Platycodin D, a metabolite of Platycodin grandiflorum, inhibits highly metastatic MDA-MB-231 breast cancer growth in vitro and in vivo by targeting the MDM2 oncogene.

The objective of the present study was to explore the in vitro and in vivo anticancer effects of Platycodin D (PD), derived from Platycodin grandiflorum, on highly metastatic MDA-MB-231 breast cancer cells. Using the MTT assay, we found that PD inhibited MDA-MB-231 cell growth in a concentration-dependent manner, with an IC50 value of 7.77±1.86 µM. Further studies showed that PD had anti-proliferative effects and induced cell cycle arrest in the G0/G1 phase. To explore the detailed mechanism(s) by which PD suppressed MDA-MB-231 cell growth, western blot analyses were used to detect the expression levels of proteins related to cell proliferation and survival. The data showed that PD decreased the expression of proteins related to the G0/G1 phases, downregulated the protein expression of MDM2, MDMX, and mutant p53, and increased the expression levels of p21 and p27 in vitro. We verified the effects of PD on the expression of MDM2, MDMX, mutant p53, p21 and p27 using a pcDNA3-Flag-MDM2 plasmid and MDM2 siRNA transfection, and found that PD inhibited MDA-MB-231 cell viability by targeting MDM2 and mutant p53. Compared with the corresponding parental cells, the cells with siRNA-MDM2 transfection had a greater decrease in cell viability and proliferation, while those with pcDNA3-MDM2 plasmid transfection did not show any increase in the effects of PD. We also established a MDA-MB-231 xenograft model in BALB/c nude mice, and found that PD significantly inhibited the growth of MDA-MB-231 xenograft tumors in these mice. The expression levels of various proteins in the tumor tissue exhibited changes similar to those observed in vitro. These findings indicate that PD exerted in vitro and in vivo anticancer effects against MDA-MB-231 breast cancer cells, that PD is a potential MDM2/MDMX inhibitor, and that the anticancer effects of PD were likely associated with its inhibition of these proteins. Our observations help to identify a mechanism by which PD functions as an anti-breast cancer agent.

Long-term effects of Xuezhikang on blood pressure in hypertensive patients with previous myocardial infarction: data from the Chinese Coronary Secondary Prevention Study (CCSPS).

Several previous trials from Western population studies have showed that statins may help reduce blood pressure (BP). However, randomized clinical data is limited. Xuezhikang, a partially extract of red yeast rice, contains a family of naturally occurring statins, and has a marked impact on lipids, but it is unknown whether Xuezhikang has any effect on BP during long-term follow-up in the Chinese population. This is a post-hoc subgroup analysis of a randomized, double-blinded, placebo-controlled, parallel group clinical trial, Chinese Coronary Secondary Prevention Study (CCSPS). A total of 2704 hypertensive patients with previous myocardial infarction (MI) were assigned either to placebo (n = 1341) or to Xuezhikang (n = 1363) daily for an average of 4.5 years. The primary outcome was the unadjusted changes in mean arterial pressure (MAP) from baseline to 6 months. We also assessed systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure. Analysis of covariance was used to calculate the adjusted effects of treatment on changes in these outcomes at 6, 12, 24, and 48 months post-randomization, after controlling for potential confounders. This analysis included 2704/4870 (55.5%) hypertensive patients for whom BP was measured at baseline and at least one follow-up visit after randomization. Median duration of the follow-up was 4.5 years (54 months), and 25 patients (0.92%) were lost to the last follow-up because of adverse effects. The results showed that the unadjusted and adjusted changes in MAP, SBP, DBP, or pulse pressure from baseline were not significantly different for Xuezhikang or placebo recipients at 6, 12, 24, and 48 months after randomization. In this post-hoc subgroup analysis, we failed to demonstrate any significant reducing effects of Xuezhikang on BP in Chinese hypertensive patients with previous MI, suggesting that further prospective study on the effects of statins on BP would be needed, especially in high-risk patients.

Impact of Xuezhikang on coronary events in hypertensive patients with previous myocardial infarction from the China Coronary Secondary Prevention Study (CCSPS).

