Effect of Pravastatin on Levels of Malondealdehyde (MDA) And Endothelin-1 (ET-1) Preeclampsia Model Rats

@#Introduction: Pravastatin is known to have a number of pleiotropic effects including reducing endothelial dysfunction, anti-inflammatory, antioxidants, conangiogenic, and antitrombotic. Pravastatin through the pleitropic effect is expected to be one of the alternative therapies to prevent preeclampsia. The limited strategy for prevention and treatment of preeclampsia is due to the unknown etiology and pathogenesis. These two markers are thought to contribute to the occurrence of preeclampsia although they cause it in two different pathways. MDA is a marker of oxidative stress as an end product of lipid peroxidation. ET-1 is a vasoconstrictor that plays a role in the pathogenesis of preeclampsia through increasing anti-angiogenic properties. Aim: to determine the effect of pravastatin on serum levels of MDA and ET-1 in preeclampsia rat models. Methods: This study consisted of 5 groups; negative control/ K(-) consisted of normal pregnant rats, positive control/ K(+) consisted of rat model of preeclampsia (rat model of preeclampsia induced by administration of L-NAME at a dose of 125 mg/kg BW/day since gestational age 13-19 days), treatment groups 1, 2, and 3 (rat model of preeclampsia given pravastatin with 3 different doses; 2 mg/day (P1), 4 mg/day (P2) and 8 mg/day(P3)) at 13-19 days of gestation. The rat model of preeclampsia was determined based on blood pressure > 140/90 with urine protein > +1. After termination, blood was drawn to measure serum MDA and ET-1 levels. Results: Serum levels of MDA and ET-1 were decreased in groups P2 and P3 compared to groups K(+). Statistically, there was a significant difference in the mean levels of MDA (p=0.001) and ET-1 (p=0.000) between each group. Conclusion: Pravastatin can prevent preeclampsia by decreasing MDA and ET-1.

Current status and prospect of pravastatin in pregnancy / 中华围产医学杂志

Cholesterol-lowing statins such as pravastatin have been contraindicated in pregnant women for a long time, but recent clinical evidence has demonstrated its safety. Studies have found that pravastatin can correct the imbalance in angiogenesis, reduce vascular inflammation and improve the conditions in patients with placental and maternal vascular dysfunction-related diseases, such as preeclampsia, fetal growth restriction and antiphospholipid syndrome. However, universal administration of pravastatin in pregnancy still requires more evidence on its safety from human clinical trials with larger sample sizes. This article reviews the current situation and prospect of pravastatin in pregnancy.

Progress on pravastatin and its safety in prevention and treatment of preeclampsia / 中华围产医学杂志

Preeclampsia is the main cause of poor maternal-fetal outcomes. A series of cell and animal experiments, and a small number of clinical studies have shown that pravastatin can prevent and treat preeclampsia by regulating angiogenesis, increasing the expression of heme oxygenase, and stimulating the production of nitric oxide without any reported adverse effects during pregnancy. We review the latest progress on the mechanism, effect, and safety of pravastatin in the prevention and treatment of preeclampsia.

Different effects of pravastatin on sFlt-1, PlGF and VEGF in different preeclampsia-like mouse models / 中华妇产科杂志

