity in these cells. These results indicate that p38β confers protection against H₂O₂-induced astrocytes apoptosis by inducing a small heat shock protein, αB-crystallin, which inhibits caspase-3 activation.

The effect of Ag decoration on the gas sensing characteristics of SnO(2) nanowire (NW) networks was investigated. The Ag layers with thicknesses of 5-50 nm were uniformly coated on the surface of SnO(2) NWs via e-beam evaporation, which were converted into isolated or continuous configurations of Ag islands by heat treatment at 450 °C for 2 h. The SnO(2) NWs decorated by isolated Ag nano-islands displayed a 3.7-fold enhancement in gas response to 100 ppm C(2)H(5)OH at 450 °C compared to pristine SnO(2) NWs. In contrast, as the Ag decoration layers became continuous, the response to C(2)H(5)OH decreased significantly. The enhancement and deterioration of the C(2)H(5)OH sensing characteristics by the introduction of the Ag decoration layer were strongly governed by the morphological configurations of the Ag catalysts on SnO(2) NWs and their sensitization mechanism.

Hepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and also acts as an anti-apoptotic factor. Therefore, HGF is a potential therapeutic agent for treatment of fatal liver diseases. We performed a translational medicine protocol with recombinant human HGF (rh-HGF), including a phase I/II study of patients with fulminant hepatitis (FH) or late-onset hepatic failure (LOHF), in order to examine the safety, pharmacokinetics, and clinical efficacy of this molecule. Potential adverse effects identified through preclinical safety tests with rh-HGF include a decrease in blood pressure (BP) and an increase in urinary excretion of albumin. Therefore, we further investigated the effect of rh-HGF on circulatory status and renal toxicity in preclinical animal studies. In a clinical trial, 20 patients with FH or LOHF were evaluated for participation in this clinical trial, and four patients were enrolled. Subjects received rh-HGF (0.6 mg/m2/day) intravenously for 12 to 14 days. We established an infusion method to avoid rapid BP reduction in miniature swine, and confirmed reversibility of renal toxicity in rats. Although administration of rh-HGF moderately decreased BP in the participating subjects, this BP reduction did not require cessation of rh-HGF or any vasopressor therapy; BP returned to resting levels after the completion of rh-HGF infusion. Repeated doses of rh-HGF did not induce renal toxicity, and severe adverse events were not observed. Two patients survived, however, there was no evidence that rh-HGF was effective for the treatment of FH or LOHF. Intravenous rh-HGF at a dose of 0.6 mg/m2 was well tolerated in patients with FH or LOHF; therefore, it is desirable to conduct further investigations to determine the efficacy of rh-HGF at an increased dose.

Microstructural evolution of spinel Zn(2)SnO(4) nanofibers was manipulated via an in situ phase separation process of inorganic precursors and a matrix polymer during electrospinning and calcination. Chemiresistive gas sensors using porous Zn(2)SnO(4) fibers exhibited superior C(2)H(5)OH sensing response.