Objective To observe the effects of different doses of atorvastatin on bleomycin-induced pulmonary fibrosis in rats. Methods Seventy-five healthy female SD rats were randomly divided into five groups ( 15 rats in each group) , ie. a normal group , a model group, a 10 mg/ kg atorvastatin-treated group, a 20 mg/ kg atorvastatin-treated group, and a 40 mg/ kg atorvastatin-treated group. The rats in the model group and treatment groups were instilled with bleomycin in trachea( 5 mg/kg) , and the normal group were instilled with equal volume of normal saline. The treatment groups were gastric gavaged with different doses of atorvastatin each day from2 nd day on after instillation, and the normal group and model group were gavaged with normal saline. Blood samples were obtained from abdominal aorta in five rats in each group and blood gas analysis was performed on1st week, 2nd week and 4th week respectively after BLM instillation. Then the animals were killed and lung tissue samples were harvested for histopathology study. HE and Masson staining were used to determine the extent of alveolus inflammation and pulmonary fibrosis respectively.Histoimmunochemical stain were used to determine the protein levels of transforming growth factor-β1 ( TGF-β1 ) and connective tissue growth factor( CTGF) in pulmonary tissues. Results The arterial partial pressure of oxygenate ( PaO2 ) in the treatment groups were increased gradually with the increasing of therapeutic dose at each time point and decreased with prolongation of time in the same group. The protein levels of TGF-β1 and CTGF in pulmonary tissues were decreased gradually with prolongation of time. TGF-β1 and CTGF expressed obviously less in the treatment groups than those in the model group at each time point .The higher therapeutic doses were, the less the expressions of TGF-β1 and CTGF were. Conclusion Atorvastatin has remarkable inhibitory effects on BLM-induced pulmonary fibrosis of rats in a dose- and timedependentmanner.
ObjectTo observe the clinical efficacy and safety of the combination therapy of atorvastatin and JiangZhi Decoction (ZJD) for primary hyperlipidemia (Tan Zhuo Zu E Zheng) and to analyze the interactions of drugs in hypolipidemic effect. MethodsA 2*2 factorial design, single-blind, stratified randomized controlled trial according to the level of lipid was conducted. Primary hyperlipidemia (Tan Zhuo Zu E Zheng) patients met the inclusion criteria were divided into 5 groups:ATV 10 mg group (group A), ATV 20 mg group (group B), ATV 10 mg+JZD group (group C), ATV 20 mg+JZD group (group D), JZD group (group E). After two weeks treatment, the efficacy and safety among the 5 groups were compared. ResultsA total of 92 patients were included, of which, 20 were in group A, 25 in group B, 21 in group C, 17 in group D, and 9 in group E. The results showed that:(1) There was no significant difference between group C and group B in the reduction of serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (PTC=0.226, PLDL-C=0.818). (2) The results of 2*2 factorial analysis showed that, there was no significant interaction between TCM factor and western medicine factor (PTC=0.605, PLDL-C=0.843). (3) There were no significant differences in safety outcomes among 5 groups (all P values >0.05). ConclusionATV 10 mg+JZD and ATV 20 mg have a similar efficacy in reducing TC and LDL-C. There is no obvious interaction between JZD and ATV in hypolipidemic effect, and the combination therapy of ATV and JZD is safe.
ObjectiveTo investigate the effects of migration and expression from chemokine receptor 4 (chemokine receptor-4, CXCR4) of rat bone marrow mesenchymal stem cells (BMSCs) which were pretreated by atorvastatin (ATV) in vitro.MethodsIsolated, cultivated, identified the BMSCs, pretreated P4-P6 of BMSCs with different concentrations of ATV for 12 hours. The experimental group was divided into control group, 0.1 nM/L (group 0.1 nM), 1 nM/L (1 nM group), 10 nM/L (10 nM group), 100 nM/L (100 nM group), 1 000 nM/L (1 000 nM group). The mRNA and protein of CXCR4 were determined by real time-polymerase chain reaction and Western blot. Immunofluoreseence assay were used to detect the expression levels of CXCR4. The migration ability of BMSCs were measured by transwell chamber.ResultsImmunofluoreseence assay showed the protein level of CXCR4 of group 1 nM and 10 nM were significantly higher than the other group. RT-PCR and Western blot showed the protein and mRNA level of CXCR4 in 10 nM was higher than that in group 1 nM. The migration ability of group 10 nM was higher than 1 nM and control group.ConclusionsATV can be dose-dependent promote expression levels of CXCR4 of BMSCs cultivated in vitro.
