Qiansheng Hu

Aluminum-induced apoptosis in cultured cortical neurons and its effect on SAPK/JNK signal transduction pathway.

Aluminum exposure and apoptotic cell death has been implicated in several neurodegenerative diseases. The mechanisms by which aluminum interacts with the nervous system are only partly understood. In this study, we used cultured cortical neurons to investigate the ability of aluminum to induce the apoptosis of neurons and to explore the role of SAPK/JNK (stress-activated protein kinase or c-jun N-terminal kinase) signal transduction pathway on the apoptosis induced by aluminum. We found that aluminum-induced degeneration of cortical neurons involved the DNA fragmentation characteristic of apoptosis, and staining of aluminum-treated neurons with the DNA-binding fluorochrome Hoechst 33258 revealed the typical apoptotic condensation and fragmentation of chromatin. The rate of apoptosis increased significantly (from 4.9 to 13.1, 21.4, and 59.8%, P<0.01), which was measured by TdT-mediated dUTP nick end labeling. Western blot analysis showed that SAPK/JNK activities of cortical neurons varies when the exposure time of AlCl(3) were different. The phosphorylation levels were 4.2, 3.3, 1.9 and 1.1 times greater compared to control cultures for 6, 12, 24, and 48 h, respectively (P<0.01). Furthermore, a JNK pathway inhibitor, CEP-11004 (KT8138) inhibited the activation of SAPK/JNK to protect cortical neurons from apoptosis induced by aluminum chloride. Our study demonstrates that aluminum can induce the apoptosis of cortical neurons and SAPK/JNK signal transduction pathway may play an important role in the apoptosis.

Maternal low-level lead exposure reduces the expression of PSA-NCAM and the activity of sialyltransferase in the hippocampi of neonatal rat pups.

Highly polysialylated neural cell adhesion molecule (PSA-NCAM) is transiently expressed specifically in newly generated cells, and is important for cell migration and neurite outgrowth. Developmental lead (Pb) exposure has been considered to affect the expression of PSA-NCAM, which contributes to the neurotoxicity of Pb exposure. However, the effect of maternal low-level Pb exposure on the expression of PSA-NCAM in neonatal rat pups has not been reported. In the present study, female Wistar rats were exposed to vehicle or different dosages of lead chloride (0.5-4mM PbCl2) 2 weeks before and during pregnancy. This exposure protocol resulted in neonatal rat pups blood Pb levels up to 12.12+/-0.38 microg/dl, and hippocampal Pb levels up to 9.22+/-0.81 microg/g at postnatal day 1 (PND 1). Immunohistochemistry analysis and Western blot analysis revealed that the expressions of PSA-NCAM and NCAM in the hippocampi of neonatal rat pups at PND 1 were significantly reduced by the maternal low-level Pb exposures. Furthermore, the mRNA levels of NCAM and polysialyltransferases (STX and PST), measured by the fluorescent real-time quantitative RT-PCR, dosage-dependently and significantly decreased by 13.26-37.62%, 25.17-59.67%, and 10.78-47.81%, respectively. In addition, the sialyltransferase activity in neonatal rat pups was significantly reduced by 6.23-32.50% in the presence of the low-level Pb exposure, too. Taken together, these results suggest that maternal low-level Pb exposure reduces the expression of PSA-NCAM, NCAM, and the activity of sialyltransferase in the hippocampi of neonatal rat pups, which might contribute to the learning and memory impairments in the developmental pups following maternal low-level Pb exposure.