Objective@#To explore the pathways of preeclampsia by investigating different effects of pravastatin (Pra) on and soluble FMS tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) in different preeclampsia (PE)-like mouse models.@*Methods@#C57BL/6J mice were randomly subcutaneously injected with N-nitro-L-arginine methyl ester (L-NAME) or intraperitoneally injected with lipopolysaccharide (LPS) as PE-like mouse model, saline as normal pregnancy control (Con) respectively, daily at gestational 7-18 days. Pra was given daily at gestational 8-18 days in each model group and the mice were divided into Pra (L-NAME+Pra, LPS+Pra, Con+Pra) and saline (L-NAME+NS, LPS+NS, Con+NS) groups. Liver,placental tissue and blood of pregnant mice were collected on the 18th day of pregnancy. The levels of VEGF, PlGF and sFlt-1 in the liver, placenta and serum of mice in each group were compared by western blot, ELISA and real-time fluorescence quantitative PCR (RT-PCR).@*Results@#(1) ELISA: Serum VEGF (205.70±3.43, 154.60±2.31) and PlGF (131.5±3.75, 101.50±4.31) levels were significantly increased in L-NAME+Pra group compared with L-NAME+NS group (all P<0.05). Serum VEGF (202.30±4.90, 144.50±6.71) and PlGF (121.50±3.86, 95.41±4.08) levels were significantly higher in LPS+Pra group than those in LPS+NS group (all P<0.05). Serum sFlt-1 level in LPS+Pra group was significantly lower than that in LPS+NS group (3.01±0.50, 776.60±80.06), serum sFlt-1 level in L-NAME+Pra group was significantly lower than that in L-NAME+NS group (2.60±0.06, 583.70±9.83; all P<0.05). (2) Western blot: the expression levels of PlGF (1.344±0.118, 0.664±0.143) and VEGF (1.34±0.12, 0.66±0.14) in the liver of mice in the L-NAME+Pra group were significantly higher than those in the L-NAME+NS group (all P<0.05), but the expression levels of PlGF and VEGF in the placenta of L-NAME+Pra group were not significantly different from those of L-NAME+NS group (all P>0.05). The expression levels of PlGF and VEGF in placenta and liver of pregnant mice in LPS+Pra group were not significantly different from those in LPS+N group (all P>0.05). (3) RT-PCR: the mRNA expression of PlGF and VEGF in placenta and liver of L-NAME+Pra group were not significantly different from those in L-NAME+NS group (all P>0.05). The mRNA expression levels of PlGF and VEGF in placenta and liver of LPS+Pra group were not significantly different from those of LPS+NS group (all P>0.05).@*Conclusions@#Pra has different regulatory effects on vascular endothelial function in different PE-like models. It reveals that different pathogenesis and pathways exist in different PE-like changes.

Different effects of pravastatin on sFlt?1, PlGF and VEGF in different preeclampsia?like mouse models / 中华妇产科杂志

Objective To explore the pathways of preeclampsia by investigating different effects of pravastatin (Pra) on and soluble FMS tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) in different preeclampsia (PE)?like mouse models. Methods C57BL/6J mice were randomly subcutaneously injected with N?nitro?L?arginine methyl ester (L?NAME) or intraperitoneally injected with lipopolysaccharide (LPS) as PE?like mouse model, saline as normal pregnancy control (Con) respectively, daily at gestational 7-18 days. Pra was given daily at gestational 8-18 days in each model group and the mice were divided into Pra (L?NAME+Pra, LPS+Pra, Con+Pra) and saline (L?NAME+NS, LPS+NS, Con+NS) groups. Liver,placental tissue and blood of pregnant mice were collected on the 18th day of pregnancy. The levels of VEGF, PlGF and sFlt?1 in the liver, placenta and serum of mice in each group were compared by western blot, ELISA and real?time fluorescence quantitative PCR (RT-PCR). Results (1) ELISA: Serum VEGF (205.70±3.43, 154.60±2.31) and PlGF (131.5±3.75, 101.50± 4.31) levels were significantly increased in L?NAME+Pra group compared with L?NAME+NS group (all P<0.05). Serum VEGF (202.30 ± 4.90, 144.50 ± 6.71) and PlGF (121.50 ± 3.86, 95.41 ± 4.08) levels were significantly higher in LPS+Pra group than those in LPS+NS group (all P<0.05). Serum sFlt?1 level in LPS+Pra group was significantly lower than that in LPS+NS group (3.01±0.50, 776.60±80.06), serum sFlt?1 level in L?NAME+Pra group was significantly lower than that in L?NAME+NS group (2.60±0.06, 583.70±9.83;all P<0.05). (2) Western blot: the expression levels of PlGF (1.344±0.118, 0.664±0.143) and VEGF (1.34±0.12, 0.66 ± 0.14) in the liver of mice in the L?NAME+Pra group were significantly higher than those in the L?NAME+NS group (all P<0.05), but the expression levels of PlGF and VEGF in the placenta of L?NAME+Pra group were not significantly different from those of L?NAME+NS group (all P>0.05). The expression levels of PlGF and VEGF in placenta and liver of pregnant mice in LPS+Pra group were not significantly different from those in LPS+N group (all P>0.05). (3) RT?PCR: the mRNA expression of PlGF and VEGF in placenta and liver of L?NAME+Pra group were not significantly different from those in L?NAME+NS group (all P>0.05). The mRNA expression levels of PlGF and VEGF in placenta and liver of LPS+Pra group were not significantly different from those of LPS+NS group (all P>0.05). Conclusions Pra has different regulatory effects on vascular endothelial function in different PE?like models. It reveals that different pathogenesis and pathways exist in different PE?like changes.

