Design, Synthesis, and Activity Evaluation of Novel Acyclic Nucleosides as Potential Anticancer Agents In Vitro and In Vivo.

In the present work, 103 novel acyclic nucleosides were designed, synthesized, and evaluated for their anticancer activities in vitro and in vivo. The structure-activity relationship (SAR) studies revealed that most target compounds inhibited the growth of colon cancer cells in vitro, of which 3-(6-chloro-9H-purin-9-yl)dodecan-1-ol (9b) exhibited the most potent effect against the HCT-116 and SW480 cells with IC50 values of 0.89 and 1.15 µM, respectively. Furthermore, all of the (R)-configured acyclic nucleoside derivatives displayed more potent anticancer activity compared to their (S)-counterparts. Mechanistic studies revealed that compound 9b triggered apoptosis in the cancer cell lines via depolarization of the mitochondrial membrane and effectively inhibited colony formation. Importantly, compound 9b inhibited the growth of the SW480 xenograft in a mouse model with low systemic toxicity. These results indicated that acyclic nucleoside compounds are viable as potent and effective anticancer agents, and compound 9b may serve as a promising lead compound that merits further attention in future anticancer drug discovery.

Blood lipid profiles and factors associated with dyslipidemia assessed by a point-of-care testing device in an outpatient setting: A large-scale cross-sectional study in Southern China.

OBJECTIVE: To promote the concept of POCT and to investigate dyslipidemia in Guangzhou, China, we performed a study examining blood lipids assessed by POCT and reported factors associated with dyslipidemia. DESIGN AND METHODS: This multicenter, cross-sectional study enrolled outpatients from 9 Guangzhou hospitals from May through September 2013. After informed consent was obtained, the following information was collected: age; gender; the presence of diabetes mellitus, obesity, and hypertension as well as current use of cigarettes or alcohol. Patients were asked to fast for 8h before the blood examination performed on a POCT device, the CardioChek PA. RESULTS: Of 4012 patients enrolled (1544 males, 2468 females; mean age 60.35±9.41 years), 1993 (49.7%) patients had dyslipidemia, but only 101 (5.1%) took statins. The multivariate tests of associations between demographic variables, comorbidities, and the risk of having dyslipidemia found that the significant predictors of dyslipidemia were male gender, age ≥60 years, being a current smoker or alcohol drinker, and hypertension. CONCLUSION: Most dyslipidemia patients in Guangzhou remain untreated. POCT in China is feasible, and its widespread use might improve dyslipidemia awareness, treatment and control.

[Effects of high-density lipoprotein on the cholesterol efflux from endothelial cells].

OBJECTIVE: To study the effects of high-density lipoprotein (HDL) and oxidized high-density lipoprotein (ox-HDL) on the expression of ATP-binding cassette transporter A1 (ABCAl) and cholesterol efflux in human umbilical vein endothelial cells (HUVECs). METHODS: In vitro cultured HUVECs were incubated in the presence of 100 microg/ml HDL or 100 microg/ml ox-HDL for 24 h, using PBS as the negative control. ABCA1 mRNA level and cholesterol efflux rate were determined using RT-PCR and a liquid scintillator, respectively. RESULTS: HDL and ox-HDL significantly elevated the level of ABCA1 mRNA by 58% and 23% relative to the control level, respectively (P<0.05). The cholesterol efflux rate in ox-HDL group was significantly lower than that in HDL group (P<0.01). CONCLUSION: HDL increases ABCAl expression and cholesterol efflux in HUVECs. Oxidative modification of HDL decrease cholesterol efflux by inhibiting the expression of ABCAl, suggesting a possible mechanism of ox-HDL in the pathogenesis of atherosclerosis.

[Effects of simvastatin on DNA synthesis in rat cardiac fibroblasts].

