Objective:To investigate the preventive and therapeutic effect and mechanism of simvastatin on secondary inflammatory damage of rats with cerebral hemorrhage.Methods:Sixty SD rat aged 9-12 weeks were chosen and divide...Objective:To investigate the preventive and therapeutic effect and mechanism of simvastatin on secondary inflammatory damage of rats with cerebral hemorrhage.Methods:Sixty SD rat aged 9-12 weeks were chosen and divided into the control group,model group and simvastatintreated group randomly with 20 rats in each group.Rats in the model group and simvastatintreated group were infused with autologous fresh uncoagulated blood to the right brain tissue of the basal ganglia to build the cerebral hemorrhage model,while rats in the control group were treated with the same amount of normal saline.Then,rats in the simvastatin-treated group were given a gavage of 3 mg/kg of simvastatin once a day after modeling.Rats in the three groups were given nerve dysfunction score(NDS) and wet-dry weighting method was used to detect the brain water content(BWC) of brain tissues around the lesion of the rats.Then Nissl staining was conducted and the undamaged neurons were counted.Immunohistochemical SP method was applied to count the number of NF-d the immuno fluorκB,TLR4 and IL-1escence method wasβ positive cells in brain tissues around the lesions,an employed to determine the expression levels of NF-κB,TLR4 and IL-1me points were aβ proteins.Results:The NDS results of the simvastatin-treated group at all till significantly higher than those of the model group(P < 0.05);the BWC values of the simvastatin-treated group at all time points were all significantly lower than those of the model group at the same periods(P < 0.05);the number of the undamaged neurons around the lesions of the simvastatin-treated group at all time points were all significantly higher than those of the model group(P < 0.05);seven days after treatment,the number of the NF-κB,TLR4 and IL-1β positive cells in brain tissues around the lesions of the simvastatin-treated group were all significantly lower than those of the model group(P < 0.05),and its expression levels of NF-ower than those of the model group(κB,TLR4 and IL-1P < 0.05).Conclusioβ protein were also significantly lns:Simvastatin can inhibit the expressions of NF-κB,TLR4 and IL-1β proteins in rats with cerebral hemorrhage,and protect neurons and reduce secondary inflammatory damages by down-regulating the above protein-mediated inflammatory responses.展开更多
AIM To determine whether addition of simvastatin could be an important pharmacological rescue therapy for carvedilol non-responders. METHODS One hundred and two consecutive patients of cirrhosis of liver with signific...AIM To determine whether addition of simvastatin could be an important pharmacological rescue therapy for carvedilol non-responders. METHODS One hundred and two consecutive patients of cirrhosis of liver with significant portal hypertension were included. Hepatic venous pressure gradient(HVPG) was measured at the base line and after proper optimization of dose; chronic response was assessed at 3 mo. Carvedilol non-responders were given simvastatin 20 mg per day(increased to 40 mg per day at day 15). Carvedilol plus simvastatin was continued for 1 mo and hemodynamic response was again measured at 1 mo.RESULTS A total of 102 patients with mean age of 58.3 ± 6.6 years were included. Mean baseline HVPG was 16.75 ± 2.12 mmH g and after optimization of dose and reassessment of HVPG at 3 mo, mean reduction of HVPG from baseline was 5.5 ± 1.7 mm Hg and 2.8 ± 1.6 mm Hg among responders and non-responders respectively(P < 0.001). Addition of simvastatin to carvedilol non-responders resulted in significant response in 16 patients(42.1%) and thus overall response with carvedilol and carvedilol plus simvastatin was seen in 78 patients(80%). Two patients were removed in chronic protocol study with carvedilol and three patients were removed in carvedilol plus simvastatin study due to side effects.CONCLUSION Addition of simvastatin to carvedilol non-responders may prove to be an excellent rescue therapy in patients with portal hypertension.展开更多
BACKGROUND: Many studies have showed that apoptosis of endothelial cells plays a curial role in the progress of sepsis. But the role of simvastatin in apoptosis of endothelial cells induced by sepsis is not clear. The...BACKGROUND: Many studies have showed that apoptosis of endothelial cells plays a curial role in the progress of sepsis. But the role of simvastatin in apoptosis of endothelial cells induced by sepsis is not clear. The present study aimed to investigate the role of simvastatin in apoptosis of endothelial cells induced by sepsis and its mechanism.METHODS: Human umbilical vein endothelial cells(HUVECs) were randomly divided into three groups: control group, sepsis serum intervention group(sepsis group) and simvastatin+sepsis serum intervention group(simvastatin group). After 24-hour incubation with corresponding culture medium, the relative growth rate of HUVECS in different groups was detected by MTT assay; the apoptosis of HUVECs was detected by Hoechst33258 assay and fl ow cytometry; and the expression of the Bcl-2 and Bax genes of HUVECs was detected by PCR.RESULTS: Compared with the sepsis group, HUVECs in the simvastatin group had a higher relative growth rate. Apoptotic HUVECs decreased significantly in the simvastatin group in comparison with the sepsis group. Expression of the Bcl-2 gene in HUVECs decreased obviously, but the expression of the Bax gene increased obviously after 24-hour incubation with sepsis serum; however, the expression of the Bcl-2 and Bax genes was just the opposite in the simvastatin group.CONCLUSIONS: Our study suggests that simvastatin can inhibit apoptosis of endothelial cells induced by sepsis through upregulating the expression of Bcl-2 and downregulating Bax. It may be one of the mechanisms for simvastatin to treat sepsis.展开更多
