Epigallocatechin Gallate Attenuates ß-Amyloid Generation and Oxidative Stress Involvement of PPARγ in N2a/APP695 Cells.

The accumulation of ß-amyloid (Aß) peptide plaques is a major pathogenic event in Alzheimer's disease (AD). Aß is a cleaved fragment of APP via BACE1, which is the rate-limiting enzyme in APP processing and Aß generation. Nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is considered to be a potential target for AD treatment, because of its potent antioxidant and inhibitory effects on Aß production by negatively regulating BACE1. Epigallocatechin gallate (EGCG), a highly active catechin found in green tea, is known to enhance metabolic activity and cognitive ability in the mice model of AD. To investigate whether the therapeutic effect of EGCG is related to the PPARγ pathway, we analysed the alterations in the intracellular molecular expression of PPARγ after EGCG treatment in the N2a/APP695 cell line. In this study, we observed that EGCG attenuated Aß generation in N2a/APP695 cells, such as the PPARγ agonist, pioglitazone, by suppressing the transcription and translation of BACE1 and that its effect was attenuated by the PPARγ inhibitor, GW9662. Intriguingly, EGCG significantly reinforced the activity of PPARγ by promoting its mRNA and protein expressions in N2a/APP695 cells. Moreover, EGCG also decreased the expression of pro-apoptotic proteins (Bax, caspase-3), reduced the activity of the anti-inflammatory agent NF-κB and inhibited the oxidative stress by decreasing the levels of ROS and MDA and increasing the expression of MnSOD. Co-administration of GW9662 also significantly decreased the EGCG-mediated neuroprotective effect evidenced by the increase in oxidative stress and inflammatory markers. The therapeutic efficacy of EGCG in AD may be derived from the up-regulation of PPARγ mRNA and protein expressions.

Fuzhisan ameliorates Aß production and tau phosphorylation in hippocampal of 11month old APP/PS1 transgenic mice: A Western blot study.

Accumulation of amyloid-ß (Aß) peptide and deposition of hyperphosphorylated tau protein are two major pathological hallmarks of Alzheimer's disease (AD). Glycogen synthase kinase-3ß (GSK3ß) is increasingly thought to play a pivotal role in the pathogenesis of AD, both as a regulator of the production of Aß and through its well-established role on tau phosphorylation. The phosphoinositide 3 kinase (PI3K)/Akt pathway plays an import role in neuronal survival and cognitive function, and is known as an upstream element of GSK3ß. Fuzhisan (FZS), a Chinese herbal complex prescription, has been used for the treatment of AD for over 20years, and is known to enhance the cognitive ability in AD patients as well as in AD model rats. However, it still remains unclear whether FZS is responsible for regulation of PI3K/AKT/GSK3ß signaling and contributes to subsequent down-regulation of Aß and phosphorylated tau. Thus, we treated APP/PS1 transgenic mice, a useful model of AD-related memory impairment, with FZS by intragastrical administration for 60days and Donepezil was used as a positive control. The results showed that treatment with FZS significantly reversed the memory deficit in the Tg APP/PS1 mice in the Morris water maze test. Moreover, FZS significantly attenuated Aß production through inhibition of APP procession and phosphorylation of tau in the hippocampus of Tg APP/PS1 mice. In addition, FZS treatment also increased PI3K and pSer473-AKT levels, inhibited GSK3ß activity by increasing phosphorylation of GSK3ß at Ser9. These results indicated that the memory ameliorating effect of FZS may be, in part, by regulation the PI3K/AKT/GSK3ß signaling which may contribute to down-regulation of Aß and tau hyperphosphorylation.

Fuzhisan Ameliorates the Memory Deficits in Aged SAMP8 Mice via Decreasing Aß Production and Tau Hyperphosphorylation of the Hippocampus.