Changes of Rheb gene and protein expression in preeclampsia-like mouse model treated with pravastatin / 中华妇产科杂志

Objective To explore whether pravastatin (Pra) inhibits mammalian target of rapamycin (mTOR) signal pathway by regulating Ras homolog enriched in brain (Rheb) protein through the comparison of gene and protein expression changes of Rheb in liver and placenta in preeclampsia (PE)-like mouse model treated with Pra. Methods C57BL/6J pregnant mice were randomly divided into two groups. The PE group was established by injecting N-nitro-L-arginine methyl ester (L-NAME) daily at gestational 7-18 days, saline was injected as contol group (Con);then giving mice Pra (PE+Pra, Con+Pra group, n=8) or normal saline (PE+N, Con+N group, n=8) every day from the 8th gestational day of pregnancy. The maternal liver and placenta tissues were collected on the 18th day of pregnancy. Western blot, real-time quantitative PCR and immunohistochemistry were used to compare the levels of Rheb protein and mRNA expression in the liver and placenta. Results (1)The results of western blot:there were no significant differences in Rheb protein expression between PE+N group (liver:0.706±0.123;placenta:0.866±0.128) and Con+N group (liver:0.732 ± 0.123; placenta: 0.909 ± 0.097), and the differences between PE+Pra group (liver: 0.669 ± 0.134;placenta:0.940 ± 0.221) and PE+N group were not significant either in liver or in placenta (all P>0.05). (2) The results of real-time quantitative PCR:when PE+N group (liver:1.026 ± 0.480;placenta:1.102 ± 0.361) compared with Con+N group (liver:1.058±0.389;placenta:1.067±0.400), PE+Pra group (liver:0.735±0.356;placenta:0.822±0.304) compared with PE+N group, there were no significant differences either in liver or in placenta (all P>0.05). (3) The results of immunohistochemistry: Rheb protein expression did not change significantly in maternal liver and placenta, there were no significant differences in protein expression levels between PE+N group and Con+N group, and between PE+Pra group and PE+N group (all P>0.05). Conclusion The inhibition of Pra on mTOR signaling pathway in some PE-like model may be independent of the expression of Rheb gene and protein.

Effects of Atorvastatin, Rosuvastatin, and Pravastatin on Antiplatelet Activity of Clopidogrel in Patients with Acute Coronary Syndrome and Different CYP2C19 Genotypes / 中国药学杂志

OBJECTIVE: To investigate the effects of atorvastatin, rosuvastatin, and pravastatin on antiplatelet activity of clopidogrel in patients with acute coronary syndrome(ACS) and different CYP2C19 genotypes. METHODS: Between November 2017 and November 2018, a total of 300 patients admitted for ACS were enrolled in this study and randomly assigned to three groups. All patients received standard dual antiplatelet therapy. A, B, and C groups received atorvastatin calcium 20 mg•d-1, rosuvastatin calcium 20 mg•d-1, and pravastatin sodium 20 mg•d-1, respectively. The CYP2C19 genotype was detected by pyrosequencing. Thromboelastogram(TEG) was applied to detect the ADP-induced platelet inhibition rate 7 days after treatment. RESULTS: No significant difference was observed in baseline clinical characteristics between three groups. It was also no statistically significant difference in ADP inhibition rate and proportion of clopidogrel resistance between three groups(P>0.05). However, compared with rosuvastatin group and pravastatin group, the ADP inhibition rate was significantly reduced in atorvastatin group in poor metabolizers of CYP2C19. CONCLUSION: In intermediate metabolizers and extensive metabolizers of CYP2C19, there is no significant difference in the effects of atorvastatin, rosuvastatin, and pravastatin on antiplatelet activity of clopidogrel. Compared with rosuvastatin and pravastatin, atorvastatin significantly attenuates the antiplatelet function of clopidogrel in poor metabolizers of CYP2C19.

