A novel GSK-3ß inhibitor YQ138 prevents neuronal injury induced by glutamate and brain ischemia through activation of the Nrf2 signaling pathway.

AIM: To discover neuroprotective compounds and to characterize the discovered active compound YQ138 as a novel GSK-3ß inhibitor. METHODS: Primary rat cerebellar granule cells (CGCs) were treated with glutamate, and cell viability was analyzed with MTT assay, which was used as in vitro model for screening neuroprotective compounds. Active compound was further tested in OGD- or serum deprivation-induced neuronal injury models. The expression levels of GSK-3ß downstream proteins (Nrf2, HO-1, NQO1, Tau and ß-catenin) were detected with Western blotting. For evaluating the neuroprotective effects in vivo, adult male rats were subjected to transient middle cerebral artery occlusion (tMCAO), then treated with YQ138 (10 mg/kg, iv) at 2, 4 and 6 h after ischemia onset. RESULTS: From a compound library consisting of about 2000 potential kinase inhibitors, YQ138 was found to exert neuroprotective effects: pretreatment with YQ138 (0.1-40 µmol/L) dose-dependently inhibited glutamate-induced neuronal death. Furthermore, pretreatment with YQ138 (10 µmol/L) significantly inhibited OGD- or serum deprivation-induced neuronal death. Among a panel of seven kinases tested, YQ138 selectively inhibited the activity of GSK-3ß (IC50=0.52 nmol/L). Furthermore, YQ138 dose-dependently increased the expression of ß-catenin, and decreased the phosphorylation of Tau in CGCs. Moreover, YQ138 significantly increased the expression of GSK-3ß downstream antioxidative proteins Nrf2, HO-1, NQO1, GSH and SOD in CGCs. In rats with tMCAO, administration of YQ138 significantly decreased infarct volume, improved the neurological deficit, and increased the expression of Nrf2 and HO-1 and the activities of SOD and GSH in the cerebral cortex. CONCLUSION: A novel GSK-3ß inhibitor YQ138 effectively suppresses brain ischemic injury in vitro and in vivo.

Design, synthesis and biological evaluation of tricyclic diterpene derivatives as novel neuroprotective agents against ischemic brain injury.

Lead compound 7 has neuroprotective effects, and it was discovered by screening a small synthetic natural product-like (NPL) library. Based on the lead, a series of tricyclic diterpene derivatives was designed and synthesized, and their neuroprotective effects were further evaluated against glutamate-, oxygen and glucose deprivation (OGD)- and nutrient deprivation-induced neuronal injury using cell-based assays. To our delight, most of these synthetic compounds exhibited increased neuroprotective effects and blood-brain barrier (BBB) permeability without cellular toxicity. The most potent compound, compound 30, showed significantly improved neuroprotection against neuronal injury in primary neurons. Furthermore, compound 30 exhibited remarkable neuroprotection in transient middle cerebral artery occlusion (tMCAO) rats by reducing their infarct sizes and neurological deficit scores. A mechanistic exploration using in vitro and in vivo experiments showed that the neuroprotection of these compounds was at least partly mediated by improving the levels of glutathione (GSH), superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) protein. Therefore, these tricyclic diterpene derivatives could be used as promising leads for the development of a new type of neuroprotective agents against ischemic brain injury.

Assessment of organochlorine pesticide contamination in relation to soil properties in the Pearl River Delta, China.

High levels of organochlorine pesticides (OCPs) such as hexachlorocyclohexanes (HCHs) and dichlorodiphenyltrichloroethanes (DDTs) have been found in soil of the Pearl River Delta (PRD), attributable to high pesticide application in this area. Consequently, the occurrence and environmental effect of HCHs and DDTs in the PRD have attracted considerable attention. However, study focusing on the influence of potential factors such as soil property on the environmental fate of HCHs and DDTs in the PRD has been rare. The present study aimed to investigate the impact of soil physiochemical properties on the distribution patterns and fate of soil HCHs and DDTs on a large spatial scale. Levels of HCHs (sum of α-, ß-, γ- and δ-HCH) and DDTs (sum of 1,1,1-trichloro-2,2-bis-(p-chlorophenyl)ethane (p,p'-DDT), 1,1-dichloro-2,2-bis-(p-chlorophenyl)ethane (p,p'-DDD), and 1,1-dichloro-2,2-bis-(p-chlorophenyl)ethylene (p,p'-DDE)) in 151 soil samples covering all areas of the PRD and physiochemical parameters related to soil properties including pH, total organic carbon (TOC), total Fe (TFe), DCB-Fe (DFe), amorphous-Fe (AFe), complexed-Fe (CFe), total Mn (TMn), DCB-Mn (DMn), amorphous-Mn (AMn), complexed-Mn (CMn) and cation exchange capacity (CEC) were determined. The residual levels of HCHs and DDTs in soils of the present study, which are mainly controlled by soil TOC and CFe content and varying spatially with land use types, may potentially pose ecological risk to plants and animals. On the other hand, transformation of soil HCHs may be affected by pH and DDT transformation correlated significantly with AFe and CFe. Currently, soil has become an important secondary source of OCPs and the re-emission potential of OCPs in soil was mainly affected by soil OCP concentrations and land use types.

