Targeted silencing of genes related to acute monocytic leukaemia by CpG(B)-MLAA-34 siRNA conjugates.

Acute monocytic leukaemia (AML-M5) associated antigen-34 (MLAA-34) is a novel antigen overexpressed in patients with acute monocytic leukaemia. RNA interference is a promising therapy in oncology, especially for refractory acute leukaemia. In this study, we delivered MLAA-34 siRNA into AML-M5 THP-1 cells using CpG(B)-MLAA-34 siRNA conjugates, in the absence of any other transfection reagent. The uptake efficiency and the rate of apoptosis were measured by using flow cytometry. The level of relevant mRNAs was measured by quantitative PCR. THP-1 cell invasion was assessed by transwell assay. Protein expression was analysed by western blotting. The spleen and liver of AML-M5 nude mice were measured and weighted after euthanisation. Spleen sections were analysed by immunohistochemistry. We found that MLAA-34 siRNA was successfully delivered into THP-1 cells and induced MLAA-34 gene silencing via the blockade of JAK2/STAT3 and Wnt/-catenin signalling pathways. In addition, CpG(B)-MLAA-34 siRNA upregulated Gsk3ß protein expression, resulting in retraining of the JAK2/STAT3 and Wnt/ß-catenin signalling pathways. Importantly, CpG(B)-MLAA-34 siRNA reduced the survival and invasiveness of THP-1 cells. We further demonstrated that CAB39L was effectively downregulated by CpG(B)-MLAA-34 siRNA in vivo. These findings suggested CpG(B)-MLAA-34 siRNA conjugates may provide a novel therapeutic strategy for acute monocytic leukaemia.

Resveratrol down-regulates endothelin type B receptors in vascular smooth muscle cells via Sirt1/ERK1/2/NF-кB signaling pathways.

Silent information regulator family protein 1 (Sirt1) has gained attention for protective effects against cardiovasc diseases. Vascular smooth muscle endothelin type B (ETB) receptors are related to the pathogenesis of cardiovascular diseases. Elevated oxidized low-density lipoprotein (ox-LDL) is associated with atherosclerosis. This study will investigate whether resveratrol (a Sirt1 activator, Res) is involved in oxidized low density lipoprotein (ox-LDL)-mediated- regulation of ETB receptors in rat superior mesenteric arteries (SMA). The rat SMA segments were cultured in the presence and absence of ox-LDL with or without Res and specific inhibitor (U0126) for the extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) for 24 h. After organ culture, the contractile responses to sarafotoxin 6c (S6c) were studied using a sensitive myograph, and the ETB receptor protein expression was detected using Western blotting. The results showed that Res concentration-dependently suppressed the ox-LDL -induced up-regulation of ETB receptors expression and receptor-mediated vasoconstriction. In addition, these effects could be inhibited by U0126. Furthermore, activity of ERK1/2 phosphorylation and P65 acetylation induced by ox-LDL were blocked by Res. In conclusion, Res down-regulated ETB receptors through up-regulating Sirt1 and followed by ERK1/2/NF-кB signaling pathways in the organ culture SMA.

[Comparison of the Effectiveness and Safety of Combined Chemotherapy with PEG-Asp for Treatment of ALL and T-NHL Patients].