Objective::To investigate the neuroprotective effects of simvastatin on lipopolysaccharide(LPS)-indueed rat model of Parkinson's disease(PD) and the mechanisms involved.Methods:Hemiparkinsonian rat models were ind...Objective::To investigate the neuroprotective effects of simvastatin on lipopolysaccharide(LPS)-indueed rat model of Parkinson's disease(PD) and the mechanisms involved.Methods:Hemiparkinsonian rat models were induced by stereotaxieal injection of LPS in the right substantia nigra compacts.After 2 weeks of simvastatin treatment,rotational behavior test was performed after the intraperitoneal injection of apomorphine.Expression of tyroxine hydroxylase(TH) and glial fibrillan acidic protein were analyzed through immunohistochemical staining of substantia nigra and striatum,and the level of TNF-α was evaluated using enzyme-linked immunosorbent assay.Results:Comparing with untreated group,behavioral symptoms of the rats were significantly less in the rats that received simvastatin treatment.The TH positive cell count in substantia nigra and striatum were significantly increased(P<0.05) and TNF- α expression was significantly decreased(P<0.05) in simvastatin group compared to untreated group.Conclusions:Simvastatin could effectively inhibit the activation of astrocytes,reduce TNF-α expression,and exert anti-inflammatory effects,and thus protect the dopaminergic neurons in substantia nigra and striatum of the rat model of PD.展开更多
Objective:To investigate the effect of simvastatin treatment on lipid pr of ile and oxidative stress in hypercholesterolaemic Indian population and determine the effect of simvastatin treatment on the activity of para...Objective:To investigate the effect of simvastatin treatment on lipid pr of ile and oxidative stress in hypercholesterolaemic Indian population and determine the effect of simvastatin treatment on the activity of paraoxonase（PON）.Methods:Analyzed initially before medication administration and four months later after medication.Lipid and lipoprotein measurement were done by enzymatic kits,high density lipoprotein（HDL） was determined by phosphotungstic acid precipitation method and low density lipoprotein（LDL） was calculated by Friedewald’s formula.Lipid peroxidation was measured by three markers namely,conjugated diene,total peroxide,and malondialdehyde.Conjugated diene was assayed by Buege and Aust method.Total peroxide was determined by FOX2 method.Malondialdehyde determination was carried out by Flemming method and total antioxidant status was determined by Ozacan.Paraoxonase activity was determined by measuring the absorbance inrease of p-nitrophenol at 405 nm.Arylesterase activity was calculated from the molar coefficient of 1 310 M<sup>-1</sup> cm<sup>-1</sup>.Results:Simvastatin significantly reduced total cholesterol,triglycerides,LDL,conjugated diene,total peroxide and MDA levels,where as antioxidant status was significantly increased.Besides,simvastatin significantly increased PON1 activity towards paraoxon.Conclusions:The results from the current study indicate simvastatin may have important antioxidant properties via increasing PON activity.展开更多
Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductases, collectively known as statins, have been shown to minimize cerebral ischemic events in patients. We assessed the mechanisms of simvastatin pretreatment i...Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductases, collectively known as statins, have been shown to minimize cerebral ischemic events in patients. We assessed the mechanisms of simvastatin pretreatment in preventing cerebral ischemia/reperfusion injury in rats using a model of middle cerebral artery occlusion(MCAO).Rats were pretreated with simvastatin 14 days prior to MCAO induction. At 3, 24, and 48 hours after reperfusion,bradykinin levels in the ischemic penumbra were assayed by ELISA, mRNA levels of bradykinin B2 receptors(BK-2Rs) and CD11b were measured by fluorescent quantitative real-time PCR(RT-PCR), and co-expression of microglia and BK-2Rs was determined by immunofluorescence. Simvastatin had no effect on bradykinin expression in the ischemic penumbra at any time point. However, the levels of BK-2R and CD11b mRNA in the ischemic penumbra,which were significantly decreased 3 hours after ischemia-reperfusion, were increased in simvastatin-pretreated rats.Moreover, the co-expression of BK-2Rs and microglia was confirmed by immunofluorescence analysis. These results suggest that the beneficial effects of simvastatin pretreatment before cerebral ischemia/reperfusion injury in rats may be partially due to increased expression of BK-2R and CD11b in the ischemic penumbra.展开更多
The present study examined the functional profile of dendritic cells (DCs) in patients with rheumatoid arthritis (RA) and the effects of simvastatin on the function of DCs.A total of 40 patients who was recently diagn...The present study examined the functional profile of dendritic cells (DCs) in patients with rheumatoid arthritis (RA) and the effects of simvastatin on the function of DCs.A total of 40 patients who was recently diagnosed as having RA were equally assigned to two groups:the routine treatment group (group R) and the routine treatment plus simvastatin group (group R+S).Twenty healthy individuals served as control.The peripheral blood mononuclear cells (PBMCs) were isolated before and 4 weeks after the treatment and then cultured with interleukin-4 (IL-4) and granulocyte-macrophage colony stimulatory factor (GM-CSF) to prepare mature DCs.The expression of co-stimulating factor CD86 on the surface of DCs was assessed by flow cytometry.And the stimulating capacity of DCs was measured by mixed lymphocyte reaction (MLR).The contents of cytokines in culture supernatants of DCs in MLR were detected by ELISA.Blood lipids and high-sensitivity C-reactive protein (hs-CRP) were detected.The relationship between the expression of CD86 and the blood CRP level was also investigated.The results showed that,as compared with the control group,the CD86 expression and the level of cytokines secreted by DCs were significantly increased in RA patients and greater stimulating capacity of DCs in MLR was demonstrated in RA patients.T lymphocytes in MLR secreted higher levels of proinflammatory cytokines (IL-2,IL-17,TNF-α and INF-γ) and lower level of anti-inflammation cytokine (IL-10).The function of DCs was markedly weakened and the level of hs-CRP and low-density lipoprotein was substantially lowered in group R+S in comparison to group R.The CD86 expression was positively correlated with hs-CRP.It was concluded that DCs in RA are highly activated and DC-initiated immune reaction may play an important role in the pathogenesis of RA.Simvastatin administration can significantly inhibit the DCs function and reduce the level of hs-CRP,indicating the suppression on inflammatory reaction may be one of the mechanisms by which simvastatin exerts its effect in treating RA.展开更多
