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Liu X.,PLA Fourth Military Medical University | Shi M.,PLA Fourth Military Medical University | Xia F.,PLA Fourth Military Medical University | Han J.,PLA Fourth Military Medical University | And 9 more authors.
International Journal of Stroke | Year: 2015

Rationale: Epidemiological studies suggest that elevated homocysteine is linked to stroke and heart disease. However, the results of lowering homocysteine levels in reducing the risk of stroke recurrence are controversial. Aims: The study aims to evaluate whether homocysteine-lowering therapy with folic acid and vitamins B6 and B12 reduces recurrent stroke events and other combined incidence of recurrent vascular events and vascular death in ischemic stroke patients of low folate regions. Design: This is a multicenter, randomized, double-blinded, placebo-controlled trial. Patients (n=8000, α=0·05, β=0·10) within one-month of ischemic stroke (large-artery atherosclerosis or small-vessel occlusion) or hypertensive intracerebral haemorrhage with plasma homocysteine level ≥15μmol/l will be enrolled. Eligible patients will be randomized by a web-based, random allocation system to receive multivitamins (folic acid 0·8mg, vitamin B6 10mg, and vitamin B12 500μg) or matching placebo daily with a median follow-up of three-years. Study Outcomes: Patients will be evaluated at six monthly intervals. The primary outcome event is the composite event 'stroke, myocardial infarction, or death from any vascular cause', whichever occurs first. Secondary outcome measures include nonvascular death, transient ischemic attack, depression, dementia, unstable angina, revascularization procedures of the coronary, and cerebral and peripheral circulations. Discussion: This is the first multicenter randomized trial of secondary prevention for ischemic stroke in a Chinese population with a higher homocysteine level but without folate food fortification. © 2013 World Stroke Organization.

Chi L.,451st Hospital of Peoples Liberation Army | Peng L.,451st Hospital of Peoples Liberation Army | Pan N.,451st Hospital of Peoples Liberation Army | Hu X.,Ninth Hospital of Xian | Zhang Y.,451st Hospital of Peoples Liberation Army
International Journal of Molecular Medicine | Year: 2014

Berberine (BBR) is a botanical alkaloid that has been reported to have effects in cardiovascular diseases; however, the mechanisms involved are not yet fully understood. In the present study, the protective effects of BBR were evaluated, and the underlying molecular mechanisms were investigated. The effects of a combination of atorvastatin and BBR on foam cell formation were also investigated. THP-1-derived macrophages were pre-treated with BBR (5, 10 and 20 mg/l) for 2 h prior to the addition of oxidized low density lipoprotein (ox-LDL; 50 mg/l). Small interfering RNA (siRNA) targeting sirtuin 1 (SIRT1) and the adenosine 5′-monophosphate-activated protein kinase (AMPK) inhibitor, compound C, were used to investigate the mechanisms through which BBR exerts its effects. To determine the effect of a combination of atorvastatin and BBR, the macrophages were treated with atorvastatin and BBR separately or jointly for 2 h, and then treated with ox-LDL (50 mg/l) or lipopolysaccharide (LPS; 10 μM) for 12 h. Oil Red O staining was used to detect foam cell formation. Lipid amounts were assessed by high-performance liquid chromatography (HPLC). Gene and protein expression was evaluated by RT-qPCR, western blot analysis and enzyme-linked immunosorbent assay (ELISA) carried out separately or jointly. The results from Oil Red O staining and HPLC revealed that BBR effectively suppressed foam cell formation and lipid and cholesterol accumulation. Furthermore, BBR upregulated the expression of SIRT1 and AMPK and downregulated the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ). Pre-treatment of the cells with SIRT1-siRNA or compound C attenuated the anti-atherosclerotic effects of BBR. The results obtained in the present study demonstrate that the combination of atorvastatin and BBR is more effective in inhibiting foam cell formation than using atorvastatin alone. These data suggest that BBR suppresses foam cell formation by activating the AMPK-SIRT1-PPAR-γ pathway and diminishing the uptake of ox-LDL. Combination therapy with BBR and atorvastatin was more effective in preventing atherosclerotic processes than atorvastatin alone.