OBJECTIVE: To explore the effectiveness and safety of combined chemotherapy with pegasparaginase (PEG-Asp) for treatment of patients with acute lymphoblastic leukemia (ALL) and T cell non-Hodgkin's lymphoma (T-NHL) patients. METHODS: A total of 62 ALL or T-NHL patients were diagnosed and treated in our department and were enrolled in this study. Among them, 22 patients received the combined chemotherapy with PEG-Asp, while the other 40 patients received the standard chemotherapy with L-asparaginase (L-Asp) as the control. Therapeutic effectiveness, adverse effects, duration and expense of hospitalization, treatment-related mortality and survival were evaluated and compared in 2 different groups. RESULTS: In group of combined chemotherapy with PEG-Asp, the overall response rate was 90.91% (20 cases), among them CR rate and PR rate are 77.27% (17 cases) and 13.64% (3 cases), respectively. In the group of standard chemotherapy with L-Asp, the overall response rate was 87.5% (35 cases), among them CR rate and PR rate were 72.5% (29 cases) and 15% (6 cases), respectively. The difference neither between PEG-Asp and L-Asp chemotherapy groups nor between ALL and T-NHL subgroups was significant (P > 0.05). The 6-month and 12-month overall survival rates were not significantly different between the PEG-Asp and L-Asp chemotherapy groups, respectively (P > 0.05). The adverse effects were identified as degree 1-2 according to the WHO criteria of drug toxicity. Neither the adverse effects identified as degree 3-4 nor the treatment-related death were observed. Expect for allergy and hyperglycaemia, the difference of side-effect incidence between the two groups were not significant (P > 0.05). The treatment for all the patients in PEG-Asp chemotherapy group was completed, while the treatment with L-Asp was completed only in 29 cases. Moreover, both average duration and expense of hospitalization after the combined chemotherapy were less than the control. CONCLUSION: With higher response rate, lower drug toxicity and allergy incidence, the combined chemotherapy with PEG-Asp can replace the standard chemotherapy with L-Asp in the treatment of ALL and T-NHL. The optimization of the combined chemotheropeutic protocols for more cases and long-term survival rates need to further and deeply explorate.

Probucol and cilostazol exert a combinatorial anti-atherogenic effect in cholesterol-fed rabbits.

INTRODUCTION: Probucol (PB) and cilostazol (CZ) both exhibit anti-atherogenic effects. However, their combinatorial effects are unclear. This study was designed to investigate their combinatorial anti-atherogenic effect in cholesterol-fed rabbits. MATERIALS AND METHODS: Rabbits were fed a cholesterol diet with PB or CZ alone or both PB and CZ for 16 weeks. The plasma levels of total cholesterol, LDL-cholesterol, HDL-cholesterol, C-reactive protein, superoxide dismutase, malondialdehyde, and nitric oxide (NO) were measured. The aortic atherosclerotic lesions were grossly and microscopically evaluated. Additionally, in vitro experiments were conducted using human umbilical vein endothelial cells. RESULTS AND CONCLUSION: We found that the PB group and the PB+CZ group exhibited a reduction in the lesion areas (70% in the PB+CZ group, 56% in the PB group) compared with the vehicle group. However, although PB alone and PB+CZ led to a reduction in the lesion size, the histological analysis revealed that only PB+CZ significantly decreased the macrophage accumulation and smooth muscle cell proliferation in the lesions compared with the vehicle group. The plasma levels of total cholesterol in the PB+CZ group were decreased compared with the vehicle group, Moreover, PB+CZ exerted obvious anti-oxidant and anti-inflammatory effects. Interestingly, the PB+CZ treatment led to a marked increase in the levels of plasma NO. The in vitro experiments showed that the combinatorial treatment up-regulated the levels of NO and protein S-nitrosylation in endothelial cells treated with oxidized LDL. In summary, these results suggest that PB and CZ exert combinatorial anti-atherogenic effects.

Characteristics of Himalayan marmots and their response to an atherogenic diet.

The purpose of the present study was to characterize Himalayan marmot lipoprotein profiles and investigate their response to an atherogenic diet. Sixteen marmots were randomly divided into two groups. The control group was fed with a standard chow diet, and the other group was fed with a chow diet containing 0.3% cholesterol, 6.7% lard, and 3.3% corn oil (designated as HFCD) for 16 weeks. The plasma lipids were measured, and lipoprotein profiles were analyzed. With the chow diet, the major lipoproteins were high density lipoproteins. HFCD feeding increased not only plasma total cholesterol levels but also body weight compared with the control group (P<0.05). Plasma lipoprotein (a) was detected in marmots, and the plasma lipoprotein (a) levels were 4.5-fold higher after being fed HFCD for 16 weeks. However, atherosclerotic lesions were not found in the aorta of HFCD-fed marmots. This study suggested that marmots are HDL-rich mammals and resistant to HFCD-induced atherosclerosis.

Association between TaqIB polymorphism of cholesteryl ester transfer protein and coronary artery disease in the Chinese population.