Background and Objective To investigate the effects of simvastatin on lipid lowering therapy and platelet activation in elderly patients with hypercholesterolemia. Methods Fasting serum lipids, CD63, CD41a, serum gluc...Background and Objective To investigate the effects of simvastatin on lipid lowering therapy and platelet activation in elderly patients with hypercholesterolemia. Methods Fasting serum lipids, CD63, CD41a, serum glucose, hepatic and renal function, routine urine analysis (UA) were measured in 50 healthy subjects, and in 50 elderly patients with hypercholesterolemia before and after 4 weeks treatment with simvastatin (20mg daily for 4 weeks). Results 1. After simvastatin treatment for 4 weeks, the fasting serum level of lipids in elderly patients with hypercholesterolemia was significantly lower than before treatment (P<0.01). 2. CD63 and CD41a were decreased after treatment compared with before, respectively (1.36 0.34) vs (4.26 1.06), (P<0.01) and (123.54 19.73) vs (253.78 16.75), (P<0.01). 3. Changes in serum lipid level tended to be positively correlated with the declines in CD63 and CD41a, but there was no statistical significance (P>0.05). Conclusions The results suggested that lipid lowering therapy with simvastatin inhibit platelet activity.(J Geriatr Cardiol 2007;4:215-217.)展开更多
In order to investigate the effects of simvastatin on secretion and mRNA expression of interleukin-6 (IL-6) and adiponectin in 3T3-L1 adipocytes, mouse 3T3-L1 adipocytes were stimu- lated with lipopolysaccharide (LPS)...In order to investigate the effects of simvastatin on secretion and mRNA expression of interleukin-6 (IL-6) and adiponectin in 3T3-L1 adipocytes, mouse 3T3-L1 adipocytes were stimu- lated with lipopolysaccharide (LPS). Production and mRNA expression of IL-6 and adiponectin in 3T3-L1 adipocytes were measured using enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase polymerase chain reaction (RT-PCR), respectively. The results showed that simvastatin could significantly suppress LPS-induced IL-6 production and mRNA expression in adipocytes (P<0.05), but increase the LPS-induced adiponectin secretion and mRNA expression in a dose-dependent manner (P<0.05). It was suggested that simvastatin could exert beneficial effects on prevention of obesity-induced metabolic changes in adipocytes.展开更多
Chitosan nanofiber membranes have been known to have a high degree of biocompatibility and support new bone formation with controllable biodegradation. The surface area of these membranes may allow them to serve as lo...Chitosan nanofiber membranes have been known to have a high degree of biocompatibility and support new bone formation with controllable biodegradation. The surface area of these membranes may allow them to serve as local delivery carriers for different biologic mediators. Simvastatin, a drug commonly used for lowering cholesterol, has demonstrated promising bone regenerative capability. The aim of this study was to evaluate simvastatin loaded chitosan nanofiber membranes for guided bone regeneration (GBR) applications and their ability to enhance bone formation in rat calvarial defects. Nanofibrous chitosan membranes with random fiber orientation were fabricated by electrospinning technique and loaded with 0.25 mg of simvastatin under sterile conditions. One membrane was implanted subperiosteally to cover an 8 mm diameter critical size calvarial defect. Two groups: 1) Control: non-loaded chitosan membranes;2) Experimental: chitosan membranes loaded with 0.25 mg of simvastatin were evaluated histologically and via micro-computed tomography (micro-CT) for bone formation at 4 and 8 weeks time points (n = 5/group per time point). Both groups exhibited good biocompatibility with only mild or moderate inflammatory response during the healing process. Histologic and micro-CT evaluations confirmed bone formation in calvarial defects as early as 4 weeks using control and experimental membranes. In addition, newly-formed bony bridges consolidating calvarial defects histologically along with partial radiographic defect coverage were observed at 8 weeks in both groups. Although control and experimental groups demonstrated no significant statistical differences in results of bone formation, biodegradable chitosan nanofiber membranes loaded with simvastatin showed a promising regenerative potential as a barrier material for guided bone regeneration applications.展开更多
Objective To determine whether the myotoxic side effects of statin simvastatin affect skeletal muscle's sensitivity to caffeine and halothane. Methods Primary cultured neonate rat skeletal myotubes were treated wi...Objective To determine whether the myotoxic side effects of statin simvastatin affect skeletal muscle's sensitivity to caffeine and halothane. Methods Primary cultured neonate rat skeletal myotubes were treated with 0.01-5.0 μmol/L simvastatin for 48 hours. MTT was used to evaluate cellular viability. The gross morphology and microstructure of the myotubes were observed with a light and electron microscope, respectively. The intracellular calcium concentrations([Ca^(2+)]i) at rest and in response to caffeine and halothane were investigated by fluorescence calcium imaging. Data were analyzed by analysis of variance(ANOVA) test. Results Simvastatin(0.01-5.0 μmol/L) decreased myotube viability, changed their morphological features and microstructure, and increased the resting [Ca^(2+)]i in a dose-dependent manner. Simvastatin did not change myotube's sensitivity to low doses of caffeine(0.625-2.5 mmol/L) or halothane(1.0-5.0 mmol/L). In response to high-dose caffeine(10.0 mmol/L, 20.0 mmol/L) and halothane(20.0 mmol/L, 40.0 mmol/L), myotubes treated with 0.01 μmol/L simvastatin showed a significant increase in sensitivity, but those treated with 1.0 μmol/L and 5.0 μmol/L simvastatin showed a significant decrease. The sarcoplasmic reticulum Ca^(2+) storage peaked in the myotubes treated with 0.01 μmol/L simvastatin, but it decreased when cells were treated with higher doses of simvastatin(0.1-5.0 μmol/L).Conclusions The myotoxic side effect of simvastatin was found to change the sensitivity of myotubes in response to high-dose caffeine and halothane. When dose was low, sensitivity increased mainly because of increased Ca^(2+) content in the sarcoplasmic reticulum, which might explain why some individuals with statin-induced myotoxic symptoms may show positive caffeine-halothane contracture test results. However, when the dose was high and the damage to the myotubes was severer, sensitivity was lower. It is here supposed that the damage itself might put individuals with statin-induced myotoxic symptoms at greater risks of presenting with rhabdomyolysis during surgery or while under anesthesia.展开更多