Objective To study the effect and mechanism of atorvastatin on improving airway function of mice with chronic obstructive pulmonary disease (COPD) by inhibiting the expression of inducible nitric oxide synthase (iNOS). Methods Wild type (WT) mice were randomly divided into WT control group, WT+COPD group, WT+COPD+atorvastatin group, NC lentivirus group, NC lentivirus+COPD group, NC lentivirus+COPD+atorvastatin group, and iNOS lentivirus+COPD+atorvastatin group. Lung specific iNOS knockout (KO) mice were randomly divided into KO control group and KO+COPD group. The COPD model was established by passive inhalation of cigarette smoke. Atorvastatin (10 mg·kg–1·d–1) was given by gavage, and the negative control (NC) lentivirus or iNOS lentivirus was given by tail vein injection. The lung function indexes including peak inspiratory flow (PIF) and peak expiratory flow (PEF), the number of neutrophils (N), eosinophils (E), lymphocytes (L) and Interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) in bronchoalveolar lavage fluid (BALF), the expression levels of iNOS, endothelium nitric oxide synthase (eNOS) and neural nitric oxide synthase (nNOS) in lung tissue were measured. Results Compared with WT control group, the levels of PIF and PEF decreased, typical pathological changes of COPD appeared in lung tissue, the numbers of N, E, L and the contents of TNF-α, IL-1β in BALF, the expression of iNOS, eNOS and nNOS in lung tissue increased in WT+COPD group (all P<0.05). After atorvastatin intervention, the levels of PIF and PEF increased, the pathological changes of COPD in lung tissue ameliorated, the numbers of N, E, L and the contents of TNF-α, IL-1β in BALF, the expression of iNOS in lung tissue decreased in WT+COPD+atorvastatin group (all P<0.05). After specific knockout of iNOS in lung tissue, the levels of PIF and PEF increased, the pathological changes of COPD in lung tissue ameliorated, the numbers of N, E, L and the contents of TNF-α, IL-1β in BALF decreased in KO+COPD group (all P<0.05). After overexpression of iNOS by tail vein injection of lentiviral, the levels of PIF and PEF decreased, the pathological changes of COPD in lung tissue aggravated, the numbers of N, E, L and the contents of TNF-α, IL-1β in BALF increased in iNOS lentiviral+COPD+atorvastatin group (all P<0.05). Conclusion The effect of atorvastatin on improving airway function and inflammatory response of COPD mice is related to the inhibition of iNOS expression.
ObjectivesTo systematically review the influence of nifedipine combined with atorvastatin on hypertension in patients with hypertension.MethodPubMed, EMbase, The Cochrane Library, CBM, CNKI, WanFang Data and VIP databases were electronically searched to collect randomized controlled trials (RCTs) of nifedipine combined with atorvastatin on hypertension in patients with hypertension from inception to November 20th, 2018. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies, then, meta-analysis was performed by using Stata 12.0 software.ResultsA total of 17 RCTs involving 1 838 patients were included. The results of meta-analysis indicated that nifedipine combined with atorvastatin was superior to nifedipine alone on SBP (MD=−8.937, 95%CI−11.913 to −5.962, P<0.001), DBP (MD=−3.702, 95%CI−6.626 to −0.778, P=0.013) and total effective rate (RR=1.24, 95%CI 1.07 to 1.44, P=0.003). There was no significant difference between two groups in the incidence of adverse reactions (P>0.05).ConclusionsCurrent evidence shows that nifedipine combined with atorvastatin can significantly improve total effective rate, decrease the level of SBP and DBP, and increasing of dose not increase the incidence of adverse reactions. Due to limited quality and quantity of the included studies, more high quality studies are required to verify above conclusions.
