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Abstract: Seizure is one kind of severe side effects during clozapine (Clo) treatment. However, the mechanism of seizure associated with Clo therapy is not completely clear. Strychnine-sensitive glycine receptors (GlyRs) play an important role in regulating the excitability in the hippocampus. In the present study, we investigated the effect of Clo on GlyRs in cultured hippocampal neurons of rats. Clo reversibly inhibited the glycine-induced chloride currents (I Gly) in a concentration-dependent manner. The half-maximal effect concentration (EC50) for glycine alone was 25.6±0.7 μM with the Hill coefficient 1.5±0.1; in the presence of Clo, the EC50 and the Hill coefficient were 28.9±6.3 μM and 1.2±0.3 respectively, which were not significantly affected by Clo. In addition, Clo inhibition of I Gly was not influenced by blocking D1 and D2 dopamine receptors with haloperidol (Hal). Taken together, these results suggest that Clo is a non-competitive antagonist of GlyR independent of its activation of dopamine receptors, which may contribute to seizure associated with Clo therapy. [Copyright &y& Elsevier]

Abstract: Atherogenesis is associated with inflammation and oxidative stress. Activation of renin-angiotensin system with generation of angiotensin II and type 1 receptor (AT1R) stimulation has been amply reported in atherosclerosis. Since angiotensin II type 2 receptor (AT2R) activity is purported to oppose the effects of AT1R, we hypothesized that AT2R (agtr2) over-expression would inhibit atherogenesis. We prepared recombinant adeno-associated virus type-2 (AAV) carrying AT2R cDNA (AAV/AT2R), and homozygous LDLR-deficient (KO) mice were given AAV/AT2R, AAV/Neo or saline. All mice were placed on a high cholesterol diet. After 18 weeks, AT2R was found to be over-expressed systemically in AAV/AT2R-treated mice. Atherogenesis in aorta was reduced in the AAV/AT2R group by ≈50% compared to other LDLR KO mice groups. Expression of NADPH oxidase, nitrotyrosine and NF-κB was increased in aortic tissues of the LDLR KO mice given saline or AAV/Neo, but not in mice with AT2R upregulation. Expression of endothelial nitric oxide synthase (eNOS) and heme-oxygenase-1 (HO-1) was decreased and that of the lectin-like oxidized-LDL receptor (LOX-1) increased in the LDLR KO mice, but not in the mice with AT2R over-expression. Further, Akt-1 phosphorylation was reduced in the LDLR KO mice, but not in the mice with AT2R over-expression. Thus, AT2R upregulation can reduce atherogenesis, possibly by modulating oxidative stress and the pro-inflammatory cascade, mediated via Akt-1. Over-expression of AT2R may be an important therapeutic approach in atherosclerosis. [Copyright &y& Elsevier]

By comparing the usage of structural equation model (SEM) and tetra-class model (TCM) in the model structure, data analysis method, and result presentation when evaluating Chinese academic libraries, this study aims to illustrate the strategies in evaluating satisfaction of academic library services. The study sample consists of 353 academic library users who are asked to evaluate 27 Chinese typical academic library service elements. The findings show that SEM could reveal the influence relations among constructs by path coefficients, while TCM focuses on the visual classification and comparison of specific service elements based on their contributions to user satisfaction. These two models are complementary to each other. They can be used for comprehensively showing the influence factors and current situation of service satisfaction, which are valuable and instructive for improving the service quality of a digital library. The results also indicate that a digital library needs to ensure the quality of retrieval service elements and to improve the service capability of information-organizing service elements. Meanwhile, the developments of characteristic resources and library community are critical to the promotion of user satisfaction of academic library service. [ABSTRACT FROM AUTHOR]

Mulberry leaf, an important traditional Chinese medicine, possesses many biological activities, including effects of anti-obesity. However, which constituents of mulberry leaf are responsible for its anti-adipogenic action is unclear. This study primarily investigated the chemical constituents from mulberry leaf and their bioactivity on the proliferation and differentiation of 3T3-L1 preadipocytes. A new flavane derivative, (2 S )-4′-hydroxy-7-methoxy-8-prenylflavan ( 1 ), together with twelve known compounds including three flavanes ( 2 – 4 ), three chalcones ( 5 – 7 ), two flavones ( 8 – 9 ), two benzofurans ( 10 – 11 ) and two coumarin ( 12 – 13 ) was isolated from mulberry leaf. The structure of the new compound was elucidated by various spectroscopic methods including UV, HR-ESI-MS, 1 H and 13 C NMR and CD. The results of activity screening showed that compound 2 , 6 and 7 inhibited the proliferation and differentiation of 3T3-L1 preadipocytes. [ABSTRACT FROM AUTHOR]