Promising multifunctional anti-Alzheimer's dimer bis(7)-Cognitin acting as an activator of protein kinase C regulates activities of α-secretase and BACE-1 concurrently

We have recently demonstrated that bis(7)-Cognitin, a promising multifunctional anti-Alzheimers dimer, can remarkably reduce the generation of amyloid beta peptide (Abeta) by inhibiting beta-secretase (BACE-1) and activating alpha-secretase activity. In this study, the mechanism(s) underlying bis(7)-Cognitins regulation of the activity of these two proteases was further investigated. In N2a cells stably expressing human amyloid precursor protein with the Swedish mutation (APPswe), the reduction in Abeta production induced by 1microM bis(7)-Cognitin was not altered by the co-pretreatment of muscarinic and nicotinic cholinergic receptor antagonists, indicating that the regulation of APP processing by this dimer is independent of cholinergic transmission. Furthermore, bis(7)-Cognitin (0.1-3microM) significantly increased protein kinase C (PKC) activity in cells and in vitro in a concentration-dependent manner. Administration of a PKC activator, phorbol 12-myristate 13-acetate (PMA), concentration-dependently increased the alpha-secretase cleavage products, and reduced the BACE-1 cleavage products. In addition, the inhibition of PKC prevented PMA- or bis(7)-Cognitin-induced alterations in alpha-secretase and BACE-1 activities, eliminating reductions in Abeta production seen with PMA or the dimer. These results strongly suggest that bis(7)-Cognitin may reduce the biosynthesis of Abeta by inhibiting BACE-1 and activating alpha-secretase concurrently through the direct activation of PKC. Combined with previous findings of direct inhibition of AChE and BACE-1 by this dimer, this work indicates that strategy may have potential to provide new insights into designing novel drugs that target multiple steps of aberrant APP processing to treat Alzheimers disease.

Interactions Between Air Pollution and Obesity on Blood Pressure and Hypertension in Chinese Children.

Background: Little information exists regarding the effect of interaction of obesity and long-term air pollution exposure on children’s blood pressure and hypertension in areas with high levels of air pollution. The aim of this study is to assess effect modification by obesity on the association between exposure and blood pressure in Chinese children. Methods: We studied 9,354 Chinese children, ages 5–17 years old, from 24 elementary schools and 24 middle schools in the Seven Northeastern Cities during 2012–2013. Four-year average concentrations of particles with an aerodynamic diameter ⩽10 µm (PM10), sulfur dioxide, nitrogen dioxides, and ozone (O3) were measured at the monitoring stations in the 24 districts. We used generalized additive models and two-level logistic regression models to examine the health effects. Results: Consistent interactions were found between exposure and obesity on blood pressure and hypertension. The association between exposure and hypertension was consistently larger for overweight/obese children than for children with normal-weight, with odds ratios for hypertension ranging from 1.16 per 46.3&mgr;g/m3 for O3 (95% confidence interval [CI] = 1.12, 1.20) to 2.91 per 30.6&mgr;g/m3 for PM10 (95% CI = 2.32, 3.64), and estimated increases in mean systolic and diastolic blood pressure ranging from 0.57 mmHg (95% CI = 0.36, 0.78) and 0.63 mmHg (95% CI = 0.46, 0.81) per 46.3 &mgr;g/m3 for O3 to 4.04 mmHg (95% CI = 3.00, 5.09) and 2.02 mmHg (95% CI = 1.14, 2.89) per 23.4 &mgr;g/m3 for sulfur dioxide. Conclusions: Obesity amplifies the association of long-term air pollution exposure with blood pressure and hypertension in Chinese children.

Prenatal and postnatal lead exposure and cognitive development of infants followed over the first three years of life: a prospective birth study in the Pearl River Delta region, China.

