大鼠急性心肌梗死后心脏炎症细胞因子基因和蛋白表达及辛伐他汀干预研究

目的探讨辛伐他汀对急性心肌梗死(AMI)后大鼠心脏炎症细胞因子肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)和白细胞介素-10(IL-10)mRNA表达和蛋白质产生的影响。方法Wistar大鼠36只分3组:(1)假手术(Sham)组;(2)心肌梗死对照(MI-C)组;(3)辛伐他汀(MI-S)组。动物笼养4周取出心脏,沿乳头肌等分为二,一半用逆转录聚合酶链反应法测定心脏细胞因子mRNA表达,另一半用Western blot测定细胞因子蛋白质生成量。结果Sham组上述细胞因子均无明显表达,MI-C组TNF-α,IL-1β,IL-6和IL-10 mRNA和蛋白产生均显著高于Sham组;同MI-C组比较,MI-S组的TNF-α,IL-1β,IL-6 mRNA和蛋白生成均显著下降,而IL-10的mRNA和蛋白明显升高。结论辛伐他汀明显降低AMI后大鼠心脏的致炎症细胞因子,而升高炎症保护因子IL-10。     

Behavior of Lp(a) and apoproteins (A1, B,C2, C3, E) during and after therapy with simvastatin

Summary The efficacy of simvastatin in reducing plasma cholesterol is well documented. Other molecules within the apo lipoprotein family, particularly lipoprotein (a) Lp(a), have recently been found to have a predictive and/or causative role in atherosclerosis. Based on these considerations, we studied 15 patients affected by primary hypercholesterolemia to evaluate the effect of simvastatin in Lp(a) and apoprotein plasma levels (A1, B, C2, C3, E), in addition to the classic lipid parameters. Clinical and laboratory parameters were evaluated before therapy, after 12 weeks of therapy, and after 5 weeks of drug withdrawal. Simvastatin therapy produced a significant reduction in total cholesterol (CH) and LDL-CH (p<0.0001), and a significant increase in HDL-CH (p<0.01); no variation was observed in triglyceride (TG) levels. Simvastatin therapy further showed a significant decrease in apoC2 (p<0.05), the apo C2/C3 ratio (p<0.01), and apoE (p<0.01), as well as a significant increase in Lp(a) plasma levels (p<0.05). All of the parameters studied returned to pretreatment values 5 weeks after drug withdrawal; only HDL-CH persisted above the values reached during therapy. Our data agree with those documenting the beneficial effect of simvastatin in greatly decreasing CH and LDL-CH, but point out the need for further studies on the long-term effect of simvastatin on apoprotein molecules, such as on Lp(a), in order to fully establish its role in the secondary prevention of atherosclerosis.     

3种抗菌药物对辛伐他汀在人肝微粒体中代谢的影响

目的 体外研究人肝微粒体中罗红霉素、左氧氟沙星和氟康唑分别对辛伐他汀代谢的影响。方法 分别将罗红霉素、左氧氟沙星、氟康唑与辛伐他汀在人肝微粒体中共孵育,采用UPLC-MS/MS测定辛伐他汀的浓度。结果 罗红霉素和左氧氟沙星对辛伐他汀的代谢没有影响,氟康唑剂量依赖性抑制辛伐他汀的代谢,其IC₅₀值为36.6 μmol·L^-1。结论 氟康唑显著抑制辛伐他汀的代谢,罗红霉素与左氧氟沙星对辛伐他汀在人肝微粒体中代谢无明显药物相互作用。     

Inhibition of autophagy potentiates pemetrexed and simvastatin-induced apoptotic cell death in malignant mesothelioma and non-small cell lung cancer cells