Objective:To observe the intervention influence and effect of simvastatin on the expression of interleukin 17(L117),high mobility group protein 1(HMGB1)and TLR4 path in Lupus nephritis(LN)rats.Methods:A total of 28 BS...Objective:To observe the intervention influence and effect of simvastatin on the expression of interleukin 17(L117),high mobility group protein 1(HMGB1)and TLR4 path in Lupus nephritis(LN)rats.Methods:A total of 28 BSXSB male mice with LN(16 weeks)were randomlv divided into observation group and the comparison group,observation group was given 6 mg·kg^(-1)·d^(-1)simvastatin in 0.1%PBS lavage for 4 weeks.the comparison group was not given any trestment.Blood urea nitrogen(BUN)level and urine trace albumin(Scr)level of two groups were determined.The expression of IL17.HMGB1 and TLR4 protein was detected using immune histochemical method,and the kidney histological damage was observed.Results:BNU,LI17.HMGB1,TLR4protein and HMGB1 mRNA in observation group was significantly lower than that in control group(P<0.05):There was no statistical difference of Scr level between two goups(P<0.05).Histological observation showed glomerular lesions integral of observation group was obviously lower than that of control group.Conclusions:Simvastatin can reduce the expression of IL17.HMGB1 and TLR4 protein in LN mice,thereby can inhibit the autoimmune response as a potential treatment function of LN.展开更多
Objective To investigate the effects of simvastatin on membrane ionic currents in left ventricular myocytes after acute myocardial infarction (AMI,so as to explore the ionic mechanism of statin treatment for antiarrhy...Objective To investigate the effects of simvastatin on membrane ionic currents in left ventricular myocytes after acute myocardial infarction (AMI,so as to explore the ionic mechanism of statin treatment for antiarrhythmia.Methods Fourty-five New Zeland rabbits were randomly divided into three groups:AMI group,simvastatin intervention group （statin group） and sham-operated control group （CON）.Rabbits were infarcted by ligation of the left anterior descending coronary artery after administration of oral simvastatin 5 mg·kg<sup>-1</sup>·d<sup>-1</sup> （Statin group） or placebo （AMI group）for 3 days.Twenty-four hours later,single ventricular myocytes were isolated enzymatically from the epicardial zone of the infracted region.Whole cell patch clamp technique was used to record membrane ionic currents,including sodium current (I<sub>Na</sub>),L-type calcium current (I<sub>Ca-L</sub>) and transient outward potassium current (I<sub>to</sub>).Results①There was no significant difference in serum cholesterol concentration among three groups.②The peak I<sub>Na</sub> current density （at-30 mV） was significantly decreased in AMI group （-23.26±5.18） compared with CON （-42.78±5.48,P【0.05）,while it was significantly increased in Statin group （-39.23±5.45） compared with AMI group （P【0.01）;The peak I<sub>Ca-L</sub> current density （at 0 mV） was significantly decreased in AMI group （-3.23±0.91） compared with CON （-4.56±1.01,P【0.05）,while it was significantly increased in Statin group （- 4.18±0.95） compared with AMI group （P【0.05）;The I<sub>to</sub> current density（at +60 mV） was significantly decreased in AMI group（10.41±1.93）compared with CON （17.41±3.13,P【0.01）,while it was significantly increased in Statin group（16.21±2.42）compared with AMI group （P【0.01）.Conclusions AMI induces significant down-regulation of I<sub>Na</sub>,I<sub>Ca-L</sub> and I<sub>to</sub>.Pretreatment with simvastatin could attenuate this change without lowering the serum cholesterol level,suggesting that simvastatin reverse this electrical remodeling,thus contributing to the ionic mechanism of statin treatment for antiarrhythmia.展开更多
Nanoliposome is a useful dosage form to increase solubility and absorption of simvastatin(SMV), and consequently improves its therapeutic effects. However, in vivo toxicity of SMV could also be elevated accompanied by...Nanoliposome is a useful dosage form to increase solubility and absorption of simvastatin(SMV), and consequently improves its therapeutic effects. However, in vivo toxicity of SMV could also be elevated accompanied by the absorption enhancement, which is a decisive factor for the clinical application of SMV nanoliposome(SMV-Lipo), but has not been studied systematically and reported so far. In this study, organ toxicity of SMV-Lipo was evaluated in mice in the presence and absence of isoproterenol and compared to those of free SMV. Results demonstrated that compared to free SMV, the SMV-Lipo administrated at an equal dose of 25 mg/kg/d led to severe myocardiotoxicity, hepatotoxicity at baseline and more pronounced liver injury with elevation of alanine aminotransferase. In addition, muscular adverse effect was also observed in SMV-Lipo treated group but not in SMV group. Pharmacokinetic studies revealed that compared to free SMV, the SMV-Lipo administration significantly improved the plasma SMV concentration, and the oral bioavailability was 6.5 times of free SMV. Notably, when the dosage of free SMV increased to 50 mg/kg/d, yielding the comparable plasma concentration as SMV-Lipo given at 25 mg/kg/d, the myocardiotoxicity was observed in free SMV treated mice as well, which further confirmed that the enhanced absorption of SMV by the nanoliposomal formulation resulted in more severe myocardiotoxicity than the equal dose of free SMV.展开更多