Study of effect of rifampin and tanshinone II A on pravastatin transport via BSEP in sandwich-cultured rat hepatocytes / 中国药理学通报

Aim To elucidate the effect of rifampin and tanshinone II A on BSEP transport capacity using pravastatin as the BSEP substrate in sandwich-cultured rat hepatocytes (SCRH). Methods SCRH model was established. The doses of drugs were determined by MIT. A HPLC-MS/MS method was developed and was conducted method validation to detect the concentration of pravastatin. The effect of rifampin and tanshinone D A on the concentration of pravastatin in the bile duct was investigated. And the biliary excretion index ( BEI) was calculated. Results The SCRH model was successfully developed. The appropriate doses of rifampin, tanshinone DA, glibenclamide and pravastatin were determined. A stable and reliable HPLC-MS/MS method for the determination of pravastatin was established Compared with blank control group, rifampin reduced the concentration of pravastatin in the bile duct and the BEI of pravastatin. The high concentration of rifampin caused the steepest downward trends ( P < 0 . 0 1 ) . Compared with high concentration group of rifampin, the concentration of pravastatin in the bile duct and the BEI of pravastatin gradually increased after the combination of rifampin and tanshinone II A, and the effect of high concentration of tanshinone II A was the most significant ( P < 0. 0 1 ) . Conclusions Rifampin could inhibit the function of BSEP in SCRH. The combination of tanshinone D A and rifampin could reverse the inhibitor)' effect of BSEP transport capacity caused by rifampin.

Sensory multiple mononeuropathy induced by pravastatin use: from a case report to literature's review / Mononeuropatia múltipla sensitiva induzida pelo uso de pravastatina: de um relato de caso à revisão de literatura

Statins are frequently prescribed in clinical practice for their proven efficacy in prevention of cardiovascular and cerebrovascular diseases. Despite the recognized beneficial effects of this class of drugs, in recent years, many studies published in medical literature have shown a wide range of adverse effects as a consequence of this therapy, including the risk of peripheral neuropathy. The purpose of this article is to report a case in which clinical features consistent with multiple mononeuropathy probably secondary to use of pravastatin were observed. The case report is followed by a review of the relevant literature.

As estatinas são frequentemente prescritas na prática clínica por sua comprovada eficácia na prevenção de doenças cardiovasculares e cérebrovasculares. Apesar dos reconhecidos efeitos benéficos dessa classe medicamentosa, nos últimos anos, diversos estudos publicados na literatura médica vem evidenciando uma ampla variedade de efeitos colaterais como consequência desta terapia, incluindo o risco de neuropatias periféricas. O objetivo deste artigo é relatar um caso no qual foram observadas manifestações clínicas compatíveis com o diagnóstico de mononeuropatia múltipla sensitiva, provavelmente secundária ao uso de pravastatina. O relato de caso é acompanhando de uma revisão de dados pertinentes da literatura.

Effect of the anti-IL-17 antibody on allergic inflammation in an obesity-related asthma model

