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Angiotensin-converting enzyme (ACE) 2 overexpression ameliorates glomerular injury in a rat model of diabetic nephropathy: a comparison with ACE inhibition. 1B: the immunohistochemical images in the ACEI and AD-ACE2 + ACEI groups were mistakenly used, which were partially overlapped with the correct image in the Ad-ACE2 group. [Extracted from the article]

Astrocyte elevated gene 1 (AEG-1), a novel gene that was cloned in 2002, has emerged in recent years as a potentially crucial mediator of tumor malignancy and aberrant elevation of AEG-1 expression frequently occurs in several human cancers, including breast cancer, prostate cancer, gastric cancer. However, whether AEG-1 deregulation also occurs in neuroblastoma remains unclear. In previous study we reported that AEG-1 was over expressed in neuroblastoma cell lines and knockdown of AEG-1 inhibits proliferation and enhancing chemo-sensitivity to cisplatin or doxorubicin in neuroblastoma cells. In this study, we investigated the expression of AEG-1 and evaluate its prognostic significance by correlating AEG-1 expression levels with clinic pathologic features and survival in 32 archived neuroblastoma patients We found that positive AEG-1 immunoreactivities were present in all neuroblastoma cases, 75% showed high expression of AEG-1. And high expression of AEG-1 was commonly seen in vascular endothelial cells and glandula in neuroblastoma samples. AEG-1 expression was strongly correlated with age at diagnosis (P=0.012), clinical stage (P=0.030) and tumor histology stage (P=0.041). However, our analyses did not show significant associations between AEG-1 expression and other clinical features including gender and primary tumor site. Importantly, our data presented in this report provide, for the first time, evidence that elevated expression of AEG-1 protein is correlated with poor prognosis and reduced survival of patients with neuroblastoma (P= 0.031). Overall, the data support the notion that AEG-1 might be used as a biomarker for neuroblastoma patients. [ABSTRACT FROM AUTHOR]

Background and Purpose: Previous studies demonstrated that intraplaque haemorrhage increased the contents of cholesterol and oxidants in atherosclerotic plaques. The present study was aimed to test the hypothesis that enhanced expression of haem oxygenase-1 (HO-1) may stabilize vulnerable plaques.Experimental Approach: Intravascular ultrasound (IVUS) was performed to identify three similar abdominal aortic plaques in each of 58 fat-fed New Zealand rabbits after aortic balloon injury. With the guidance of IVUS, 50 microL autologous erythrocytes (RBC) or normal saline (NS) were injected from adventitia into two of the pre-selected plaques, respectively, whereas the third plaque served as a blank control. All rabbits were randomly divided into two groups, receiving intraperitoneal injection of haemin and saline respectively.Key Results: Compared with NS or control plaques, RBC plaques had more macrophage infiltration and lipid content, thinner plaque fibrous cap, and higher expression of inflammatory factors and incidence of plaque rupture. RBC plaques in the haemin group had about a 50% lower incidence of plaque rupture than those in the control group.Conclusions and Implications: Haem oxygenase-1 may eliminate haem or other oxidants, exert unexpected anti-oxidative and anti-inflammatory effects and serve as a promising approach to the direct inhibition of erythrocyte-induced plaque instability. [ABSTRACT FROM AUTHOR]

Abstract: Extracellular acidic pH activated chloride channels (ICl,acid) have been characterized in HEK 293 cells and mammalian cardiac myocytes. This study was designed to evaluate the expression of ICl,acid in RAW264.7 monocytic-macrophage and human peripheral monocytes and to investigate the effect of simvastatin on ICl,acid. In two kinds of cells, the activation and deactivation of the current rapidly and repeatedly followed the change of the extracellular solution to pH=4.3. Compared with the outward current (pA/pF) activated at pH 4.3, the currents inhibited by simvastatin at concentrations of 0.1 μM were all decreased a little, however the currents at concentrations of 1 μM and 10 μM simvastatin were decreased significantly. The IC50 for simvastatin inhibiting ICl,acid of RAW264.7 was 13.77 μM. In summary, we report for the first time that simvastatin inhibits the ICl,acid of RAW264.7 monocytic-macrophage and human peripheral monocytes in a concentration-dependent manner. [Copyright &y& Elsevier]