It is assumed that acute myocardial infarction affects renal function. To study the mechanism, we used mice following permanent ligation of their left coronary artery that results in extensive myocardial infarction. Soon after ligation, there was a marked rise in circulating pro-inflammatory cytokines and malondialdehyde (thiobarbituric acid-positive evidence of lipid peroxidation). Renal function had significantly declined by the third day in association with mild fibrosis, and swelling of glomeruli and tubules. There was a significant increase in the expression of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), interelukin-1β, vascular cell adhesion molecule-1, and thiobarbituric acid-reactive substances in the kidney. Renal function showed some recovery by Day 21; however, there was progressive fibrosis of the kidneys. LOX-1 knockout mice had significantly diminished increases in systemic and renal pro-inflammatory cytokines, malondialdehyde, structural alterations, and decline in renal function than the wild-type mice following ligation of the left coronary artery. Cardiac function and survival rates were also significantly better in the LOX-1 knockout mice than in the wild-type mice. Hence, severe myocardial ischemia results in renal dysfunction and histological abnormalities suggestive of acute renal injury. Thus, LOX-1 is a key modulator among multiple mechanisms underlying renal dysfunction following extensive myocardial infarction. [ABSTRACT FROM AUTHOR]

Abstract: Previous studies have indicated that GABAergic disinhibition contributes to cognitive deficits mediated by NMDA receptor hypofunction in schizophrenia model of rats. However, the underlying mechanism of GABAergic disinhibition in schizophrenia remains elusive. In this study, we found that the maintenance of long term potentiation (LTP) was impaired in the hippocampus of rats with MK-801-induced cognitive impairments. The impairment of LTP maintenance was significantly reversed by picrotoxinin, a specific GABAA receptor-chloride channel blocker and furosemide, a K+–Cl− cotransporter 2 (KCC2) blocker, respectively. Furthermore, immunoblotting results indicated KCC2 expression in hippocampal CA1 of MK-801-treated rats was lower than that of normal rats before LTP induction. Additionally, LTP-accompanied downregulation of KCC2 was prevented in MK-801-treated rats during LTP induction. Our results suggested that KCC2 expression in hippocampal CA1 of MK-801-treated rats was not further decreased by LTP induction because of its low expression caused by MK-801 treatment. Accordingly, GABAergic inhibition was not further decreased during LTP induction due to the depressed basal GABAergic tone in MK-801-treated rats, Therefore, GABAergic disinhibition in MK-801-treated rats restricts the further downregulation of KCC2 during LTP induction and contributes to the stable GABAergic inhibition and the impaired LTP expression. Our results thus reveal the mechanism that GABAergic disinhibition contributes to cognitive deficits. [Copyright &y& Elsevier]

Continuous recruitment and inappropriate activation of platelets in pulmonary arteries contribute to pulmonary vascular remodeling in pulmonary hypertension (PH). Our previous study has demonstrated that lectin like oxidized low-density lipoprotein receptor-1 (LOX-1) regulates the proliferation of pulmonary arterial smooth muscle cells (PASMCs). Phosphatidylserine exposed on the surface of activated platelets is a ligand for LOX-1. However, whether hypoxia-activated platelets stimulate the proliferation and migration of PASMCs by phosphatidylserine/LOX-1 signaling-impelled intercellular communication remains unclear. The present study found that rats treated with hypoxia (10% O 2) for 21 days revealed PH with the activation of platelets and the recruitment of platelets in pulmonary arteries, and LOX-1 knockout inhibited hypoxia-induced PH and platelets activation. Notably, co-incubation of PASMCs with hypoxic PH rats-derived platelets up-regulated LOX-1 expression in PASMCs leading to the proliferation and migration of PASMCs, which was inhibited by the phosphatidylserine inhibitor annexin V or the LOX-1 neutralizing antibody. LOX-1 knockout led to decreased proliferation and migration of PASMCs stimulated by hypoxia-activated platelets. In rats, hypoxia up-regulated the phosphorylation of signal transducer and activator of transcription 3 (Stat3) and the expression of Pim-1 in pulmonary arteries. Hypoxia-activated platelets also up-regulated the phosphorylation of Stat3 and the expression of Pim-1 in PASMCs, which was inhibited by annexin V, the LOX-1 neutralizing antibody, the protein kinase C inhibitor and LOX-1 knockout. In conclusion, we for the first time demonstrated that hypoxia-activated platelets stimulated the proliferation and migration of PASMCs by phosphatidylserine/LOX-1/PKC/Stat3/Pim-1 signaling-impelled intercellular communication, thereby potentially contributing to hypoxic pulmonary vascular remodeling. • Continuous recruitment and inappropriate activation of platelets in PAs contribute to pulmonary vascular remodeling in PH. • Phosphatidylserine (PS) exposed on the surface of activated platelets is a ligand for LOX-1. • PS/LOX-1 signaling-impelled intercellular communication mediating the interaction between platelets and PASMCs is unclear. • Hypoxia-activated platelets stimulated the proliferation and migration of PASMCs by PS/LOX-1/PKC/Stat3/Pim-1signaling. [ABSTRACT FROM AUTHOR]