BACKGROUND/AIMS: The co-occurrence of obesity aggravates asthma symptoms. Diet-induced obesity increases helper T cell (TH) 17 cell differentiation in adipose tissue and the spleen. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pravastatin can potentially be used to treat asthma in obese patients by inhibiting interleukin 17 (IL-17) expression. This study investigated the combined effects of pravastatin and anti-IL-17 antibody treatment on allergic inflammation in a mouse model of obesity-related asthma. METHODS: High-fat diet (HFD)-induced obesity was induced in C57BL/6 mice with or without ovalbumin (OVA) sensitization and challenge. Mice were administered the anti-IL-17 antibody, pravastatin, or both, and pathophysiological and immunological responses were analyzed. RESULTS: HFD exacerbated allergic airway inflammation in the bronchoalveolar lavage fluid of HFD-OVA mice as compared to OVA mice. Blockading of the IL-17 in the HFD-OVA mice decreased airway hyper-responsiveness (AHR) and airway inflammation compared to the HFD-OVA mice. Moreover, the administration of the anti-IL-17 antibody decreased the leptin/adiponectin ratio in the HFD-OVA but not the OVA mice. Co-administration of pravastatin and anti-IL-17 inhibited airway inflammation and AHR, decreased goblet cell numbers, and increased adipokine levels in obese asthmatic mice. CONCLUSIONS: These results suggest that the IL-17–leptin/adiponectin axis plays a key role in airway inflammation in obesity-related asthma. Our findings suggest a potential new treatment for IL-17 as a target that may benefit obesity-related asthma patients who respond poorly to typical asthma medications.

Pravastatin sodium inhibits the release and activity of human peripheral blood neutrophil elastase induced by lipopolysaccharide / 安徽医科大学学报

Objective To study the effects of pravastatin sodium on the release and activity of neutrophil elastase ( NE) in human neutrophile granulocyte induced by lipopolysaccharide( LPS) . Methods Human neutrophile gran-ulocyte were isolated by Ficoll density gradient centrifugation, neutrophils and intracellular azurophilic granules were identified by myeloperoxidase( MPO) staining, LPS stimulated degranulation of neutrophils. The MPO activity in the supernatant was measured by colorimetric assay to determine the appropriate stimulus time and concentration, and neutrophil was treated with pravastatin sodium after LPS stimulation. ELISA mothed was used to detect the cell culture supernatant of NE content and NE activity was detected by colorimetric method. Results The content and activity of NE in the supernatant were significantly increased after LPS stimulation. The NE in the supernatant of the cells treated with pravastatin was significantly lower( P＜0.05) . Conclusion Pravastatin sodium can reduce neutrophil degranulation induced by LPS stimulation and decrease the release and activity of NE.

Different Effects of Pravastatin on Preeclampsia-like Symptoms in Different Mouse Models / 中华医学杂志(英文版)

<p><b>Background</b>Pravastatin (Pra) exerts protective effects on preeclampsia. Preeclampsia is a multifactorial and pathogenic pathway syndrome. The present study compared the effects of Pra on clinical manifestations of preeclampsia in different pathogenic pathways.</p><p><b>Methods</b>Two different preeclampsia-like mouse models used in this study were generated with Nω-nitro-L-arginine methyl ester (L-NAME) and used lipopolysaccharide (LPS) from day 7 of gestation, respectively. Pra treatment was administered on day 2 after the models were established in each group (L-NAME + Pra, LPS + Pra, and Control + Pra, n = 8) or normal saline (NS) for the control group (L-NAME + NS, LPS + NS, and Control + NS, n = 8). Maternal weight, serum lipids, the histopathological changes, and lipid deposition in the liver and placenta were observed. The pregnancy outcomes were compared. The blood pressure analysis was carried out on repeated measurements of variance. Student's t-test was used for comparing the two groups. The enumeration data were compared by Chi-square test.</p><p><b>Results</b>The mean arterial pressure (MAP) and 24-h urinary protein in the L-NAME + NS and LPS + NS groups were significantly higher than the Control + NS group (F = 211.05 and 309.92 for MAP, t = 6.63 and 8.63 for 24-h urinary protein; all P < 0.05) and reduced in the L-NAME + Pra group as compared to the L-NAME + NS group (F = 208.60 for MAP, t = 6.77 for urinary protein; both P < 0.05). Urinary protein was decreased in the LPS + Pra group as compared to the LPS + NS group (t = 5.33; P < 0.05), whereas MAP had no statistical significance (F = 3.37; P > 0.05). Compared to the Control + NS group, the placental efficiency in the L-NAME + NS and LPS + NS groups decreased significantly (t = 3.09 and 2.89, respectively; both P < 0.05); however, no significant difference was observed in L-NAME + Pra and LPS + Pra groups (t = 1.37 and 0.58, respectively; both P > 0.05). Free fatty acid was elevated in the L-NAME + NS group as compared to the Control + NS group (t = 3.99; P < 0.05) at day 18 of pregnancy and decreased in the L-NAME + Pra group as compared to the L-NAME + NS group (t = 3.28; P < 0.05); however, no significant change was observed in the LPS model (F = 0.32; P > 0.05).</p><p><b>Conclusion</b>This study suggested that Pra affected the clinical manifestations differently in preeclampsia-like mouse models generated in various pathogenic pathways.</p>