Pemetrexed, a multitarget antifolate used to treat malignant mesothelioma and non-small cell lung cancer (NSCLC), has been shown to stimulate autophagy. In this study, we determined whether autophagy could be induced by pemetrexed and simvastatin cotreatment in malignant mesothelioma and NSCLC cells. Furthermore, we determined whether inhibition of autophagy drives apoptosis in malignant mesothelioma and NSCLC cells. Malignant mesothelioma MSTO-211H and A549 NSCLC cells were treated with pemetrexed and simvastatin alone and in combination to evaluate their effect on autophagy and apoptosis. Cotreatment with pemetrexed and simvastatin induced greater caspase-dependent apoptosis and autophagy than either drug alone in malignant mesothelioma and NSCLC cells. 3-Methyladenine (3-MA), ATG5 siRNA, bafilomycin A, and E64D/pepstatin A enhanced the apoptotic potential of pemetrexed and simvastatin, whereas rapamycin and {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 attenuated their induction of caspase-dependent apoptosis. Our data indicate that pemetrexed and simvastatin cotreatment augmented apoptosis and autophagy in malignant mesothelioma and NSCLC cells. Inhibition of pemetrexed and simvastatin-induced autophagy was shown to enhance apoptosis, suggesting that this could be a novel therapeutic strategy against malignant mesothelioma and NSCLC.     

Simvastatin delivery on PEEK for bioactivity and osteogenesis enhancements

Abstract

A strategy developed for obtaining positive cellular responses remains to be focused in the filed of functional biomimetics. In this study, a hydrogel covered simvastatin-loaded polyetheretherketone (PEEK) bio-composites was constructed with the purpose of bone tissue regeneration therapy. Briefly, a three-dimensional (3D) porous structure was fabricated on PEEK surface; then the substrate was functionalized with the poly(L-lactic acid)/simvastatin porous film and hyaluronic acid hydrogel subsequently. In vitro cell attachment, proliferation, and cytoskeletal observation experiments reveal that our scaffolds show better bio-affinity due to the layer of hyaluronic acid hydrogel compared with control. Furthermore, the alkaline phosphatase activity, calcium mineral deposition evaluation, and gene expression for osteogenic potential all exhibit that the superior osteogenic differentiation of MC3T3-E1 pre-osteoblasts on our scaffolds. Therefore, our PEEK samples loaded with simvastatin and covered with hyaluronic acid hydrogel hold great potential in clinical applications for bone repair.     

Simvastatin induces the osteogenic differentiation of human periodontal ligament stem cells

Periodontal ligament stem cells (PDLSCs) are considered as potential mesenchymal stem cell sources for future clinical applications in periodontal regeneration therapy. Simvastation, widely used for lowering serum cholesterol, is known to have a bone stimulatory effect. However, it is not clear whether simvastation affects the differentiation of PDLSCs. This study examined the effects of simvastatin on human PDLSCs in vitro and in vivo. Using the limiting dilution technique, human PDLSCs were isolated and expanded. PDLSCs were cultured with simvastatin (0.01–10 μm ), and the proliferation was measured. The osteogenic differentiation was characterized by alkaline phosphatase (ALP) activity and Alizarin Red‐S staining for calcium deposition. The gene expression levels of osteogenic markers were evaluated by RT‐PCR. In addition, PDLSCs were transplanted into nude mice with ceramic bovine bone powders as carriers to observe the capacity of mineralized tissue formation in vivo. Simvastatin at concentrations <1 μm did not suppress the proliferation of PDLSCs. After the administration of 0.1 μm simvastatin, the expression of ALP, bone sialoprotein, and bone morphogenetic protein‐2 genes were significantly upregulated, and the ALP activity and mineralized nodule formation were significantly higher in the simvastatin‐treated cells than the control cells. In addition, the in vivo transplantation results showed that simvastatin treatment promoted the degree of mineralized tissue formation. Collectively, simvastatin has positive effects on osteogenic differentiation of human PDLSCs in vitro and in vivo. This suggests that simvastatin might be a useful osteogenic induction agent for periodontal bone regeneration.     

Primary and secondary prevention of heart failure with statins

Statins are effective in the prevention of coronary heart disease (CHD), a leading cause of heart failure (HF). Secondary analyses from 11 randomized clinical trials of patients with high-risk acute or stable coronary heart disease, but without HF, suggest that statins may prevent new-onset HF or HF-related hospitalization. In persons with established HF, several cohort studies found an approximate 35% relative risk reduction in all-cause mortality. While ongoing randomized clinical trials will help to determine the efficacy of statins in persons with established HF, it is reasonable to consider this class of medications in patients with a history of cardiovascular disease, dyslipidemia or diabetes mellitus, and who have either developed, or who remain at risk of, HF.