BACKGROUND: The lowering of cholesterol concentrations in individuals at high risk for cardiovascular disease improves clinical outcome. Xuezhikang has a marked impact on lipids. METHODS: In this randomized, double-blinded, placebo-controlled, parallel-group clinical trial, a total of 2704 hypertensive patients with previous myocardial infarction (MI) were assigned either to placebo (n = 1341) or to Xuezhikang (0.6 g twice daily, n = 1363) for an average of 4.5 years. The primary end-point was recurrent coronary events; the secondary end-point was all-cause mortality and other clinical events, including adverse effects. RESULTS: There were no differences between the Xuezhikang and placebo group in base-line characteristics. However, Xuezhikang treatment reduced the incidence of coronary events by 43.0% (P = 0.02), deaths from coronary heart disease (CHD) by 30.0% (P < 0.01), and all-cause mortality by 35.8% (P = 0.001). CONCLUSIONS: This study, for the first time, demonstrated that long-term Xuezhikang therapy resulted in significant reduction in cardiovascular events and death in Chinese hypertensive patients with previous MI in a safe manner.

Beneficial impact of Xuezhikang on cardiovascular events and mortality in elderly hypertensive patients with previous myocardial infarction from the China Coronary Secondary Prevention Study (CCSPS).

Coronary heart disease, hypertension, and dyslipidemia are highly prevalent and commonly coexist in people who are middle-aged and older. Previous data suggested that lowering cholesterol concentrations in individuals at high risk of cardiovascular disease improved clinical outcomes. Xuezhikang, a partial extract of red yeast rice containing statin, has a marked impact on lipids. The purpose of this study, therefore, was to evaluate the impact of Xuezhikang on reducing cardiovascular events and mortality in elderly Chinese hypertensive patients with a history of myocardial infarction (MI) enrolled in the Chinese Coronary Secondary Prevention Study. In this randomized trial, 1530 elderly hypertensive patients (> or = 65-years-old) with previous MI were assigned either to placebo (n = 758) or to Xuezhikang (n = 772) daily for an average of 4.5 years. The primary endpoint was recurrent coronary events; the secondary endpoint was all-cause mortality and other clinical events, including adverse effects. There were 68 cases of coronary events (8.8%) detected in the Xuezhikang group and 108 cases (14.3%) in the placebo group (38.2% risk reduction by Xuezhikang therapy). Death from coronary heart disease (CHD) totaled 49 cases in the Xuezhikang group (6.4%) and 68 cases in the placebo group (9.0%), indicating that Xuezhikang significantly decreased the risk of CHD death by 29.2%. Our study demonstrated that Xuezhikang therapy could effectively and safely reduce cardiovascular events and all-cause death in Chinese elderly hypertensive patients with previous MI. This finding may have an important implication for the treatment of elderly hypertensive patients with CHD.

Effect of xuezhikang on cardiovascular events and mortality in elderly patients with a history of myocardial infarction: a subgroup analysis of elderly subjects from the China Coronary Secondary Prevention Study.

OBJECTIVES: To evaluate whether lipid-lowering therapy with xuezhikang reduces the risk of coronary events and total mortality in patients with coronary heart disease (CHD) aged 65 and older. DESIGN: Subgroup analysis of the China Coronary Secondary Prevention Study, a randomized, double-blind, placebo-controlled, clinical trial. SETTING: Sixty-six hospitals in China. PARTICIPANTS: A total of 1,445 patients, aged 65 to 75, were chosen from 4,780 patients with a history of myocardial infarction. INTERVENTION: The patients were randomized to the xuezhikang (n=735) or the placebo (n=710) group and followed for a mean of 4 years. MEASUREMENTS: The primary endpoint was recurrent coronary events; the secondary endpoint was all-cause mortality and other clinical events, including adverse effects. RESULTS: Elderly patients were at greater risk for coronary events, death from coronary events, all-cause mortality, and malignancies than younger patients. Xuezhikang therapy reduced the incidence of coronary events 36.9% (P=.001), death from coronary heart disease 31.0% (P=.04), all-cause mortality 31.9% (P=.01), stroke 44.1% (P=.04), the need for a percutaneous coronary intervention or coronary artery bypass graft 48.6% (P=.07), and malignancies 51.4% (P=.03). Based on the treatment of elderly patients with xuezhikang for an average of 4 years, the number needed to treat (NNT) to prevent one coronary event, one coronary death, and one mortality due to all causes was estimated to be 18, 33, and 23, respectively. In a like manner, the estimated NNT to prevent one coronary event, one coronary death, and one mortality due to all causes in younger patients was 23, 82, and 51, respectively. There was not a significantly greater number of adverse effects in the xuezhikang group than in the placebo group. CONCLUSION: This is the first study demonstrating that treatment with xuezhikang capsules is safe and effective for the secondary prevention of CHD in older Chinese people.