PURPOSE Our pilot studies showed that there was a significant relationship between low cord blood levels and scores of neonatal behavioral neurological assessment. The study was further to probe the adverse cognitive effects induced by low-level lead exposure during prenatal and postnatal period. METHOD Totally 362 mothers with their infants located the PRD, Guangdong, China participated in the study during their stay in these center: 141 in the high lead group [umbilical-cord blood lead levels (UCBLLs)≥3.92μg/dl] and 102 in the low lead group (UCBLLs≤1.89μg/dl). The other 137 subjects failed to complete the study for a variety of reasons. Blood Lead levels (BLLs) were measured by atomic absorption spectrophotometry, equipped with a graphite furnace. The developmental functioning of infants and children was assessed with BSID-II. The childrens birth outcome and the rest of information were obtained from their medical records or a comprehensive questionnaire from their parents, which contained demographic characteristics, lifestyle, mothers IQ and environmental lead sources, etc. RESULTS Of 380, 243 newborns (63.95%) had complete data collection for all variables included at 6, 12, 24 and 36 months of age. The mean UCBLLs for high and low lead group were 5.63±0.32μg/dl and 1.35±0.26μg/dl, respectively. Significant inverse associations have been found between the UCBLLs and the MDI and the PDI. The associations might attenuate over subsequent years. BLLs at 24 months were significantly associated, in an inverse direction, with MDI at 24 and 36 months. The observed trend of cognitive deficit beginning at 6 months of life might persist, and even develop over the coming years. A positive significant effect of home nurture environment was observed on MDI scores at 12, 24, 36 months of age and PDI scores at 24 and 36 months of age. CONCLUSION Our study demonstrates that prenatal and postnatal lead exposure as low as 5μg/dl has an adverse effect on neurodevelopment, best arrested by measuring UCBLLs and BLLs at 24 months of age, and suggest a reference for a blood lead critical value below 5μg/dL. The collective evidence indicate that low lead exposure must be addressed appropriately by health policy makers and argues for an improvement of home nurture environment, i.e., reduce the burden of Pb on children and, strengthen the training of cognitive ability.

Effects of low-level organic selenium on lead-induced alterations in neural cell adhesion molecules

Low-level lead (Pb) exposure has been reported to impair the formation and consolidation of learning and memory by inhibiting the expression of neural cell adhesion molecules (NCAMs) and altering the temporal profile of its polysialylation state. In this study, we investigated whether administration of low-level organic selenium (selenomethionine, Se) at different time points could affect Pb-induced changes of NCAMs in female Wistar rats. Here we reported that the exposure of Se (60μg/kg body weight/day) at different time points significantly alleviated Pb-induced reductions in the mRNA and protein levels of NCAMs, and increases in the mRNA levels of two polysialyltransferases (St8sia II, Stx; St8sia IV, Pst) as well as the sialyltransferase activity (p<0.05). The concentrations of Pb in blood and hippocampi of Wistar rats treated with the combination of Se and Pb were significantly lower than those treated with Pb alone (p<0.05). Our results suggest that low-level organic Se can not only prevent but also reverse Pb-induced alterations in the expression and polysialylated state of NCAMs as well as the concentration of Pb in rat blood and hippocampus.

Low-level lead exposure attenuates the expression of three major isoforms of neural cell adhesion molecule.

Toxic lead (Pb) exposure poses serious risks to human health, especially to children at developmental stages, even at low exposure levels. Neural cell adhesion molecule (NCAM) is considered to be a potential early target in the neurotoxicity of Pb due to its role in cell adhesion, neuronal migration, synaptic plasticity, and learning and memory. However, the effect of low-level Pb exposure on the specific expression of NCAM isoforms has not been reported. In the present study, we found that Pb could concentration-dependently (1-100 nM) inhibit the expression of three major NCAM isoforms (NCAM-180, -140, and -120) in primary cultured hippocampal neurons. Furthermore, it was verified that levels of all three major isoforms of NCAM were reduced by Pb exposure in human embryonic kidney (HEK)-293 cells transiently transfected with NCAM-120, -140, or -180 isoform cDNA constructs. In addition, low-level Pb exposure delayed the neurite outgrowth and reduced the survival rate of cultured hippocampal neurons at different time-points. Together, our results demonstrate that developmental low-level Pb exposure can attenuate the expression of all three major NCAM isoforms, which may contribute to the observed Pb-mediated neurotoxicity.