Neuronal death after traumatic brain injury (TBI) is a complex process resulting from a combination of factors, many of which are still unknown. Transient receptor potential melastatin 7 (TRPM7) is a transient receptor potential channel that has been demonstrated to mediate ischemic and traumatic neuronal injury in vitro. In the present study, TRPM7 was suppressed in the rat cerebral cortex by intracortical injections of viral vectors bearing shRNA specific for TRPM7 to investigate its potential role in an in vivo TBI model. We found that TRPM7 suppression significantly reduced brain edema, brain contusion volume and motor functional deficits, which was sustained for at least 2 weeks after the insult. These protective effects were accompanied by inhibited apoptosis in injured cortex. Also, TRPM7 suppression attenuated lipid peroxidation, decreased the expression of protein carbonyl, and preserved the endogenous antioxidant enzyme activities. The results of western blot analysis showed that TRPM7 suppression markedly increased the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS). In addition, blocking Akt/eNOS pathway activation by the specific inhibitor LY294002 (LY, 10 μL, 10 mmol/L) or L-NIO (0.5 mg/kg) partially reversed the protective effects of TRPM7 suppression and its anti-oxidative activities. Taken together, these findings demonstrated that regional inhibition of TRPM7 in cerebral cortex exerts neuroprotective effects against TBI through activation of Akt/eNOS pathway. Thus, TRPM7 might represent a potential drug development target for the treatment of TBI. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to test the hypothesis that angiotensin (Ang)-converting enzyme-2 (ACE2) overexpression may inhibit myocardial collagen accumulation and improve left ventricular (LV) remodeling and function in diabetic cardiomyopathy. Background: Hyperglycemia activates the renin-Ang system, which promotes the accumulation of extracellular matrix and progression of cardiac remodeling and dysfunction. Methods: Ninety male Wistar rats were divided randomly into treatment (n = 80) and control (n = 10) groups. Diabetes was induced in the treatment group by a single intraperitoneal injection of streptozotocin. Twelve weeks after streptozotocin injection, rats in the treatment group were further divided into adenovirus-ACE2, adenovirus–enhanced green fluorescent protein, losartan, and mock groups (n = 20 each). LV volume; LV systolic and diastolic function; extent of myocardial fibrosis; protein expression levels of ACE2, Ang-converting enzyme, and Ang-(1-7); and matrix metalloproteinase–2 activity were evaluated. Cardiac myocyte and fibroblast culture was performed to assess Ang-II and collagen protein expression before and after ACE2 gene transfection. Results: Four weeks after ACE2 gene transfer, the adenovirus-ACE2 group showed increased ACE2 expression, matrix metalloproteinase–2 activity, and LV ejection fractions and decreased LV volumes, myocardial fibrosis, and ACE, Ang-II, and collagen expression in comparison with the adenovirus–enhanced green fluorescent protein and control groups. ACE2 was superior to losartan in improving LV remodeling and function and reducing collagen expression. The putative mechanisms may involve a shift in balance toward an inhibited fibroblast-myocyte cross-talk for collagen and transforming growth factor–beta production and enhanced collagen degradation by matrix metalloproteinase–2. Conclusions: ACE2 inhibits myocardial collagen accumulation and improves LV remodeling and function in a rat model of diabetic cardiomyopathy. Thus, ACE2 provides a promising approach to the treatment of patients with diabetic cardiomyopathy. [Copyright &y& Elsevier]

Abstract: Aims: Adventitial fibroblasts (AFs) and inflammation play an important role in neointimal formation and vascular remodeling. The present study was aimed to investigate the therapeutic effects and underlying mechanisms of transcriptional regulator Gax gene transfection in aortic remodeling induced by adventitial inflammation. Methods and results: Fifty rabbits fed a chow diet were randomly divided into a normal control group (n =10) and experimental group (n =40). All rabbits in the experimental group underwent collar placement around the abdominal aorta and intra-collar injection of lipopolysaccharide (LPS) to induce adventitial inflammation and they were further divided into model control group, saline-treated group, green fluorescence protein (Ad-GFP)-treated group and Gax gene (Ad-Gax)-treated group, respectively. Four weeks after treatment, the model control group, saline-treated group and Ad-GFP-treated group showed thickened neointima and adventitia, reduced lumen size and increased eccentricity and remodeling index of the abdominal aorta in comparison with the normal control group, whereas Ad-Gax-treated group exhibited attenuated neointimal formation and vascular remodeling (P <0.01–0.05) .The vascular expression levels of interleukin (IL)-1β, IL-6, IL-8, monocyte chemoattractant protein (MCP)-1, matrix metalloproteinase (MMP)-1, MMP-2, MMP-9, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1, Smads, mitogen-activated protein kinases (MAPKs), integrins and nuclear factor kappa B (NF-kB) were significantly higher in the model control group, saline-treated group and Ad-GFP-treated group than those in the normal control group (P <0.01–0.05). In contrast, the local expression levels of these cytokines were substantially reduced by Ad-Gax gene transfer (P <0.01–0.05). Similarly, the serum levels of inflammatory cytokines including C-reactive protein (CRP), transforming growth factor (TGF)-β1, IL-1, IL-6, IL-8, tumor necrosis factor (TNF)-α, MCP-1, VCAM-1 and ICAM-1 were significantly higher in the model control group, saline-treated group and Ad-GFP-treated group than those of the Ad-Gax-treated group (P <0.01–0.05). In vitro studies showed that Gax overexpression diminished inflammatory cytokine expression in LPS-stimulated arterial fibroblasts. Conclusions: Adventitial inflammation induces vascular remodeling via the interactions of multiple inflammatory cytokines and local Gax gene transfer in vivo can significantly inhibit these interactions and thereby attenuate local inflammation and vascular remodeling. [Copyright &y& Elsevier]