Xuezhikang, an extract of cholestin, reduces cardiovascular events in type 2 diabetes patients with coronary heart disease: subgroup analysis of patients with type 2 diabetes from China coronary secondary prevention study (CCSPS).

Lipid-lowering therapy has been proven to reduce macrovascular complications of type 2 diabetes. Xuezhikang is an extract of cholestin and has a markedly modulating effect on lipids, but the effect of xuezhikang on reducing coronary events in diabetic patients with coronary heart disease (CHD) is less clear. A total of 591 diabetic patients with CHD were randomized to the xuezhikang group (n=306) and the placebo group (n=285). During the average 4 years of follow-up, there were 28 cases of CHD events (9.2%) in the xuezhikang group and 53 cases (18.6%) in the placebo group. Risk reduction for CHD events was 50.8% (P<0.001) by xuezhikang treatment. Xuezhikang decreased the risk of non-fatal MI by 63.8%, fatal MI by 58.5%, CHD sudden death by 26.9%, and other CHD death by 53.4%. CHD death totaled to 21 cases in the xuezhikang group (6.9%) and 35 cases in the placebo group (12.3%), indicating that xuezhikang significantly decreased the risk of CHD death by 44.1% (P<0.05). Seventy-two patients died from various causes, among which there were 27 patients in the xuezhikang group and 45 patients in the placebo group. The risk for all-cause death was 44.1% lower in the xuezhikang group than in the placebo group (P<0.01). This investigation demonstrates that xuezhikang therapy can be effective on reduction of cardiovascular events in diabetic patients with CHD with a reliable safety.

Apolipoprotein B is associated with metabolic syndrome in Chinese families with familial combined hyperlipidemia, familial hypertriglyceridemia and familial hypercholesterolemia.

There is a paucity of data concerning the metabolic syndrome (MetS) in families with familial combined hyperlipidemia (FCHL), familial hypertriglyceridemia (FHTG), familial hypercholesterolemia (FH) and normolipidemic families in China. This study investigated the prevalence of MetS in these families and explored potential factors relevant to MetS. We recruited 70 families with 560 individuals > or = 20 years of age, including 43 FCHL families with 379 individuals, 3 FHTG families with 30 individuals, 16 FH families with 102 individuals and 8 normolipidemic families with 49 individuals. The definition of MetS is determined using modified criteria of National Cholesterol Education Program substituting body mass index for waist circumference. MetS is identified in 60.7% of FCHL patients and 71.4% of FHTG patients. The prevalence of MetS in family members is 36.7% for FCHL, 33.3% for FHTG, 17.6% for FH and 16.3% for normolipidemic families, with an odds ratio (OR) of 2.97 (95% CI 1.29-7.07, P=0.007) in FCHL families compared with normolipidemic families. Apolipoprotein B (apoB) is associated with MetS by multiple logistic analysis with an OR of 1.05 (1.03-1.07, P<0.001) in FCHL families, OR of 1.26 (1.03-1.55, P=0.026) in FHTG and OR of 1.07 (1.01-1.12, P=0.014) in FH families, independent of variables including age, gender, apolipoprotein A1, and low density lipoprotein cholesterol. Apolipoprotein A1 provided an OR of 0.95 (0.94-0.97, P<0.001) in FCHL families and OR of 0.94 (0.90-0.97, P=0.011) in FH families, but neither in FHTG nor in normolipidemic families (both P>0.05). Thus, apoB may be regarded as a relevant factor in the assessment of MetS in FCHL, FHTG and FH families. However, this finding needs to be verified by prospective studies in diverse ethnicities and warrants additional studies to elucidate possible mechanisms linking apoB to MetS.

[China coronary secondary prevention study: analysis of patients with different myocardial infarction history].