AIM: To investigate the retinal toxicity and pharmacokinetics of simvastatin intravitreally injected into mice. METHODS: Forty-eight 6-8-week-old C57BL/6J mice were used in this study. Simvastatin was intravitreally i...AIM: To investigate the retinal toxicity and pharmacokinetics of simvastatin intravitreally injected into mice. METHODS: Forty-eight 6-8-week-old C57BL/6J mice were used in this study. Simvastatin was intravitreally injected into the right eye of each mouse; the left eye was injected with vehicle and was used as a control. Bilateral dark-adapted electroretinography(ERG) was performed 1 and 7d following injection. Histology was examined using a combination of light, fluorescence and electron microscopy. Highperformance liquid chromatography(HPLC) was used to determine the decay in the retinal simvastatin concentration.RESULTS: ERG revealed no significant changes in the simvastatin-injected eyes compared to control. Histologic studies showed normal retinal morphology in eyes injected with simvastatin up to a final vitreal concentration of 200 μmol/L. No significant changes in the number of photoreceptors, bipolar cells or ganglion cells were found. The retinal simvastatin concentration decayed exponentially, with a half-life of 1.92-2.41 h.CONCLUSION: Intravitreal injection of up to 200 μmol/L simvastatin produced no signs of adverse effects in the mouse retina. Simvastatin reaches the retina shortly after intravitreal injectionand has a short half-life.展开更多
基金supported by Hebei Social Science Fund Project in 2016(Grant No.HB16LJ006)the Dr. Start-up Fund of North China University of Science and Technology(2015)
文摘Objective:To investigate the preventive and therapeutic effect and mechanism of simvastatin on secondary inflammatory damage of rats with cerebral hemorrhage.Methods:Sixty SD rat aged 9-12 weeks were chosen and divided into the control group,model group and simvastatintreated group randomly with 20 rats in each group.Rats in the model group and simvastatintreated group were infused with autologous fresh uncoagulated blood to the right brain tissue of the basal ganglia to build the cerebral hemorrhage model,while rats in the control group were treated with the same amount of normal saline.Then,rats in the simvastatin-treated group were given a gavage of 3 mg/kg of simvastatin once a day after modeling.Rats in the three groups were given nerve dysfunction score(NDS) and wet-dry weighting method was used to detect the brain water content(BWC) of brain tissues around the lesion of the rats.Then Nissl staining was conducted and the undamaged neurons were counted.Immunohistochemical SP method was applied to count the number of NF-d the immuno fluorκB,TLR4 and IL-1escence method wasβ positive cells in brain tissues around the lesions,an employed to determine the expression levels of NF-κB,TLR4 and IL-1me points were aβ proteins.Results:The NDS results of the simvastatin-treated group at all till significantly higher than those of the model group(P < 0.05);the BWC values of the simvastatin-treated group at all time points were all significantly lower than those of the model group at the same periods(P < 0.05);the number of the undamaged neurons around the lesions of the simvastatin-treated group at all time points were all significantly higher than those of the model group(P < 0.05);seven days after treatment,the number of the NF-κB,TLR4 and IL-1β positive cells in brain tissues around the lesions of the simvastatin-treated group were all significantly lower than those of the model group(P < 0.05),and its expression levels of NF-ower than those of the model group(κB,TLR4 and IL-1P < 0.05).Conclusioβ protein were also significantly lns:Simvastatin can inhibit the expressions of NF-κB,TLR4 and IL-1β proteins in rats with cerebral hemorrhage,and protect neurons and reduce secondary inflammatory damages by down-regulating the above protein-mediated inflammatory responses.
文摘AIM To determine whether addition of simvastatin could be an important pharmacological rescue therapy for carvedilol non-responders. METHODS One hundred and two consecutive patients of cirrhosis of liver with significant portal hypertension were included. Hepatic venous pressure gradient(HVPG) was measured at the base line and after proper optimization of dose; chronic response was assessed at 3 mo. Carvedilol non-responders were given simvastatin 20 mg per day(increased to 40 mg per day at day 15). Carvedilol plus simvastatin was continued for 1 mo and hemodynamic response was again measured at 1 mo.RESULTS A total of 102 patients with mean age of 58.3 ± 6.6 years were included. Mean baseline HVPG was 16.75 ± 2.12 mmH g and after optimization of dose and reassessment of HVPG at 3 mo, mean reduction of HVPG from baseline was 5.5 ± 1.7 mm Hg and 2.8 ± 1.6 mm Hg among responders and non-responders respectively(P < 0.001). Addition of simvastatin to carvedilol non-responders resulted in significant response in 16 patients(42.1%) and thus overall response with carvedilol and carvedilol plus simvastatin was seen in 78 patients(80%). Two patients were removed in chronic protocol study with carvedilol and three patients were removed in carvedilol plus simvastatin study due to side effects.CONCLUSION Addition of simvastatin to carvedilol non-responders may prove to be an excellent rescue therapy in patients with portal hypertension.
基金supported by grants from the Medical Research Foundation of Hunan Province(B2013-040)the Science and Technology Development Foundation of Hengyang City(2010kj38)
文摘BACKGROUND: Many studies have showed that apoptosis of endothelial cells plays a curial role in the progress of sepsis. But the role of simvastatin in apoptosis of endothelial cells induced by sepsis is not clear. The present study aimed to investigate the role of simvastatin in apoptosis of endothelial cells induced by sepsis and its mechanism.METHODS: Human umbilical vein endothelial cells(HUVECs) were randomly divided into three groups: control group, sepsis serum intervention group(sepsis group) and simvastatin+sepsis serum intervention group(simvastatin group). After 24-hour incubation with corresponding culture medium, the relative growth rate of HUVECS in different groups was detected by MTT assay; the apoptosis of HUVECs was detected by Hoechst33258 assay and fl ow cytometry; and the expression of the Bcl-2 and Bax genes of HUVECs was detected by PCR.RESULTS: Compared with the sepsis group, HUVECs in the simvastatin group had a higher relative growth rate. Apoptotic HUVECs decreased significantly in the simvastatin group in comparison with the sepsis group. Expression of the Bcl-2 gene in HUVECs decreased obviously, but the expression of the Bax gene increased obviously after 24-hour incubation with sepsis serum; however, the expression of the Bcl-2 and Bax genes was just the opposite in the simvastatin group.CONCLUSIONS: Our study suggests that simvastatin can inhibit apoptosis of endothelial cells induced by sepsis through upregulating the expression of Bcl-2 and downregulating Bax. It may be one of the mechanisms for simvastatin to treat sepsis.
