Interplay of miR-137 and EZH2 contributes to the genome-wide redistribution of H3K27me3 underlying the Pb-induced memory impairment.

Compromised learning and memory is a common feature of multiple neurodegenerative disorders. A paradigm spatial memory impairment could be caused by developmental lead (Pb) exposure. Growing evidence implicates epigenetic modifications in the Pb-mediated memory deficits; however, how histone modifications exemplified by H3K27me3 (H3 Lys27 trimethylation) contribute to this pathogenesis remains poorly understood. Here we found that Pb exposure diminished H3K27me3 levels in vivo by suppressing EZH2 (enhancer of zeste homolog 2) expression at an early stage. EZH2 overexpression in Pb-treated rats rescued the H3K27me3 abundance and partially restored the normal spatial memory, as manifested by the rat performance in a Morris water maze test, and structural analysis of hippocampal spine densities. Furthermore, miR-137 and EZH2 constitute mutually inhibitory loop to regulate the H3K27me3 level, and this feedback regulation could be specifically activated by Pb treatment. Considering genes targeted by H3K27me3, ChIP-chip (chromatin immunoprecipitation on chip) studies revealed that Pb could remodel the genome-wide distribution of H3K27me3, represented by pathways like transcriptional regulation, developmental regulation, cell motion, and apoptosis, as well as a novel Wnt9b locus. As a Wnt isoform associated with canonical and noncanonical signaling, Wnt9b was regulated by the opposite modifications of H3K4me3 (H3 Lys4 trimethylation) and H3K27me3 in Pb-exposed neurons. Rescue trials further validated the contribution of Wnt9b to Pb-induced neuronal impairments, wherein canonical or noncanonical Wnt signaling potentially exhibited destructive or protective roles, respectively. In summary, the study reveals an epigenetic-based molecular change underlying Pb-triggered spatial memory deficits, and provides new potential avenues for our understanding of neurodegenerative diseases with environmental etiology.

Multiple regulatory aspects of histone methyltransferase EZH2 in Pb-induced neurotoxicity.

Pb is a pervasive environmental threat to human health. Although remarkable progress has been made in its neurotoxicity, the precise molecular mechanisms underlying this widespread toxicant still remain elusive. In this study, the detailed roles of EZH2, a transcriptional repressor, in the regulation of Pb-led neurotoxicity were investigated, highlighting its sub-functionalization, compartmentalization, functional chaperones and downstream partners. Based on the findings, EZH2's protein levels were significantly reduced in response to Pb treatment; EZH2's gain-of-function trials recovered the dampened neurite outgrowth; EZH2' recruitment to ploycomb complex, as well as its interaction with cytosolic Vav1, was altered in a distinct manner, suggesting that EZH2's multiple roles were markedly redistributed in this context; EZH2's cytosolic and nuclear presence differed in their respective response towards Pb treatment; EZH2 directly occupied the promoters of EGR2, NGFR and CaMKK2, genes responsible for various nerve functions and repair mechanisms, and essentially contributed to their aberrant expression. It indicated that EZH2 mediated the dynamic changes of a cascade of key molecules and consequently the related neurological impairments. In summary, EZH2 emerges as a central player to regulate Pb-led neurotoxicity in a transcriptionally dependent and independent manner, and thereby provided a promising molecular target for medical intervention.

Kiwifruit Alleviates Learning and Memory Deficits Induced by Pb through Antioxidation and Inhibition of Microglia Activation In Vitro and In Vivo.

Lead (Pb) exposure, in particular during early postnatal life, increases susceptibility to cognitive dysfunction and neurodegenerative outcomes. The detrimental effect of Pb exposure is basically due to an increasing ROS production which overcomes the antioxidant systems and finally leads to cognitive dysfunction. Kiwifruit is rich in the antioxidants like vitamin C and polyphenols. This study aims to investigate the effects and mechanism of kiwifruit to alleviate learning and memory deficits induced by Pb exposure. Sprague-Dawley (SD) rat pups acquired Pb indirectly through their mothers during lactation period and after postnatal day 21 (PND21) directly acquired Pb by themselves. Five kinds of kiwifruits were collected in this study and the amounts of vitamin C and polyphenols in them were measured and the antioxidation effects were determined. Among them, Qinmei kiwifruit (Qm) showed the strongest antioxidation effects in vitro. In vivo, Qm significantly repaired Pb-induced learning and memory deficits and dendritic spine loss. In addition, Pb compromised the enzymatic activity and transcriptional levels of SOD and GSH-Px and decreased the microglial activation, which, to some extent, could be reversed by Qm kiwifruit administration. The results suggest that kiwifruit could alleviate Pb-induced cognitive deficits possibly through antioxidative stress and microglia inactivation. Consequently, kiwifruit could be potentially regarded as the functional food favorable in the prevention and treatment of Pb intoxication.

ß-Asarone Rescues Pb-Induced Impairments of Spatial Memory and Synaptogenesis in Rats.