Effects of metoprolol or/and pravastatin on the pharmacokinetics of metformin in rats / 药学学报

This study investigates the effects of metoprolol (METO) or/and pravastatin (PRAV) on the pharmacokinetics of metformin (METF) in rats. Twenty-eight male SD rats were divided into METF group, METF+METO group, METF+PRAV group and METF+METO+PRAV group. Blood samples were collected at 10, 20, 40, 60, 90, 120, 180, 240, 360, 480 and 600 min after oral administration of metformin, and concentration of metformin in plasma was determined by HPLC. Compared to the METF group, Cmax of metformin was significantly decreased (P0-t, t1/2 and V were significantly increased in the METF+METO group; t1/2 was significantly decreased in the METF+PRAV group; Cmax was significantly decreased and MRT0-t was significantly increased in the METF+METO+PRAV group. Compared to the METF+METO group, MRT0-t of metformin was significantly decreased in the METF+METO+PRAV group. Compared to the METF+PRAV group, Cmax of metformin was significantly decreased (P0-t, t1/2 and V were significantly increased in the METF+METO+PRAV group. There exist multiple drug interactions of metformin, metoprolol and pravastatin in rats.

Study on pravastatin for improving carotid atherosclerosis in patients type 2 diabetes mellitus complicating hypertension / 重庆医学

Objective To explore the effect of pravastatin on carotid atherosclerosis in the patients with type 2 diabetes mellitus (T2DM) complicating hypertension.Methods One hundred and six patients.with T2DM complicating hypertension treated in this hospital from April 2015 to April 2016 were selected and divided into the conventional treatment group (n=52) and pravastatin group (n=54).The patients of conventional treatment group were given the conventional therapy of diet control,reducing blood glucose,controlling hypertension,symptomatic and support treatment,while on the basis of conventional therapy the patients of pravastatin group were added with pravastatin.The carotid intima-medial thickness (IMT),detection rate of carotid atherosclerotic plaque and carotid plaque score were measured by ultrasound before and after the treatment in all cases.Meanwhile the levels of serum lipid and hyper sensitive C reactive protein (hs-CRP) were determined.Results The above indicators in the conventional treatment group had no statistically significant difference between before and after treatment (P＞0.05),but the IMT value,detection rate of carotid atherosclerotic plaque and carotid plaque score after treatment in the pravastatin group were decreased compared with before treatment,the levels of serum total cholesterol (TC),triacylglycerol (TG),low density lipoprotein cholesterol (LDL-C) and hs-CRP were also significantly reduced compared with before treatment,the differences were statistically significant (P＜0.05),moreover the above indicators after treatment in the pravastatin group were remarkably lower than those in the conventional treatment group (P＜0.05).There was no statistically significant difference in the incidence rate of adverse reactions between the two groups (P＞0.05).Conclusion Pravastatin can effectively and safely improve the carotid atherosclerosis degree in the patients with T2DM complicating hypertension.