基金supported by Provincial Natural Science Foundation of Hainan(Grant number 811214)Provincial Higher School Scientific Research Project of Hainan(Grant number Hjkj2011-35)was provided by Department of Neurology,Affiliated Hospital of Hainan Medical College
文摘Objective::To investigate the neuroprotective effects of simvastatin on lipopolysaccharide(LPS)-indueed rat model of Parkinson's disease(PD) and the mechanisms involved.Methods:Hemiparkinsonian rat models were induced by stereotaxieal injection of LPS in the right substantia nigra compacts.After 2 weeks of simvastatin treatment,rotational behavior test was performed after the intraperitoneal injection of apomorphine.Expression of tyroxine hydroxylase(TH) and glial fibrillan acidic protein were analyzed through immunohistochemical staining of substantia nigra and striatum,and the level of TNF-α was evaluated using enzyme-linked immunosorbent assay.Results:Comparing with untreated group,behavioral symptoms of the rats were significantly less in the rats that received simvastatin treatment.The TH positive cell count in substantia nigra and striatum were significantly increased(P<0.05) and TNF- α expression was significantly decreased(P<0.05) in simvastatin group compared to untreated group.Conclusions:Simvastatin could effectively inhibit the activation of astrocytes,reduce TNF-α expression,and exert anti-inflammatory effects,and thus protect the dopaminergic neurons in substantia nigra and striatum of the rat model of PD.
文摘Objective:To investigate the effect of simvastatin treatment on lipid pr of ile and oxidative stress in hypercholesterolaemic Indian population and determine the effect of simvastatin treatment on the activity of paraoxonase（PON）.Methods:Analyzed initially before medication administration and four months later after medication.Lipid and lipoprotein measurement were done by enzymatic kits,high density lipoprotein（HDL） was determined by phosphotungstic acid precipitation method and low density lipoprotein（LDL） was calculated by Friedewald’s formula.Lipid peroxidation was measured by three markers namely,conjugated diene,total peroxide,and malondialdehyde.Conjugated diene was assayed by Buege and Aust method.Total peroxide was determined by FOX2 method.Malondialdehyde determination was carried out by Flemming method and total antioxidant status was determined by Ozacan.Paraoxonase activity was determined by measuring the absorbance inrease of p-nitrophenol at 405 nm.Arylesterase activity was calculated from the molar coefficient of 1 310 M<sup>-1</sup> cm<sup>-1</sup>.Results:Simvastatin significantly reduced total cholesterol,triglycerides,LDL,conjugated diene,total peroxide and MDA levels,where as antioxidant status was significantly increased.Besides,simvastatin significantly increased PON1 activity towards paraoxon.Conclusions:The results from the current study indicate simvastatin may have important antioxidant properties via increasing PON activity.
文摘Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductases, collectively known as statins, have been shown to minimize cerebral ischemic events in patients. We assessed the mechanisms of simvastatin pretreatment in preventing cerebral ischemia/reperfusion injury in rats using a model of middle cerebral artery occlusion(MCAO).Rats were pretreated with simvastatin 14 days prior to MCAO induction. At 3, 24, and 48 hours after reperfusion,bradykinin levels in the ischemic penumbra were assayed by ELISA, mRNA levels of bradykinin B2 receptors(BK-2Rs) and CD11b were measured by fluorescent quantitative real-time PCR(RT-PCR), and co-expression of microglia and BK-2Rs was determined by immunofluorescence. Simvastatin had no effect on bradykinin expression in the ischemic penumbra at any time point. However, the levels of BK-2R and CD11b mRNA in the ischemic penumbra,which were significantly decreased 3 hours after ischemia-reperfusion, were increased in simvastatin-pretreated rats.Moreover, the co-expression of BK-2Rs and microglia was confirmed by immunofluorescence analysis. These results suggest that the beneficial effects of simvastatin pretreatment before cerebral ischemia/reperfusion injury in rats may be partially due to increased expression of BK-2R and CD11b in the ischemic penumbra.
基金supported by a grant from Natural Sciences Foundation of Hubei Province,China(No.2009CBD184)
文摘The present study examined the functional profile of dendritic cells (DCs) in patients with rheumatoid arthritis (RA) and the effects of simvastatin on the function of DCs.A total of 40 patients who was recently diagnosed as having RA were equally assigned to two groups:the routine treatment group (group R) and the routine treatment plus simvastatin group (group R+S).Twenty healthy individuals served as control.The peripheral blood mononuclear cells (PBMCs) were isolated before and 4 weeks after the treatment and then cultured with interleukin-4 (IL-4) and granulocyte-macrophage colony stimulatory factor (GM-CSF) to prepare mature DCs.The expression of co-stimulating factor CD86 on the surface of DCs was assessed by flow cytometry.And the stimulating capacity of DCs was measured by mixed lymphocyte reaction (MLR).The contents of cytokines in culture supernatants of DCs in MLR were detected by ELISA.Blood lipids and high-sensitivity C-reactive protein (hs-CRP) were detected.The relationship between the expression of CD86 and the blood CRP level was also investigated.The results showed that,as compared with the control group,the CD86 expression and the level of cytokines secreted by DCs were significantly increased in RA patients and greater stimulating capacity of DCs in MLR was demonstrated in RA patients.T lymphocytes in MLR secreted higher levels of proinflammatory cytokines (IL-2,IL-17,TNF-α and INF-γ) and lower level of anti-inflammation cytokine (IL-10).The function of DCs was markedly weakened and the level of hs-CRP and low-density lipoprotein was substantially lowered in group R+S in comparison to group R.The CD86 expression was positively correlated with hs-CRP.It was concluded that DCs in RA are highly activated and DC-initiated immune reaction may play an important role in the pathogenesis of RA.Simvastatin administration can significantly inhibit the DCs function and reduce the level of hs-CRP,indicating the suppression on inflammatory reaction may be one of the mechanisms by which simvastatin exerts its effect in treating RA.