Chronic lead (Pb) exposure causes cognitive deficits. This study aimed to explore the neuroprotective effect and mechanism of ß-asarone, an active component from Chinese Herbs Acorus tatarinowii Schott, to alleviate impairments of spatial memory and synaptogenesis in Pb-exposed rats. Both Sprague-Dawley developmental rat pups and adult rats were used in the study. Developmental rat pups were exposed to Pb throughout the lactation period and ß-asarone (10, 40mg kg-1, respectively) was given intraperitoneally from postnatal day 14 to 21. Also, the adult rats were exposed to Pb from embryo stage to 11 weeks old and ß-asarone (2.5, 10, 40mg kg-1, respectively) was given from 9 to 11 weeks old. The level of ß-asarone in brain tissue was measured by High Performance Liquid Chromatography. The Morris water maze test and Golgi-Cox staining method were used to assess spatial memory ability and synaptogenesis. The protein expression of NR2B subunit of NMDA receptor, Activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and Wnt family member 7A (Wnt7a) in hippocampus, as well as mRNA expression of Arc/Arg3.1 and Wnt7a, was also explored. We found that ß-asarone could pass through the blood brain barrier quickly. And ß-asarone effectively attenuated Pb-induced reduction of spine density in hippocampal CA1 and dentate gyrus areas in a dose-dependent manner both in developmental and adult rats, meanwhile the Pb-induced impairments of learning and memory were partially rescued. In addition, ß-asarone effectively up-regulated the protein expression of NR2B, Arc and Wnt7a, as well as the mRNA levels of Arc/Arg3.1 and Wnt7a, which had been suppressed by Pb exposure. The results suggest the neuroprotective properties of ß-asarone against Pb-induced memory impairments, and the effect is possibly through the regulation of synaptogenesis, which is mediated via Arc/Arg3.1 and Wnt pathway.

[Prognostic value of circulating catestatin levels for in-hospital heart failure in patients with acute myocardial infarction].

OBJECTIVE: To determine whether circulating level of catestatin (CST) could provide prognostic information independently of conventional risk markers for the development of in-hospital heart failure in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: The data of 120 STEMI patients (mean age: 61 years, 73% male) were collected from the Second Hospital of Shanxi Medical University and Taiyuan Central Hospital between November 2010 and September 2011.The patients were categorized into 4 groups according to CST (ng/L) quartile: ≤ 74.72, 74.73-79.67, 79.68 - 84.21 and ≥ 84.22 ng/L. Clinical features, therapeutic approaches were compared among groups. The patients were also grouped according to Killip class: Killip level I (n = 68), Killip level II (n = 23), Killip level III (n = 18), Killip level IV (n = 11). CST, NE and NT-proBNP were compared among groups. The Spearma rank correlation and multivariate logistic regression analysis were applied to determine the association between risk factors and in-hospital heart failure. Receiver-operator characteristic (ROC) curve was performed to evaluate the power of CST and NT-proBNP on predicting in-hospital heart failure. RESULTS: Gender, hospital days, past history of smoking, hypertension, myocardial infarction, CK-MB peak level, TnI peak level, heart rate, blood pressure, blood glucose, blood lipid levels on admission and early reperfusion therapy were similar among groups. Patients with higher CST values were more likely to be older, to have lower body mass index, to have higher white blood cell count, CysC, hs-CRP, NE, NT-proBNP, past history of angina, diabetes mellitus, being diuretic users, and to have a lower ejection fraction (all P < 0.05). Higher CST levels were also associated with increased risk of heart failure (P < 0.05). In proportion with the deterioration of the cardiac function, CST, NE, NT-proBNP concentration gradually increased (all P < 0.05). Spearman rank correlation analysis showed that the CST was negatively correlated with LVEF (r(s) = -0.923, P < 0.001) and positively correlated with NT-proBNP (r(s) = 0.884, P < 0.001). After multivariate adjustment, CST remained to be an independent risk factor for the development of in-hospital heart failure (OR = 1.125, 95%CI: 1.056 - 1.198;P < 0.001). The area under the ROC curve of CST and NT-proBNP was 0.777 and 0.874. Using CST = 77.29 ng/L as a cut-off value, the sensitivity was 92.8% and specificity was 70.6% for predicting the development of in-hospital heart failure. CONCLUSION: The plasma CST level is an independent predictor for the development of in-hospital heart failure in patients with STEMI.

[Primary percutaneous coronary intervention in patients with acute myocardial infarction induced by left main artery occlusion or severe stenosis].

OBJECTIVE: The effects of primary percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) induced by left main (LM) artery occlusion were analyzed retrospectively in this study. METHODS: A total of 1343 consecutive AMI patients who underwent primary PCI between January 1995 and December 2004 were retrospectively studied. RESULTS: LM occlusion or severe stenosis were found in 11 patients [all male, mean age (56.4 +/- 9.2) years (range 43-70 years)], cardiogenic shock was overt in 6 patients. Primary PCI were performed under the assistance of intra-aortic balloon pump (IABP) in these patients [8 stent implantation, 3 balloon dilation and 2 necessitating emergency CABG after balloon dilation]. In-hospital mortality was 45.5% (5/11). Three-month follow-up were made in all survivals (6/11). Analysis showed good collateral circulation flow from right coronary artery to left coronary artery was existed in all survival cases before PCI. CONCLUSION: Prognosis of AMI patients with LM artery obstruction or severe stenosis was poor. Patients with pre-existed collateral circulation before primary PCI and IABP had a better clinical outcomes.