Effect of inhaled pravastatin on acute lung inflammation in cigarette smoking-exposed rat / 安徽医科大学学报

Objective To investigate the effect of inhaled pravastatin on the acute inflammation of lung in smoked rats.Methods 32 male SD rats were randomly divided into four groups(n=8 per group),as the controls,cigarette-smoking exposure group,saline or pravastatin treatment groups.The rats in the control group were treated routinely,the other groups were exposed to cigarette smoking for one week.Rats in saline or pravastatin group were treated with saline or pravastatin inhalation respectively.During smoking exposure period rats were weighted before and after the treatment,executed at day eight,blood,bronchoalveolar lavage fluid(BALF),and lung tissue were collected.The morphological alternations of lung tissue were observed.Total cell numbers in BALF were counted.Enzyme-linked immunosorbent assay(ELISA) was used to detect the levels of serum IL-10 and IL-17 content.Results The increase of body weight of smoke-exposed rats were less than that of the controls.In smoking-exposed rats,acute inflammatory changes were remarkable in the lung.The total cell numbers in BALF and levels of IL-10 were increased significantly(P<0.05).These changes were mitigated in pravastatin treated rats and an IL-10/IL-17 rebalance was observed.Conclusion Inhalation of pravastatin sodium has a certain inhibitory effect on cigarette smoke-induced acute lung inflammation in rats.

Establishment of double-transfected MDCK Ⅱ cells expressing human organic anion transporting polypeptide 1B1 and multidrug resistance-associated protein 2 and identification of its functions / 复旦学报（医学版）

Objective To establish double-transfected Madin-Darby canine kidney (MDCK) [Ⅱ cells expressing human organic anion transporting polypeptide 1B1 (hOATP1B1) and multidrug resistanceassociated protein 2 (hMRP2)and to testify their functions,moreover,to study the transcellur transport of indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyltryptophan (1-MT) in the transfectants.Methods hOATP1B1/hMRP2 eukaryotic vectors pVITRO2-SLCO1B1-ABCC2 was obtained by genetic engineering method and then transfected into MDCK cells.Stably expressed MDCK cells were screened by using the geneticin G418.Real-time PCR,Western blot analysis and immuno fluorescent confocal microscopy were used to verify the proteins expression.Transport of the representative substrate pravastatin in different pH values and substrate concentrations and 1-MT were evaluated using the double transfectants.Results MDCK-OATP1B1/MRP2 was successfully established.Pravastatin displayed the optimal transcellular transport when pH value was 6.5.Transport of pravastatin demonstrated the concentration-dependent in the concertation range of 0) to 500 μmol/L.Transport of 1-MT showed no significant difference in MDCK cells and transfectants.Conclusions MDCK-OATP1B1/MRP2 was successful established;1-MT was not the substrate of OATP1B1 or MRP2 protein;and the eatablished double transfectant cell lines can be used to evaluate OATP1B1/MRP2-medicated transport of xenobiotics (e.g.new drug candidates) and endogenous compounds (e.g.bilirubin).

Pravastatin inhibits microRNA-155 expression and improves functions of lipopolysaccharide-treated human extravillous trophoblast cells / 中华围产医学杂志

