Statins are the first choice for lowering low-density lipoprotein cholesterol (LDL-C) and preventing atherosclerotic cardiovascular disease (ASCVD). However, statins can also upregulate proprotein convertase subtilisin/kexin type 9 (PCSK9), which in turn might limits the cholesterol-lowering effect of statins through the degradation of LDL receptors (LDLR). Di’ao Xinxuekang (DXXK) capsule, as a well-known traditional Chinese herbal medicine for the prevention and treatment of coronary heart disease, can alleviate lipid disorders and ameliorate atherosclerosis in atherosclerosis model mice and downregulate the expression of PCSK9. In this study, we further explored whether DXXK has a synergistic effect with atorvastatin (ATO) and its underlying molecular mechanism. The results showed that both ATO monotherapy (1.3 mg/kg) and ATO combined with DXXK therapy significantly lowered serum lipid levels and reduced the formation of atherosclerotic plaques and the liver lipid accumulation. Moreover, compared with ATO monotherapy, the addition of DXXK (160 mg/kg) to the combination therapy further lowered LDL-C by 15.55% and further reduced the atherosclerotic plaque area by 25.98%. In addition, the expression of SREBP2, PCSK9 and IDOL showed a significant increase in the model group, and the expression of LDLR was significantly reduced; however, there were no significant differences between the ATO (1.3 mg/kg) and the model groups. When ATO was combined with DXXK, the expression of LDLR was significantly increased and was higher than that of the model group and the expression of SREBP2 and PCSK9 in the liver was also significantly inhibited. Moreover, it can be seen that the expression of SREBP2 and PCSK9 in the combination treatment group was significantly lower than that in the ATO monotherapy group (1.3 mg/kg). Besides, the expression of IDOL mRNA in each treatment group was not significantly different from that of the model group. Our study suggests that DXXK might have a synergistic effect on the LDL-C lowering and antiatherosclerosis effects of ATO through the SREBP2/PCSK9 pathway. This indicates that a combination of DXXK and ATO may be a new treatment for atherosclerosis.

Bufadienolide-like chemicals are mostly composed of the active ingredient of Chansu and they have anti-inflammatory, tumor-suppressing, and anti-pain activities; however, their mechanism is unclear. This work used bioinformatics analysis to study this mechanism via gene expression profiles of bufadienolide-like chemicals: (1) Differentially expressed gene identification combined with gene set variation analysis, (2) similar small -molecule detection, (3) tissue-specific co-expression network construction, (4) differentially regulated sub-networks related to breast cancer phenome, (5) differentially regulated sub-networks with potential cardiotoxicity, and (6) hub gene selection and their relation to survival probability. The results indicated that bufadienolide-like chemicals usually had the same target as valproic acid and estradiol, etc. They could disturb the pathways in RNA splicing, the apoptotic process, cell migration, extracellular matrix organization, adherens junction organization, synaptic transmission, Wnt signaling, AK-STAT signaling, BMP signaling pathway, and protein folding. We also investigated the potential cardiotoxicity and found a dysregulated subnetwork related to membrane depolarization during action potential, retinoic acid receptor binding, GABA receptor binding, positive regulation of nuclear division, negative regulation of viral genome replication, and negative regulation of the viral life cycle. These may play important roles in the cardiotoxicity of bufadienolide-like chemicals. The results may highlight the potential anticancer mechanism and cardiotoxicity of Chansu, and could also explain the ability of bufadienolide-like chemicals to be used as hormones and anticancer and vasoprotectives agents.

While several studies have demonstrated the preventive and therapeutic effects of red yeast rice (RYR), a traditional Chinese medicine, on carotid atherosclerosis through the reduction of low-density lipoprotein cholesterol (LDL-C) level and other risk factors, the evidence remains inconsistent. This study aimed to further evaluate the effects of RYR in carotid atherosclerosis. Several databases were searched for original trials of RYR for the treatment of carotid atherosclerosis that reported plaque indicators. Carotid plaque area (AREA), carotid plaque score (SCORE), and intima-media thickness (IMT) were set as the primary outcomes, while lipid profile and safety indicators were set as the secondary outcomes. Meta-analyses were performed on the randomized controlled trials (RCTs) using Comprehensive Meta-analysis software. Heterogeneity was evaluated using the I² index and Q statistic. Subgroup, sensitivity, and dose-effect analyses were conducted. Twenty RCTs with 2217 patients were included. Compared to the control group, AREA (SMD = −0.855, 95%CI: −1.259 to −0.451, p < 0.001), IMT (SMD = −0.588, 95%CI: −0.792 to −0.384, p < 0.001), SCORE (SMD = −0.708, 95%CI: −1.135 to −0.282, p = 0.001), LDL-C (SMD = −0.938, 95%CI: −1.375 to −0.502, p < 0.001), triglyceride (SMD = −0.766, 95%CI: −0.980 to −0.551, p < 0.001), and total cholesterol (SMD = −0.858, 95%CI: −1.254 to −0.462, p < 0.001) were significantly decreased and HDL-C (SMD = 0.389, 95%CI: 0.044–0.733, p = 0.027) was significantly increased following RYR therapy. The indicators for safety were not significant and did not differ between the two groups (p > 0.050). Heterogeneities mainly existed for the treatment time or control group setting. Most results showed no changes in the sensitivity analysis. Dose-effect relationships were observed for all indicators except for TC and HDL-C. We concluded that RYR therapy showed considerable efficacy and an acceptable safety profile for the treatment of carotid atherosclerosis in the Chinese population.