文摘Background and Objective To investigate the effects of simvastatin on lipid lowering therapy and platelet activation in elderly patients with hypercholesterolemia. Methods Fasting serum lipids, CD63, CD41a, serum glucose, hepatic and renal function, routine urine analysis (UA) were measured in 50 healthy subjects, and in 50 elderly patients with hypercholesterolemia before and after 4 weeks treatment with simvastatin (20mg daily for 4 weeks). Results 1. After simvastatin treatment for 4 weeks, the fasting serum level of lipids in elderly patients with hypercholesterolemia was significantly lower than before treatment (P<0.01). 2. CD63 and CD41a were decreased after treatment compared with before, respectively (1.36 0.34) vs (4.26 1.06), (P<0.01) and (123.54 19.73) vs (253.78 16.75), (P<0.01). 3. Changes in serum lipid level tended to be positively correlated with the declines in CD63 and CD41a, but there was no statistical significance (P>0.05). Conclusions The results suggested that lipid lowering therapy with simvastatin inhibit platelet activity.(J Geriatr Cardiol 2007;4:215-217.)
文摘In order to investigate the effects of simvastatin on secretion and mRNA expression of interleukin-6 (IL-6) and adiponectin in 3T3-L1 adipocytes, mouse 3T3-L1 adipocytes were stimu- lated with lipopolysaccharide (LPS). Production and mRNA expression of IL-6 and adiponectin in 3T3-L1 adipocytes were measured using enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase polymerase chain reaction (RT-PCR), respectively. The results showed that simvastatin could significantly suppress LPS-induced IL-6 production and mRNA expression in adipocytes (P<0.05), but increase the LPS-induced adiponectin secretion and mRNA expression in a dose-dependent manner (P<0.05). It was suggested that simvastatin could exert beneficial effects on prevention of obesity-induced metabolic changes in adipocytes.
文摘Chitosan nanofiber membranes have been known to have a high degree of biocompatibility and support new bone formation with controllable biodegradation. The surface area of these membranes may allow them to serve as local delivery carriers for different biologic mediators. Simvastatin, a drug commonly used for lowering cholesterol, has demonstrated promising bone regenerative capability. The aim of this study was to evaluate simvastatin loaded chitosan nanofiber membranes for guided bone regeneration (GBR) applications and their ability to enhance bone formation in rat calvarial defects. Nanofibrous chitosan membranes with random fiber orientation were fabricated by electrospinning technique and loaded with 0.25 mg of simvastatin under sterile conditions. One membrane was implanted subperiosteally to cover an 8 mm diameter critical size calvarial defect. Two groups: 1) Control: non-loaded chitosan membranes;2) Experimental: chitosan membranes loaded with 0.25 mg of simvastatin were evaluated histologically and via micro-computed tomography (micro-CT) for bone formation at 4 and 8 weeks time points (n = 5/group per time point). Both groups exhibited good biocompatibility with only mild or moderate inflammatory response during the healing process. Histologic and micro-CT evaluations confirmed bone formation in calvarial defects as early as 4 weeks using control and experimental membranes. In addition, newly-formed bony bridges consolidating calvarial defects histologically along with partial radiographic defect coverage were observed at 8 weeks in both groups. Although control and experimental groups demonstrated no significant statistical differences in results of bone formation, biodegradable chitosan nanofiber membranes loaded with simvastatin showed a promising regenerative potential as a barrier material for guided bone regeneration applications.
文摘Objective To determine whether the myotoxic side effects of statin simvastatin affect skeletal muscle's sensitivity to caffeine and halothane. Methods Primary cultured neonate rat skeletal myotubes were treated with 0.01-5.0 μmol/L simvastatin for 48 hours. MTT was used to evaluate cellular viability. The gross morphology and microstructure of the myotubes were observed with a light and electron microscope, respectively. The intracellular calcium concentrations([Ca^(2+)]i) at rest and in response to caffeine and halothane were investigated by fluorescence calcium imaging. Data were analyzed by analysis of variance(ANOVA) test. Results Simvastatin(0.01-5.0 μmol/L) decreased myotube viability, changed their morphological features and microstructure, and increased the resting [Ca^(2+)]i in a dose-dependent manner. Simvastatin did not change myotube's sensitivity to low doses of caffeine(0.625-2.5 mmol/L) or halothane(1.0-5.0 mmol/L). In response to high-dose caffeine(10.0 mmol/L, 20.0 mmol/L) and halothane(20.0 mmol/L, 40.0 mmol/L), myotubes treated with 0.01 μmol/L simvastatin showed a significant increase in sensitivity, but those treated with 1.0 μmol/L and 5.0 μmol/L simvastatin showed a significant decrease. The sarcoplasmic reticulum Ca^(2+) storage peaked in the myotubes treated with 0.01 μmol/L simvastatin, but it decreased when cells were treated with higher doses of simvastatin(0.1-5.0 μmol/L).Conclusions The myotoxic side effect of simvastatin was found to change the sensitivity of myotubes in response to high-dose caffeine and halothane. When dose was low, sensitivity increased mainly because of increased Ca^(2+) content in the sarcoplasmic reticulum, which might explain why some individuals with statin-induced myotoxic symptoms may show positive caffeine-halothane contracture test results. However, when the dose was high and the damage to the myotubes was severer, sensitivity was lower. It is here supposed that the damage itself might put individuals with statin-induced myotoxic symptoms at greater risks of presenting with rhabdomyolysis during surgery or while under anesthesia.