The pathological features of Alzheimer's disease (AD) include extracellular neuritic plaques containing ß-amyloid (Aß) peptide, a cleaved fragment of amyloid precursor protein (APP) via ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Cyclin-dependent kinase 5 (Cdk5) is increasingly thought to play a pivotal role in the pathogenesis of AD, both as a regulator of the production of Aß and through its well-established role as a tau kinase. Fuzhisan (FZS), a Chinese herbal complex prescription, has been used for the treatment AD for over 20 years, and is known to enhance the cognitive ability in AD patients as well as in AD model rats. To investigate mechanisms of AD and the potential therapy of FZS in AD, we treated senescence-accelerated mouse SAMP8 mice, a useful model of AD-related memory impairment, with FZS by intragastrical administration for 8 weeks and Donepizel was used as a positive control. The results showed that FZS (0.3, 0.6, and 1.2 g/kg/day) improved impaired cognitive ability of aged SAMP8 mice in a dose-dependent manner. FZS robustly decreased Aß level and phosphorylation of tau. This was accompanied by a significant decrease in the BACE1 level and phosphorylated APP (Thr668). Futhermore, The p25/Cdk5 pathway was markedly down-regulated by FZS treatment. These results indicated that the memory ameliorating effect of FZS may be, in part, by regulation the p25/Cdk5 pathway which may contribute to down-regulation of Aß and tau hyperphosphorylation.

Diagnostic value of Flash dual-source CT coronary artery imaging combined with dual-energy myocardial perfusion imaging for coronary heart disease.

The present study aimed to investigate the diagnostic value of Flash dual-source CT coronary angiography (DS-CTA) combined with dual-energy myocardial perfusion imaging (DS-CTP) for coronary heart disease (CHD), as a single-stage examination. A total of 60 patients with CHD underwent DS-CT examination, as well as coronary angiography (CAG), as the reference standard. The patients were divided into <50% and ≥50% stenosis groups based on their coronary angiograms. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the method for diagnosing stenosis of ≥50% were evaluated via DS-CTA combined with DS-CTP. Of the 60 patients, 59 showed satisfactory results that conformed to the diagnostic requirements. Using CAG as the reference standard, the sensitivity, specificity and positive and negative predictive values of the Flash DS-CT results in the ≥50% vascular stenosis group were 83.7, 92.7, 88.9 and 89.1%, respectively. The respective values for DS-CTA combined with DS-CTP for diagnosing CHD were 94.2, 91.1, 88.0 and 95.8%. Therefore, the results obtained indicate that DS-CTA combined with DS-CTP has a high diagnostic value for CHD. DS-CT is advantageous for diagnosing and prognosticating CHD.

The efficacy and safety of pharmacoinvasive therapy with prourokinase for acute ST-segment elevation myocardial infarction patients with expected long percutaneous coronary intervention-related delay.

OBJECTIVES: To elucidate the efficacy and safety of pharmacoinvasive therapy by using prourokinase (prouk) in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Patients with STEMI often have long percutaneous coronary intervention (PCI)-related delays due to various reasons, which are associated with poor outcomes. METHODS: A randomized study which enrolled patients from four centers in China was conducted. Patients were randomly assigned to accept routine primary PCI or prouk-PCI. The primary end points were the angiographic parameters, including thrombolysis in myocardial infarction (TIMI) flow grade, TIMI frame count, and myocardial blush grade. Secondary endpoints were incidence of major adverse cardiac events (MACE, defined as death from all causes, reinfarction, revascularization, or rehospitalization due to new or worsening congestive heart failure) at 30 days and 1 year. RESULTS: One hundred and ninety-seven eligible patients were enrolled, of whom 100 were randomized to the prouk-PCI group. Significantly more patients in the prouk-PCI group than in the PCI group had an opened infarct-related artery on arrival in the catheterization laboratory (48% vs. 21%, P = 0.0002) and better TIMI frame count after PCI (33 ± 6 vs. 40 ± 10, P < 0.001). At 1-year follow-up, there was a trend that patients in the prouk-PCI group had less chances to have MACE (7.0% vs. 12.6%, P = 0.235) or be readmitted to hospital due to new or worsening congestive heart failure (1.0% vs. 4.1%, P = 0.209). CONCLUSION: A strategy of emergent PCI preceded by fibrinolysis with prouk results in a better myocardial perfusion in infarct-related artery compared with primary PCI alone in patients with STEMI and long PCI-related delay.