OBJECTIVE: To assess whether Xuezhikang was effective in the secondary prevention of coronary heart disease (CHD) for patients with different length of myocardial infarction (MI) history. METHODS: 2135 patients with MI history of 28 days to 3 months and 2735 patients with MI history of 3 months to 60 months were recruited separately to receive treatment with Xuezhikang capsule or placebo. The primary end-points were nonfatal myocardial infarction and death from CHD. RESULTS: The occurrence of coronary events were found to be not statistically significantly different for the two groups of patients. For patients with MI history of 28 days to 3 months, Xuezhikang significantly reduced the risk of CHD events by 56.7% (P < 0.0001) and resulted in a 48.6% (P = 0.0002) risk reduction in all-cause mortality as compared with placebo. For patients with MI history of 3 months to 60 months, Xuezhikang significantly decreased the risk of CHD events by 35.3% (P = 0.0008) and led to a 20.0% (P = 0.1181) risk reduction in the all-cause mortality as compared with placebo. Adverse effects and abnormal laboratory parameters did not differ significantly in the two groups of patients. CONCLUSIONS: Xuezhikang is more effective for patients with MI history of 28 days to 3 months as compared with patients with MI history of 3 months to 60 months. Patients with MI history should be treated with Xuezhikang early in order to achieve better prevention of CHD.

[The beneficial effects of lipid-lowering therapy with xuezhikang on cardiac events and total mortality in coronary heart disease patients with or without hypertension: a random, double-blinded, placebo controlled clinical trial].

OBJECTIVE: To evaluate whether lipid-lowering therapy with Xuezhikang can reduce the risk of cardiac events and total mortality in coronary heart disease (CHD) patients with or without hypertension. METHODS: In this random, double-blinded, placebo controlled clinical trial, 2704 patients with hypertension and 2166 patients without hypertension were enrolled and capsule Xuezhikang 0.6 g Bid or placebo on the top of conventional therapy without other lipid-lowering drugs. The mean follow-up period was four years. The primary end-points were nonfatal myocardial infarction and total mortality. RESULTS: Compared to placebo group, the incidence of cardiac events was reduced by 44.0% (P<0.0001) and 47.4% (P<0.0001) respectively in CHD patients with or without hypertension, and the total mortality was lowered by 35.8% (P=0.0012) and 28.6% (P=0.0737) respectively in CHD patients with or without hypertension. There was no significant difference in side effects between study groups. CONCLUSION: Xuezhikang can reduce the cardiac events and mortality in CHD patients with or without hypertension.

[China coronary secondary prevention study (CCSPS)].

OBJECTIVE: The mean level of serum cholesterol in Chinese population with coronary heart disease (CHD) is relatively lower compared to that of western population. Our study aimed to evaluate whether lipid-lowering therapy with Xuezhikang can reduce the risk of cardiac events and total mortality in Chinese CHD patients. METHODS: This study was designed as a random, double-blinded, placebo controlled clinical trial in 66 centers in China and was conducted from may, 1996 to December, 2003. 4870 CHD patients (serum cholesterol level 4.40 - 6.47 mmol/L, age 18 - 75 years, with definite myocardial infarction history) were selected and treated with capsule Xuezhikang (0.6 g Bid) or placebo in addition to conventional therapy (control group). The mean follow-up period was four years. The primary end-points were nonfatal myocardial infarction and deaths from CHD. RESULTS: It has been shown at the end of the trial: (1) The incidence of the primary end-points were 5.72% in Xuezhikang treatment group and 10.41% in control group, with a reduction of relative risk by 45.1% for treatment group (P = 0.0000). Among the primary end points, the incidence of deaths from CHD was 3.79% in the treatment group and 5.49% in the control group, with a reduction of relative risk by 31.0% in treatment group (P < 0.0048); (2) The incidence of nonfatal myocardial infarction reduced by 60.8% in treatment group compared to control group (1.93% vs 4.92%, P < 0.0000); (3) The incidence of the secondary end-points (stroke, tumor, PCI/CABG) also decreased by 31.1% in treatment group compared to control group (6.92% vs 10.04% P < 0.0004). Among the secondary end points, the demand for PCI/CABG was 3.01% in the treatment group and 4.51% in the control group, with a reduction of relative risk by 33.3% in treatment group (P = 0.097); (4) The total mortality was lower in treatment group than control group, with a reduction of relative risk by 33.0% in treatment group (5.19% vs 7.74% P = 0.0003). There were no significant differences in side effects and abnormal laboratory references between the two groups. CONCLUSIONS: Compared to placebo, Xuezhikang can significantly decrease the incidence of nonfatal myocardial infarction and deaths from CHD. It can also reduce significantly the demand for PCI/CABG, the total mortality and the deaths from tumor.

[Apolipoprotein B is associated with metabolic syndrome in Chinese pedigrees with familial hyperlipidemia].