ObjectiveTo investigate the effects and mechanism of atorvastatin in the experimental pulmonary fibrosis. MethodsFifty-four C57BL/6 mice were randomly divided into a control group,a bleomycin group and an atorvastatin group. The mice in the bleomycin group and the atorvastatin group received a single dose intratracheal injection of bleomycin (2.5 mg/kg),while the mice in the control group were injected with isodose physiological saline. The mice in the atorvastatin group were treated with atorvastatin 10 mg·kg-1·d-1 by intragastric administration the day after bleomycin instillation. All groups were sacrificed on the day 3,14 and 28,respectively. HE staining and Masson staining were used to detect the architecture of alveolar and the deposition of cellularity and collagen. RT-PCR and immunohistochemical technology were performed to detect the expression of Krüppel like factor 4 (KLF4). Zymography was used to investigate the activation of matrix metalloproteinase-2(MMP-2). ResultsAfter the treatment of bleomycin,the lung tissues showed acute inflammation on the day 3,the collagen deposition was more obvious and the architecture of alveolar was destroyed on the day 14. The alveolar structure,the inflammation and collagen deposition were attenuated on the day 28 compared with the day 14. Compared with the bleomycin group,the inflammation and the collagen deposition were significantly reduced in the atorvastatin group (P<0.05). Compared with bleomycin group,the expression of KLF4 significantly decreased in the atorvastatin group,although the expression of KLF4 mRNA increased on the day 3 compared with the bleomycin group (0.502±0.261 vs. 0.326±0.164,P<0.05). The expression of KLF4 protein on the day 3 was significantly decreased compared with the bleomycin group (0.048±0.015 vs. 0.130±0.017,P<0.05). After the intervention of bleomycin,the activation of MMP-2 on the day 3 and 14 significantly increased compared with the control group (3.136±1.321 and 3.449±0.356 vs. 0.983±0.147,P<0.05),and significantly decreased after the treatment of atorvastatin (2.191±0.800 and 2.506±0.761). ConclusionAtorvastatin may have anti-inflammation and anti-fibrosis activities in experimental pulmonary fibrosis through KLF4 pathway.
目的:观察阿托伐他汀对抗糖尿病肾病患者肾氧化损伤作用。方法:56例糖尿病肾病患者随即分为对照组和阿托伐他汀组。对照组给予降糖、降压等治疗,阿托伐他汀组则在对照组治疗基础上加用阿托伐他汀10 mg/d,疗程共12周。检测两组患者治疗前后FBG、BUN、Scr、尿微量白蛋白以及血脂、血清SOD和MDA水平。结果:12周后两组患者FBG、BUN、Scr、尿微量白蛋白均较治疗前下降;与治疗前相比,阿托伐他汀组患者血脂水平较治疗前明显改善,同时患者血清SOD活性增,MDA含量下降,二者之间的差异具有显著性意义。结论:阿托伐他汀除具有降血脂作用外,还可改善糖尿病肾病患者的氧化应激状态。
Objective To systematically review the effectiveness and safety of Zhibitai vs. atorvastatin in the treatment of hyperlipidemia. Methods Randomized controlled trials (RCTs) about Zhibitai vs. atorvastatin for hyperlipidemia were electronically retrieved in databases of PubMed, CENTRAL (Issue 7, 2010), CBM,CNKI, VIP and WanFang Data from inception to July, 2012. Two reviewers independently screened literature, extracted data, and assessed methodological quality. Then, meta-analysis was conducted using RevMan 5.2 software. Results A total of 4 RCTs involving 519 cases were included. The results of meta-analysis showed, Zhibitai was superior to atorvastatin in reducing TG levels after 8-week treatment (MD= −0.12, 95%CI −0.23 to −0.01, P=0.03) and increasing HDL-C levels after 8-week treatment (MD= −0.16, 95%CI −0.22 to −0.11, P=0.000 01). But there was no significant difference in decreasing TC levels and LDL-C levels after 4-week treatment and 8-week treatment as well as decreasing TG levels after 4-week treatment between the two groups. No obvious adverse reaction occurred in the two groups, but atorvastatin may impair liver function. Conclusion Current evidence with weak strength shows that, Zhibitai is superior to atorvastatin in reducing TG levels, and increasing HDL-C levels after 8 weeks. However, they are alike in other blood-fat index and safety. Due to the limited quantity and quality of the included studies, more high quality RCTs are needed to verify the above conclusion.