Abstract: Aims: To evaluate the reliability of velocity vector imaging (VVI) for detecting vulnerable plaques. Methods and Results: After aortic balloon injury, 60 rabbits were fed a 1% cholesterol diet for 10 weeks and normal chow for another 6 weeks. Adenovirus containing p53 or lac Z was then injected into the aortic plaques and rabbits were divided into p53-treated group (n =20), lac Z-treated group (n =20) and blank control group (n =20). Peak longitudinal (LSp), radial (RSp) and circumferential (CSp) strain of plaques was measured using VVI at the end of week 18 before pharmacological triggering. Higher RSp and CSp and lower LSp were found in ruptured than those in non-ruptured plaques, and RSp, CSp and LSp correlated well with the fibrous cap thickness and plaque content of macrophages, smooth muscle cells and collagen (all p <0.01). A logistic regression model showed that both RSp (RR: 8.96, 95% CI: 5.3575–10.4857, p <0.001) and CSp (RR: 8.45, 95% CI: 5.9043–9.1043, p <0.001) were significant predictors of plaque rupture. RSp and CSp had a sensitivity of 88.0% and 88.6% and a specificity of 88.6% and 92.0% to predict plaque disruption, respectively. Conclusion: VVI offers a new and noninvasive technique for measuring the peak strain of atherosclerotic plaques and RSp and CSp are a novel index with a high sensitivity and specificity for detecting plaques vulnerable to rupture. [Copyright &y& Elsevier]

The human neonate is at a higher risk for hypoglycemia-induced neuronal injury than other pediatric and adult patients. Repetitive and profound neonatal hypoglycemia can result in severe neurologic sequelae, of which the mechanisms was not elucidated by hitherto. Moreover, no reliable animal model of brain injury induced by neonatal hypoglycemia is available in order to carry out more research. Therefore, we tried to induce neonatal hypoglycemia in newborn rats by fasting and insulin injection, and then examined the neuronal degeneration after repetitive hypoglycemic insults by Fluoro-Jade B (FJB) staining. Experimental animals were randomly divided into four groups: insulin-treated rats with short hypoglycemia, insulin-treated rats with prolonged hypoglycemia, fasted rats, and control rats. Insulin injection and fasting both could induce consistent hypoglycemia in newborn rats. But from FJB staining results, only in insulin-treated rats with prolonged hypoglycemia could extensive neurodegeneration be detected. We can conclude that FJB staining is a useful method of marking neuronal degeneration in neonatal rats following hypoglycemic brain damage. Repetitive and profound neonatal hypoglycemia can result in extensive neurodegeneration, and it seems that neurons of the cortex, dentate gyrus of the hippocampus, the thalamus, and the hypothalamus are more vulnerable to hypoglycemic insult in newborn rats. Repetitive and profound insulin-induced hypoglycemia in newborn rats can establish a reliable animal model of brain injury resulting from neonatal hypoglycemia. [ABSTRACT FROM AUTHOR]

Abstract: Extracellular acidic pH-activated chloride channel I Cl, acid, has been characterized in HEK 293 cells and mammalian cardiac myocytes. This study was designed to characterize I Cl,acid in human umbilical vein endothelial cells(HUVECs). The activation and deactivation of the current rapidly and repeatedly follows the change of the extracellular solution at pH 4.3, with the threshold pH 5.3. In addition, at very positive potentials, the current displays a time-dependent facilitation. pH-response relationship for I Cl,acid revealed that EC50 is pH 4.764 with a threshold pH value of pH 5.3 and nH of 14.545. The current can be blocked by the Cl− channel inhibitor DIDS (100μM). In summary, for the first time we report the presence of proton-activated, outwardly rectifying chloride channel in HUVECs. Because an acidic environment can develop in local myocardium under pathological conditions such as myocardial ischemia, I Cl,acid would play a role in regulation of EC function under these pathological conditions. [Copyright &y& Elsevier]