[Distribution of phthalic acid esters in agricultural soils in typical regions of Guangdong Province].

To understand the distribution characteristics of phthalic acid esters (PAEs) in agricultural soils in typical regions of Guangdong Province, surface soil (0-20 cm) samples were collected, and the concentrations of 6 PAEs were determined by gas chromatography. The results showed that the total concentration of the PAEs (sigma PAEs) ranged from not detected to 25.99 mg x kg(-1), and was < or = 1.00 mg x kg(-1) in 92.8% of the samples. The sigma PAEs differed with land use types and regions, and decreased in the sequences of paddy soil > banana soil > vegetable soil > sugarcane soil > orchard soil, and Dongguan > Shantou > Shunde > Zhanjiang > Zhongshan > Zhuhai > Huizhou. Among the test PAEs, DEHP had the highest detection rate (85.1%), DnBP had the highest concentration (not detected to 17.51 mg x kg(-1)). Comparing with the corresponding control limits of soil PAEs in USA, all test PAEs except DnOP were exceeded the limits to some extent, and DnBP, DMP and DEP exceeded seriously, indicating that the agricultural soils in the typical regions of Guangdong Province were contaminated by PAEs.

[Source and distribution characteristics of polycyclic aromatic hydrocarbons in agricultural soils in the Pearl River Delta].

260 samples of surface agricultural soils (0-20 cm depth) were collected in the typical areas of Pearl River Delta from October 2002 to November 2005. The concentrations of polycyclic aromatic hydrocarbons (16 US EPA priority PAHs) in the collected soil samples were determined by gas chromatography equipped with a mass spectrometry detector (GC-MS). The results showed that the concentrations of Sigma PAHs in the collected soil samples ranged from 3.3 to 4,079.0 ng x g(-1) with the average concentration of 224.2 ng x g(-1). PAHs in the collected samples were dominated by its 3-ring and 4-ring members. There were the higher concentrations of Sigma PAHs in the collected samples of urban sites than those of remote sites. The concentrations of PAHs in the collected samples related to different land use types the order: vegetable soils > paddy soils > banana soils > orchard soils > sugarcane soils. According to the distributions of fluoranthene/pyrene, 2 + 3 ring and 4 ring PAHs in these regions, it is supposed that the major contribution to the pollution of PAHs in these typical areas might be the incomplete combustion of fossil fuel. Compared with those in other national or international regions, the concentrations of Sigma PAHs in these typical regions were moderate.

The effect of erbium on the adsorption and photodegradation of orange I in aqueous Er3+-TiO2 suspension.

Pure TiO(2) and erbium ion-doped TiO(2) (Er(3+)-TiO(2)) catalysts prepared by the sol-gel method were characterized by means of XRD and diffusive reflectance spectra (DRS). The XRD results showed that erbium ion doping could enhance the thermal stability of TiO(2) and inhibit the increase of the crystallite size, and the DRS results showed that the optical absorption edge slightly shifted to red direction owing to erbium ion doping and the Er(3+)-TiO(2) catalysts had three typical absorption peaks located at 490, 523 and 654 nm owing to the transition of 4f electron from (4)I(15/2) to (4)F(7/2), (2)H(11/2) and (4)F(9/2). With a purpose of azo dyes degradation, orange I was used as a model chemical. And the adsorption isotherm, degradation and mineralization of orange I were investigated in aqueous suspension of pure TiO(2) or Er(3+)-TiO(2) catalysts. The results showed that Er(3+)-TiO(2) catalysts had higher adsorption equilibrium constants and better adsorption capacity than pure TiO(2). The adsorption equilibrium constants (K(a)) of Er(3+)-TiO(2) catalysts were about twice of that of pure TiO(2). The maximum adsorption capacity (Q(max)) of 2.0% Er(3+)-TiO(2) catalyst was 13.08x10(-5)mol/g, which was much higher than that of pure TiO(2) with 9.03x10(-5)mol/g. Among Er(3+)-TiO(2) catalysts, 2.0% Er(3+)-TiO(2) catalyst achieved the highest Q(max) and K(a) values. The kinetics of the orange I degradation using different Er(3+)-TiO(2) catalysts were also studied. The results demonstrated that the degradation and mineralization of orange I under both UV radiation and visible light were more efficient with Er(3+)-TiO(2) catalyst than with pure TiO(2), and an optimal dosage of erbium ion at 1.5% achieved the highest degradation rate. The higher photoactivity under visible light might be attributable to the transitions of 4f electrons of Er(3+) and red shifts of the optical absorption edge of TiO(2) by erbium ion doping.