OBJECTIVE: To investigate the effects of simvastatin (Sim) and the interference by mevalonate (MVA) against its effect on DNA synthesis in rat cardiac fibroblasts (CFs). METHODS: CFs were isolated from neonatal SD rats by trypsin digestion and growth-arrested CFs were stimulated with Sim and/or MVA at varied concentrations for different time lengths, and the DNA synthesis in the cells was measured by (3)H-thymidine ((3)H-TdR) incorporation assay. RESULTS: Sim decreased (3)H-TdR incorporation in the CFs in a concentration-dependent manner, and (3)H-TdR incorporation was significantly lower in cells treated with 1 x 10(-6) and 1 x 10(-5) mol/L Sim (1,175+/-202.66 and 771+/-164.86 cpm/2000 cells, respectively) than in the control cells (1,608+/-204.32 cpm/2000 cells, P<0.01). As the treatment time with 1 x 10(-5) mol/L Sim prolonged (for 6, 12, 18, 24, 36, 42, and 48 h), (3)H-TdR incorporation in CFs decreased gradually, showing an obvious inverse correlation with the treatment time (r=-919, P<0.01). (3)H-TdR incorporation in cells treated with 1 x 10(-6) to 1 x 10(-3) mol/L MVA and 1 x 10(-5) mol/L Sim rose steadily as MVA concentration increased. A significant difference in the incorporation was found between cells treated with both 1 x 10(-4)/1 x 10(-3) mol/L MVA and 1 x 10(-5) mol/L Sim (1,612+/-308.57 and 1,995+/-353.83 cpm/2000 cells, respectively) and the cells with 1 x 10(-5) mol/L Sim treatment alone (P<0.01); difference was also noted between cells treated with 1 x 10(-5) mol/L MVA and the control cells (P<0.05), but treatment with 1 x 10(-6) mol/L MVA did not produce much difference in comparison with the control cells (P>0.05) With the increase of treatment time (for 6, 12, 18, 24, 36, 42, 48 h), 1 x 10(-3) mol/L MVA caused steady increase in (3)H-TdR incorporation in the CFs, showing a significant positive correlation with the treatment time (r=0.968, P<0.01). CONCLUSION: Sim can decrease DNA synthesis in rat CFs and postpone the occurrence of myocardial fibrosis, which can be reversed by MVA.

[Effect of percutaneous intervention on adrenomedullin and tumor necrosis factor in the coronary circulation].

OBJECTIVE: To evaluate the effect of percutaneous intervention (PCI) on coronary circulation levels of adrenomedullin (ADM) and tumor necrosis factor alpha (TNF-alpha) in patients with coronary heart disease (CHD). METHODS: Thirty-three CHD patients underwent percutaneous transluminal coronary angioplasty (PTCA) and stenting (altogether 48 stents were implanted). Blood samples were collected from the coronary sinus and femoral artery at the time points of immediately before and after angioplasty, immediately after PTCA or stenting, 10 min after procedures, respectively. RESULTS: The ADM and TNF-alpha levels in the coronary sinus varied little after coronary angiography, but were elevated markedly following PTCA from the basal levels of 36.3+/-1.3 pg/ml to 28.9+/-1.9 pg/ml (P<0.01) and from 11.10+/-0.46 ng/ml to 8.84+/-0.37 ng/ml (P<0.01), respectively. Further increases of ADM and TNF-alpha levels were detected immediately after stent deployment. ADM recovered to basal levels 10 min after completion of the procedures, while TNF-alpha underwent further increase. Before the procedure, ADM and TNF-alpha levels were higher in the coronary sinus than in the femoral artery (28.9+/-1.9 pg/ml vs 22.6+/-0.8 pg/ml, P<0.01; 8.84+/-0.37 ng/ml vs 7. 56+/-0.23 ng/ml, P<0.01, respectively), and their levels in the femoral artery did not undergo significant changes in response to the operations. CONCLUSION: The coronary circulation levels of ADM and TNF-alpha increase after PTCA and stenting but not after coronary angiography in CHD patients, which might be attributed to injuries by the procedures as well as the mechanical stimulation by the stent.

[Relation of the ST-segment elevation pattern in acute phase of anterior wall acute myocardial infarction to short-term prognosis].

OBJECTIVE: To observe the relation of ST-segment elevation pattern of electrocardiogram (ECG) recorded in acute phase of anterior wall acute myocardial infarction (AMI) to short-term prognosis. METHODS: Sixty-two patients with first anterior wall AMI were divided into 3 groups according to ST-segment elevation pattern in lead V3 of a 12-lead ECG at admission. Patients in group A (n=18) were characterized by concave type of ST-segment elevation, group B (n=27) by straight type and group C (n=17) by convex type. The peak value of serum creatine phosphate kinase (CPK) and left ventricular ejection fraction (LVEF) were measured. The incidence of serious complications (including malignant arrhythmia, left ventricular dysfunction and cardiogenic shock) and mortality within the initial 4 weeks of hospitalization were recorded. RESULTS: The median value of peak CPK of the 3 groups was 2 014.4, 4 486.8 and 5 826.9 IU/L respectively, and the peak value of CPK in group A was much lower than that in groups B and C ( D<0.05 and P<0.01, respectively). LVEF measured by echocardiogram within 14 d after myocardial infarction were 61.2%, 48.6% and 38.7% respectively, showing significant difference between groups A and B and between groups B and C (P<0.05) as well as between group A and C (P<0.01). The incidences of serious complications and mortality within 4 weeks after AMI in group A were much lower than those in groups B and C (P<0.05), but there was no significant difference between groups B and C ( D>0.05). CONCLUSION: The shape of ST-segment elevation in lead V3 of a 12-lead ECG in acute phase of anterior wall AMI may reflect the severity of myocardial ischemic injury, and convex type of ST-segment elevation in lead V3 in acute phase often indicate poor short-term prognosis.