OBJECTIVE: To assess whether the TaqIB polymorphism of cholesteryl ester transfer protein (CETP) is associated with coronary artery disease (CAD) in Chinese population, we performed a meta-analysis in this paper. METHODS: We searched PubMed, Embase, the Science Citation Index (SCI), the China Biological Medicine database (CBM), the China National Knowledge Infrastructure (CNKI), and the Wanfang database for relevant articles. Data were extracted, and pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: The literature search yielded 448 studies, in which 10 case-control studies including 1694 cases and 1456 controls matched the selection criteria. The combined B1 and B2 allele frequencies were 0.587 and 0.413, respectively. The pooled OR was 1.10 (95% CI, 0.89-1.34) for comparing the B1B1 or B1B2 carriers with B2B2 carriers, and was 1.27 (95% CI, 1.09-1.49) in the B1B1 carriers versus B2B2 or B1B2 carriers. CONCLUSIONS: In the present study, the TaqIB polymorphism of CETP was found to be associated with CAD in the Chinese population.

Temporal and quantitative analysis of atherosclerotic lesions in diet-induced hypercholesterolemic rabbits.

The diet-induced atherosclerotic rabbit is an ideal model for atherosclerosis study, but temporal changes in atherosclerotic development in hypercholesterolemic rabbits are poorly understood. Japanese white rabbits were fed a high-cholesterol diet to induce sustained hypercholesterolemia, and each group of 10-12 animals was then sacrificed at 6, 12, 16, or 28 weeks. The rabbit aortas were harvested, and the sizes of the gross and intima atherosclerotic lesions were quantified. The cellular component of macrophages (Mφs) and smooth muscle cells (SMCs) in aortic intimal lesions was also quantified by immunohistochemical staining, and the correlation between plasma cholesterol levels and the progress of atherosclerotic lesions was studied. The ultrastructure of the atherosclerotic lesions was observed by transmission electron microscopy (TEM). Widely variable atherosclerotic plaques were found from 6 weeks to 28 weeks, and the lesional progress was closely correlated with cholesterol exposure. Interestingly, a relatively reduced accumulation of Mφ, an increased numbers of SMCs, and a damaged endothelial layer were presented in advanced lesions. Moreover, SMCs were closely correlated with cholesterol exposure and lesional progress for the whole period. Cholesterol exposure directly determines atherosclerotic progress in a rabbit model, and the changes in the cellular component of advanced lesions may affect plaque stability in an atherosclerotic rabbit model.

Interferon plus Chinese herbs are associated with higher sustained virological response than interferon alone in chronic Hepatitis C: a meta-analysis of randomised trials.

BACKGROUND/AIMS: Traditional Chinese herbal therapies are widely used for the treatment of chronic hepatitis C (CHC) in Asia. The aim of this study was to perform a meta-analysis of randomised controlled trials (RCTs) comparing interferon therapies with Chinese herbal therapies and/or interferon plus Chinese herb therapies for the treatment of CHC. METHODS: The Cochrane Central Register of Controlled Trials, Medline, Science Citation Index, EMBASE, China National Knowledge Infrastructure, Wanfang Database and China Biomedical Database were searched to identify RCTs that evaluated the virological response to interferon therapies, Chinese herbal therapies and interferon plus Chinese herb therapies in CHC patients. We statistically combined data using a random-effect meta-analysis according to the intention-to-treat principle. RESULTS: The literature search yielded 770 studies, and 26 RCTs comprising 1905 patients matched the selection criteria. Overall, the sustained virological response (SVR) was significantly higher in patients treated with interferon plus Chinese herbs than in patients treated with interferon alone (49% vs 33%, relative risk, 1.52; 95% confidence interval: 1.23-1.89; p<0.05). Combined therapies of interferon plus Chinese herb therapies were also superior to interferon therapies alone in achieving the end-of-treatment viral response (ETVR), and resulted in fewer relapses, fewer adverse events and more rapid alanine transaminase normalisation. Interferon therapies achieved higher ETVR than Chinese herbal therapies, but they yielded a similar SVR. CONCLUSIONS: The current evidence suggests that combined therapies of interferon plus Chinese herbs yielded a higher SVR, and resulted in fewer relapses and fewer adverse events than interferon therapies.