基金supported by National Science Foundation of China:81273731
文摘Objective:To observe the intervention influence and effect of simvastatin on the expression of interleukin 17(L117),high mobility group protein 1(HMGB1)and TLR4 path in Lupus nephritis(LN)rats.Methods:A total of 28 BSXSB male mice with LN(16 weeks)were randomlv divided into observation group and the comparison group,observation group was given 6 mg·kg^(-1)·d^(-1)simvastatin in 0.1%PBS lavage for 4 weeks.the comparison group was not given any trestment.Blood urea nitrogen(BUN)level and urine trace albumin(Scr)level of two groups were determined.The expression of IL17.HMGB1 and TLR4 protein was detected using immune histochemical method,and the kidney histological damage was observed.Results:BNU,LI17.HMGB1,TLR4protein and HMGB1 mRNA in observation group was significantly lower than that in control group(P<0.05):There was no statistical difference of Scr level between two goups(P<0.05).Histological observation showed glomerular lesions integral of observation group was obviously lower than that of control group.Conclusions:Simvastatin can reduce the expression of IL17.HMGB1 and TLR4 protein in LN mice,thereby can inhibit the autoimmune response as a potential treatment function of LN.
文摘Objective To investigate the effects of simvastatin on membrane ionic currents in left ventricular myocytes after acute myocardial infarction (AMI,so as to explore the ionic mechanism of statin treatment for antiarrhythmia.Methods Fourty-five New Zeland rabbits were randomly divided into three groups:AMI group,simvastatin intervention group （statin group） and sham-operated control group （CON）.Rabbits were infarcted by ligation of the left anterior descending coronary artery after administration of oral simvastatin 5 mg·kg<sup>-1</sup>·d<sup>-1</sup> （Statin group） or placebo （AMI group）for 3 days.Twenty-four hours later,single ventricular myocytes were isolated enzymatically from the epicardial zone of the infracted region.Whole cell patch clamp technique was used to record membrane ionic currents,including sodium current (I<sub>Na</sub>),L-type calcium current (I<sub>Ca-L</sub>) and transient outward potassium current (I<sub>to</sub>).Results①There was no significant difference in serum cholesterol concentration among three groups.②The peak I<sub>Na</sub> current density （at-30 mV） was significantly decreased in AMI group （-23.26±5.18） compared with CON （-42.78±5.48,P【0.05）,while it was significantly increased in Statin group （-39.23±5.45） compared with AMI group （P【0.01）;The peak I<sub>Ca-L</sub> current density （at 0 mV） was significantly decreased in AMI group （-3.23±0.91） compared with CON （-4.56±1.01,P【0.05）,while it was significantly increased in Statin group （- 4.18±0.95） compared with AMI group （P【0.05）;The I<sub>to</sub> current density（at +60 mV） was significantly decreased in AMI group（10.41±1.93）compared with CON （17.41±3.13,P【0.01）,while it was significantly increased in Statin group（16.21±2.42）compared with AMI group （P【0.01）.Conclusions AMI induces significant down-regulation of I<sub>Na</sub>,I<sub>Ca-L</sub> and I<sub>to</sub>.Pretreatment with simvastatin could attenuate this change without lowering the serum cholesterol level,suggesting that simvastatin reverse this electrical remodeling,thus contributing to the ionic mechanism of statin treatment for antiarrhythmia.
基金This work was supported by grants from the National Natural Science Foundation of China(No.81770268)the National Basic Research Program of China(No.2015CB932100).
文摘Nanoliposome is a useful dosage form to increase solubility and absorption of simvastatin(SMV), and consequently improves its therapeutic effects. However, in vivo toxicity of SMV could also be elevated accompanied by the absorption enhancement, which is a decisive factor for the clinical application of SMV nanoliposome(SMV-Lipo), but has not been studied systematically and reported so far. In this study, organ toxicity of SMV-Lipo was evaluated in mice in the presence and absence of isoproterenol and compared to those of free SMV. Results demonstrated that compared to free SMV, the SMV-Lipo administrated at an equal dose of 25 mg/kg/d led to severe myocardiotoxicity, hepatotoxicity at baseline and more pronounced liver injury with elevation of alanine aminotransferase. In addition, muscular adverse effect was also observed in SMV-Lipo treated group but not in SMV group. Pharmacokinetic studies revealed that compared to free SMV, the SMV-Lipo administration significantly improved the plasma SMV concentration, and the oral bioavailability was 6.5 times of free SMV. Notably, when the dosage of free SMV increased to 50 mg/kg/d, yielding the comparable plasma concentration as SMV-Lipo given at 25 mg/kg/d, the myocardiotoxicity was observed in free SMV treated mice as well, which further confirmed that the enhanced absorption of SMV by the nanoliposomal formulation resulted in more severe myocardiotoxicity than the equal dose of free SMV.
基金Supported by the National Institute of Health under Award Number R01 EY004446&R01 EY019908NIH Vision Core EY02520+1 种基金the Retina Research Foundation(Houston),Research to Prevent Blindness Inc.Hong Kong Polytechnic University grants G-UA7J and G-YBQT
文摘AIM: To investigate the retinal toxicity and pharmacokinetics of simvastatin intravitreally injected into mice. METHODS: Forty-eight 6-8-week-old C57BL/6J mice were used in this study. Simvastatin was intravitreally injected into the right eye of each mouse; the left eye was injected with vehicle and was used as a control. Bilateral dark-adapted electroretinography(ERG) was performed 1 and 7d following injection. Histology was examined using a combination of light, fluorescence and electron microscopy. Highperformance liquid chromatography(HPLC) was used to determine the decay in the retinal simvastatin concentration.RESULTS: ERG revealed no significant changes in the simvastatin-injected eyes compared to control. Histologic studies showed normal retinal morphology in eyes injected with simvastatin up to a final vitreal concentration of 200 μmol/L. No significant changes in the number of photoreceptors, bipolar cells or ganglion cells were found. The retinal simvastatin concentration decayed exponentially, with a half-life of 1.92-2.41 h.CONCLUSION: Intravitreal injection of up to 200 μmol/L simvastatin produced no signs of adverse effects in the mouse retina. Simvastatin reaches the retina shortly after intravitreal injectionand has a short half-life.