Feasibility and Diagnostic Accuracy for Assessment of Coronary Artery Stenosis of Prospectively Electrocardiogram-gated High-pitch Spiral Acquisition Mode Dual-source CT Coronary Angiography in Patients with Relatively Higher Heart Rates: in Comparison with Catheter Coronary Angiography.

Objective To prospectively investigate the diagnostic accuracy for coronary artery stenosis of prospectively electrocardiogram-triggered spiral acquisition mode (high pitch mode) dual-source computed tomography coronary angiography (CTCA) in patients with relatively higher heart rates (HR) compared with catheter coronary angiography (CCA). Methods Forty-seven consecutive patients with relatively higher HR (>65 and <100 bpm) (20 male, 27 female; age 55±10 years) who both underwent dual-source CTCA and CCA were prospectively included in this study. All patients were performed CTCA using high pitch mode setting at 20%-30% of the R-R interval for the image acquisition. All coronary segments were evaluated by two blinded and independent observers with regard to image quality on a three-point scale (1: excellent to 3: non-diagnostic) and for the presence of significant coronary stenoses (defined as diameter narrowing exceeding 50%). Considered CCA as the standard of reference, the sensitivity, specificity, positive predictive value and negative predictive value were calculated. Radiation dose values were calculated using the dose-length product. Results Image quality was rated as being score 1 in 92.4% of segments, score 2 in 6.1% of segmentsand score 3 in 1.5% of segments. The average image quality score per segment was 1.064±0.306. The HR variability of patients with image score 1, 2 and 3 were 2.29±1.06 bpm, 5.17±1.37 bpm, 8.88±1.53 bpm, respectively. The average HR variability of patients with different image scores were significantly different (F=170.402, P=0.001). The sensitivity, specificity, positive and negative predictive values were 92.6%, 97.0%, 87.6%, 98.3%, respectively, per segment and 90.0%, 95.2%, 85.3%, 96.9%, respectively, per vessel and 100%, 63.6%, 90.0%, 100%, respectively, per patient. The effective radiation dose was on average 0.86±0.16 mSv. Conclusion In patients with HR more than 65 bpm and below 100 bpm without cardiac arrhythmia, the prospectively electrocardiogram-gated high-pitch spiral acquisition mode with image acquired timing set at 20%-30% of the R-R interval provides a high diagnostic accuracy for the assessment of coronary stenoses combined with a 1.5% of non-diagnostic coronary segments and a radiation dose below 1 mSv.

Efficacy and safety of aranidipine enteric-coated tablets compared with amlodipine in Chinese patients with mild to moderate essential hypertension: a multicenter, randomized, double-blind, parallel-controlled clinical trial.

This is a multicenter, randomized, double-blind, parallel-controlled study, conducted in Chinese patients with mild to moderate essential hypertension. After a 2-week washout period, 236 eligible patients were randomly to receive aranidipine 5-10 mg/d (n = 118) or amlodipine 5-10 mg/d (n = 118) for 10 weeks. The blood pressure and heart rate were evaluated in outpatient clinics, and ambulatory blood pressure monitoring was performed in 24 patients in each group. The blood pressure was significantly decreased in both groups. Compared with amlodipine, the patients who received aranidipine had less response in blood pressure (P < 0.01). The trough/peak ratios of diastolic blood pressure in aranidipine and amlodipine groups were 0.57 ± 0.20 and 0.68 ± 0.19, respectively (P = 0.119). Adverse events occurred at 11.86% and 7.63% in the aranidipine and amlodipine groups, respectively (P = 0.348). Headache was observed at an incidence of >3.0% in both groups, and the serum glucose and lipid profile had no significant change in the amlodipine group. In conclusion, once-daily administration of aranidipine (5-10 mg) effectively controlled blood pressure, and the short-term treatment might result in it being less effective than amlodipine. It had a stable action over 24-hour period, and the mechanism of that is not yet clear. Aranidipine had a good safety similar to that of amlodipine.