The association of telomere length in peripheral blood cells with cancer risk: A systematic review and meta-analysis of prospective studies

The association between telomere length (TL) in peripheral blood cells and cancer risk remains inconclusive. We carried out a meta-analysis on prospective studies. The study-specific RR estimates were first transformed to a common comparable scale and then were pooled by a random-effects model. The dataset was composed of 13,894 cases and 71,672 controls from 28 studies in 25 articles. In the comparison of the longest versus shortest third of TL, we observed a marginally positive association between longer TL and higher risk of total cancers [OR = 1.086; 95% confidence interval (CI), 0.952–1.238]. Subgroup analyses showed that the association was stronger in lung cancer (n = 3; OR = 1.690; 95% CI, 1.253–2.280), in men (n = 6; OR = 1.302; 95% CI, 1.120–1.514) and in studies with more precise methods for DNA extraction (phenol–chloroform, salting-out or magnetic bead, n = 6, OR = 1.618; 95% CI, 1.320–1.985) and TL measurement (multiplex Q-PCR, n = 8; OR = 1.439; 95% CI, 1.118–1.852). Our meta-analysis suggested longer TL in peripheral blood cells is a likely risk factor for lung cancer or cancers in men. Accurate DNA extraction and TL measurement methods make it more liable to find significant associations between TL and cancer risk and thus should be taken into consideration in future epidemiologic studies. Cancer Epidemiol Biomarkers Prev; 26(9); 1381–90. ©2017 AACR.

Role of the mitochondrial Ca2+ uniporter in Pb2+-induced oxidative stress in human neuroblastoma cells

Lead (Pb(2+)) has been shown to induce cellular oxidative stress, which is linked to changes in intracellular calcium (Ca(2+)) concentration. The mitochondrial Ca(2+) uniporter (MCU) participates in the maintenance of Ca(2+) homeostasis in neurons, but its role in Pb(2+)-induced oxidative stress is unclear. To address this question, oxidative stress was induced in human neuroblastoma SH-SY5Y cells and in newborn rats by Pb(2+) treatment. The results showed that the production of reactive oxygen species is increased in cells upon treatment with Pb(2+) in a dose-dependent manner, while glutathione and MCU expression were reduced. Moreover, neuronal nitric oxide synthase protein expression was elevated in rats exposed to Pb(2+) during gestation, while MCU expression was decreased. Application of the MCU activator spermine or MCU overexpression reversed Pb(2+)-induced oxidative stress and inhibition of mitochondrial Ca(2+) uptake, while the MCU inhibitor Ru360 and MCU knockdown potentiated the effects of Pb(2+). These results indicate that the MCU mediates the Pb(2+)-induced oxidative stress response in neurons through the regulation of mitochondrial Ca(2+) influx.

Effects of selenium on lead-induced alterations in Aβ production and Bcl-2 family proteins.

Previous studies in humans and animals have suggested that lead (Pb) may increase the expression of amyloid precursor protein (APP) and accumulation of amyloid β protein (Aβ). Our previous studies have revealed that selenium (Se) can partially improve memory deficits induced by Pb exposure. In this study we sought to investigate the effect of Pb and Se on the endogenous expression of APP, Aβ40 and Bcl-2 family proteins. In vitro, the protein levels of APP and Aβ significantly decreased in SH-SY5Y and PC12 cells co-incubated with Pb-acetate and selenomethionine (SeMet) for 48h, compared with cells treated with Pb-acetate alone. Furthermore, these reductions induced by Se appeared to be concentration-dependent. In Wistar rats, we observed that the mRNA and protein levels of APP, the protein level of Bax, and the ratio of Bax/Bcl-2 protein significantly increased after Pb treatment at embryonic stage and in neonates. These increases were significantly reversed by the treatment of Se. Taken together, our results suggest that Se can attenuate the alterations in APP expression and Aβ production as well as Bcl-2 family proteins induced by lead exposure in cells and in animals.