OBJECTIVE: To investigate the prevalence of metabolic syndrome (MS) as well as the potential predictors in families with familial combined hyperlipidemia (FCHL), familial hypertriglyceridemia (FHTG), familial hypercholesterolemia (FH) and normolipidemic families in China. METHODS: The prevalence of MS was identified among 70 different families with 560 individuals aged > or = 20, including 43 FCHL families with 379 individuals, 3 FHTG families with 30 individuals, 16 FH families with 102 individuals and 8 normolipidemic families with 49 individuals. Diagnosis of MS was based on the modified criteria of National Cholesterol Education Program, US, substituting body mass index for waist circumference. Multivariate logistic regression was used to analyze the association between MS and different pedigrees. RESULTS: MS was identified in 60.7% of the FCHL patients and 71.4% of the FHTG patients. The prevalence of MS in the family members was 36.7% for the FCHL families, 33.3% for the FHTG families, 17.6% for the FH families, and 16.3% for the normolipidemic families, with an odds ratio (OR) of 2.97 (95% CI 1.29 to 7.07) in the FCHL families compared with in the normolipidemic families. Multivariate logistic regression showed an association between apolipoprotein (apo) B and MS with an OR of 1.05 (1.03 to 1.07) in the FCHL families, an OR of 1.26 (1.03 to 1.55) in the FHTG families, and an OR of 1.07 (1.01 to 1.12) in the FH families, independent of variables such as age, gender, apoA1, and LDL cholesterol, but showed no association in the normolipidemic families (P >0.05). Similarly, apo A1 provided an OR of 0.95 (0.94 to 0.97) in the FCHL families and an OR of 0.94 (0.90 to 0.99) in the FH families, but neither in the FHTG families nor in the normolipidemic families (both P >0.05). CONCLUSION: Apo B may be regarded as a relevant factor in the assessment of MS in FCHL, FHTG and FH families in Chinese. However, this finding needs to be verified by prospective studies in diverse ethnicities and warrants additional studies to elucidate the possible mechanisms linking apoB to MS.

[China coronary secondary prevention study (CCSPS): outcomes from analysis of coronary heart disease patients with diabetes].

OBJECTIVE: To elucidate whether lipid-lowering therapy with Xuezhikang can induce a decrease of cardiac events and an attenuation of total mortality in coronary heart disease (CHD) patients with diabetes. METHODS: We designed a random, double-blinded, placebo controlled clinical trial in selected 591 patients. All patients were administrated with capsule Xuezhikang (0.6 g, Bid) or placebo in addition to conventional therapy. The mean follow-up period was four years. The primary end-points were nonfatal myocardial infarction and death from CHD. RESULTS: (1) The incidence of CHD events and that of death from CHD were reduced by 50.8% (P = 0.0008) and by 44.1% (P = 0.0246) in treatment group, respectively; Also, the incidence of nonfatal myocardial infarction was reduced by 63.8% (P = 0.0151). (2) The incidence of stroke, tumor, and PCI/CABG were decreased by 20.2%. (3) The total mortality were lowered by 44.1% in treatment group (P = 0.0097). CONCLUSION: Xuezhikang can effectively reduce the incidence of cardiac events and total mortality in CHD patients with diabetes.

[An association of apolipoprotein B with pulse pressure in Chinese pedigrees with familial combined hyperlipidemia].

OBJECTIVE: To investigate the influencing factors of blood pressure phenotypes and the distribution of FDH in FCHL families. METHODS: Forty-two FCHL families with 435 members, 147 consanguine members and 90 members without consanguinity from Beijing area were studied. Eleven of the 42 FCHL families (26.2%) were identified as families with FDH syndrome. Stepwise regression analysis was used to analyze the association between the target variables and blood pressure phenotypes, such as systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP), of the 237 FCHL members aged 30 to 60 years. RESULTS: The prevalence of dyslipidemic hypertension in the FCHL relatives was significantly higher than that in the spouses (29.9% versus 8.9%, P < 0.01), with an odds ratio of 3.37 (95% CI 1.44 to 8.14). In the FCHL families body mass index (BMI), age and blood sugar were independent contributors to SBP, DBP, and MAP, respectively (all P < 0.05). Age and apolipoprotein B (apoB) were important contributors to pulse pressure (both P < 0.05). CONCLUSIONS: BMI and glucose are significant contributors to different phenotypes of blood pressure. Moreover, apoB is a significant contributor to pulse pressure in FCHL families.