ObjectiveTo investigate whether exosomes derived from atorvastatin (ATV)-pretreated human umbilical cord mesenchymal stem cells (ATV-MSC-EXO) alleviate high glucose-induced injury in human retinal vascular endothelial cells (HREC) via the protein kinase B (AKT)/endothelial nitric oxide synthase (eNOS) signaling pathway. MethodsThe optimal pretreatment concentration of ATV was determined using the cell counting Kit-8 (CCK-8) assay. Exosomes derived from mesenchymal stem cells (MSC-EXO) and ATV-pretreated MSC (ATV-MSC-EXO) were isolated and extracted, and their morphology and surface markers were characterized by transmission electron microscopy, nanoparticle tracking analysis, and Western blotting (WB). The uptake capacity of exosomes by human retinal vascular endothelial cells (HREC) was evaluated using a fluorescence labeling assay. In vitro cultured HREC were divided into the following groups: normal control group (NC group), high glucose group (HG group), high glucose+MSC-EXO group (MSC-EXO group), high glucose+ATV-MSC-EXO group (ATV-MSC-EXO group), high glucose+ATV-MSC-EXO+AKT inhibitor group (ATV-MSC-EXO-MK-2206-2HCL group), and high glucose+ATV-MSC-EXO+eNOS inhibitor group (ATV-MSC-EXO-L-NAME group). Cell proliferation and apoptosis were detected using CCK-8 and flow cytometry, respectively. The protein expression levels of B-cell lymphoma/leukemia-2 (Bcl-2), Bcl-2-associated protein (Bax), and Caspase-3 were measured by WB. In addition, the regulatory effects of ATV-MSC-EXO on the AKT/eNOS signaling pathway and its downstream functional molecules were analyzed by detecting the phosphorylation levels of AKT (P-AKT/AKT) and eNOS (P-eNOS/eNOS) via WB, the mRNA expression levels of AKT and eNOS by quantitative real-time polymerase chain reaction, and the concentrations of nitric oxide (NO) and endothelin-1 (ET-1) using commercial NO and ET-1 assay kits. ResultsThe optimal pretreatment concentration of ATV was 1 μmol/L. ATV-MSC-EXO exhibited similar morphology and particle size to MSC-EXO and were efficiently taken up by HREC. Under high glucose conditions, ATV-MSC-EXO significantly enhanced the viability of HREC (F=83.24, P＜0.000 1) and inhibited apoptosis (F=77.39, P＜0.000 1). WB analysis further confirmed that ATV-MSC-EXO upregulated the expression of the anti-apoptotic protein Bcl-2 (F=53.17), while downregulating the pro-apoptotic proteins Bax (F=36.49) and Caspase-3 (F=60.75) (P＜0.001). In addition, ATV-MSC-EXO markedly increased the protein levels of P-AKT/AKT (F=107.60) and P-eNOS/eNOS (F=38.59), as well as the relative mRNA expression of AKT, eNOS (F=203.60, 315.00; P＜0.000 1). Furthermore, ATV-MSC-EXO promoted NO production (F=407.40) and suppressed the relative expression of ET-1 (F=49.76) (P＜0.000 1). ConclusionATV-MSC-EXO enhances the viability and inhibits apoptosis of HREC under high glucose conditions by activating the AKT/eNOS signaling pathway.