Chi L.,451st Hospital of Peoples Liberation Army | Peng L.,451st Hospital of Peoples Liberation Army | Hu X.,Ninth Hospital of Xian | Pan N.,451st Hospital of Peoples Liberation Army | Zhang Y.,451st Hospital of Peoples Liberation Army
International Journal of Molecular Medicine | Year: 2014

Studies have shown that the oxidative modification of low-density lipoprotein (oxLDL) plays a major role in atherogenesis. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) mediated the transport of oxLDL into macrophages, which promoted foam cell formation. Targeting LOX-1 may therefore be a promising approach to inhibit atherosclerosis. In the present study, we aimed to investigate the effect of berberine combined with atorvastatin on LOX-1 and explore the underlying molecular mechanism involved. Expression of LOX-1 in monocyte-derived macrophages (MDMs) exposed to berberine (0, 0.1, 1, 10 and 100 nM) and atorvastatin (100 nM) were analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analysis. Results showed that the expression of LOX-1 was decreased in a dose-dependent manner. Additionally, knockdown of the endothelin-1 (ET-1) receptor significantly blocked the inhibitory effect of berberine on LOX-1 expression. Body weight (BW), liver weight (LW) and kidney weight (KW) in the model rats were markedly increased at concentrations of berberine ≥1 μmol/kg, while heart weight (HW) and spleen weight (SW) remained constant among all groups. Berberine combined with atorvastatin also decreased serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein-cholesterol (LDL-C) levels in the rat model as well as inflammation and oxidative stress. Furthermore, plasma ET-1 levels and LOX-1 expression were decreased by berberine combined with atorvastatin treatment, and the inhibitory effect on LOX-1 was impeded by an ET-1 receptor antagonist. The results demonstrated that berberine combined with atorvastatin downregulates LOX-1 expression through ET-1 receptors in monocyte/macrophages in vitro and in vivo.

Du J.-H.,Ninth Hospital of Xian
Zhonghua Shiyan Yanke Zazhi/Chinese Journal of Experimental Ophthalmology | Year: 2013

Choroidal neovascularization (CNV) is the leading cause of vision disorder caused by various retinal diseases. At present, many therapeutic methods are employed clinically, such as photodynamic therapy (PDT), anti-vascular endothelial growth factor (anti-VEGF) and transpupillary thermotherapy (TTT). However, none of them can cure CNV thoroughly and repeated treatment is required usually. The reason for recurrent CNV is still unclear. Choroidal hypoperfusion associated with PDT may be one of the reasons. The purpose of this review is to discuss the problem of choroidal hypoperfusion associated with PDT for CNV as well as its impact on the eye and possible solutions. This paper presents evidences of choroidal hypoperfusion after PDT and its relationship with clinical outcomes. Meanwhile, the effect of combination therapy is assessed. Finally, low-fluence PDT is recommended as a potential method to reduce choroidal hypoperfusion. Copyright © 2013 by the Chinese Medical Association.

Xue H.,Xian Jiaotong University | Chen B.,Ninth Hospital of Xian | Fan Y.,Northwestern University | Palikhe M.,Xian Jiaotong University | Li Y.,Xian Jiaotong University
Scandinavian Journal of Gastroenterology | Year: 2011

Objective. To study whether alcohol and endotoxin induce inflammation, apoptosis, and expression of downstream genes TNF-α and caspase-3 through the nuclear transcription factor NF-κB, i.e., the IκBNF- κBimportin α pathway. Methods. Flow cytometry was used to observe the apoptosis rate in human hepatoma cells (HepG2) and murine macrophages (RAW264.7) after being stimulated by alcohol and endotoxin at different concentrations. The caspase-3 activity was determined by spectrophotometry and TNF-α level in cell culture supernatant by ELISA. Western blot was used to examine the expression level of P50, importin α3 and IκBα, and indirect immunofluorescence to determine the activation level of P50, importin α3 and IκBα. Results. In human hepatoma cells, a transmembrane polypeptide, cSN50, inhibited the elevation in the level of TNF-α and caspase-3 and the expression of nuclear transport receptor importin α3 stimulated by alcohol and endotoxin. Immunofluorescence showed the nuclear translocation of NF-κB and importin α3 and cytosolic degradation of IκBα. In murine mononuclear macrophages, addition of alcohol or endotoxin or both resulted in a significant elevation of NF-κB and its downstream factors TNF-α and caspase-3 and apoptosis of RAW264.7 cells. These effects were remarkably suppressed by cSN50. However, the expression of importin α3 was not detected by Western blotting or immunofluorescence in this experiment, indicating the existence of other pathways. Conclusion. The nuclear translocation of NF-κB plays an important role in acute alcoholic hepatic injuries and the induced nuclear NF-κB activity, and its downstream gene expression can be partially suppressed by cSN50 in HepG2 and RAW264.7 cells. © 2011 Informa Healthcare.

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