Objective To investigate the effects ofpravastatin on the expression ofmicroRNA-155 (miR-155) and the functions of lipopolysaccharide (LPS)-treated extravillous trophoblast cells.Methods In vitro cultured HTR-8/SVneo cells were divided into the following groups:control group,enhanced plasmid with green fluoscent protein (pEGFP)-miR-155 group (transfected with green fluorescent protein-tagged miR-155),LPS group (treated with 100 ng/mL of LPS),miR-155 inhibitor+LPS group,pravastatin+LPS group (treated with 100 ng/mL of LPS following pretreatment with 12.50,25.00,50.00 and 100.00 μ g/ml of pravastatin),and pravastatin+pEGFP-miR-155 group (transfected with pEGFP-miR-155 following pretreatment with 50 μ g/ml of pravastatin).Levels of miR-155 in HTR-8/SVneo cells treated with different strategies were measured by real-time polymerase chain reaction.Expression of phosphorylated JunB (p-JunB) and p-FosB proteins was analyzed by Western blotting.Migration,invasion and apoptosis of HTR-8/SVneo cells were also analyzed.All data were analyzed with t test.Results (1) Compared with the control group,HTR-8/SVneo cells in the pEGFP-miR-155 group were characterized by shorter migration distance [(274.70± 18.82) vs (181.00±8.62) μ m],less transmembrane cells [(123.00±4.36) vs (63.00±6.08)] and enhanced apoptosis [(5.40± 0.68)％ vs (9.27±0.68)％] (all P＜0.05).(2) Compared with the LPS group,the miR-155 inhibitor+LPS group showed longer migration distance of HTR-8/SVneo cells [(166.30±5.07) vs (242.00±18.07) μm,P＜0.05],more transmembrane cells [(71.67±6.12) vs (109.00±7.81),P＜0.05] and decreased cell apoptosis [(14.40±1.69)％ vs (6.23± 0.44)％,P＜0.05].(3) Expression of miR-155 at mRNA level in the LPS group was increased as compared with that of the control group (1.65 0.07 vs 0.79±0.12,P＜0.05).Compared with the LPS group,pretreatment with 12.50,25.00,50.00 and 100.00 μ g/ml of pravastatin decreased the expression of miR-155 at mRNA level [(1.14±0.10),(1.02±0.10),(0.74±0.15) and (1.140.02)],especially at the concentration of 50 μμ g/ml (all P＜0.05).(4) Expression ofp-JunB and p-FosB proteins in the control,LPS and pravastatin (50 μ g/ml)+LPS groups were (0.33 ±0.06) vs (0.37±0.07),(1.22±0.20) vs (0.80±-0.13),and (0.31 ±0.02) vs (0.21 ±0.05),respectively,showing higher expression level in both p-JunB and p-FosB proteins in the LPS group compared with that of the other two groups (all P＜0.05).(5) Compared with the LPS group,the pravastatin (50 μμ g/ml)+LPS group showed increased migration distance [(166.30±5.07) vs (246.80± 13.42) μ m,P＜0.05],increased numbers of transmembrane cells [(71.67 ± 6.12) vs (95.33 ± 2.73),P＜0.05] and decreased cell apoptosis [(14.40± 1.69) vs (6.05 ± 0.35)％,P＜0.05].(6) Compared with the pEGFP-miR-155 group,the pravastatin (50.00.00 μμ g/mL)+pEGFP-miR-155 group showed longer migration distance [(197.50± 13.86) vs (275.80± 13.63) μ m,P＜0.05],more transmembrane cells [(52.67±5.49) vs (125.00±6.66),P＜0.05] and lower rate of cell apoptosis [(8.90± 1.00) vs (5.05±0.35)％,P＜0.05].Conclusions Pretreatment of extravillous trophoblast cells with pravastatin can protect them from apoptosis and loss of migratory and invasive abilities through inhibiting the activation of AP-1 and down-regulating the expression of miR-155,which may be a mechanism that inhibits the development of preeclampsia.

The Effect of Pravastatin on Insulin Resistance in Hyperglycemic Patients / 임상당뇨병

BACKGROUND: The effect of pravastatin on insulin resistance (IR) is controversial and poorly studied in prediabetes. METHODS: This study was performed in hyperglycemic patients at Saint Carollo Hospital from January 1, 2013 to December 31, 2015. Among them, we selected 40 patients (24 prediabetes and 16 new onset diabetes [NOD]) who had been treated with pravastatin 20 mg daily for 2 or 4 months and in whom fasting insulin and fasting glucose had been measured before and after administration of pravastatin. IR was defined as a fasting insulin level ≥ 12.94 µU/mL, homeostasis model for IR (HOMA-IR) ≥ 3.04 or quantitative insulin sensitivity check index (QUICKI) ≤ 0.32. RESULTS: Pravastatin treatment decreased total cholesterol and low-density lipoprotein cholesterol levels by 25.2% and 32.3% respectively (P = 0.000 for all), but did not affect fasting insulin level, HOMA-IR, or QUICKI in total, prediabetes, and NOD groups. Prevalence of IR was significantly different between prediabetes and NOD groups both before and after pravastatin treatment (0% versus 37.5%, P = 0.001), but pravastatin treatment did not affect the prevalence of IR in the prediabetes or NOD group. Fasting glucose level was not significantly different before and after pravastatin treatment in prediabetes (106.8 ± 6.4 mg/dL versus 103.8 ± 8.4 mg/dL, P = 0.223) but was significantly different in the NOD group (171.5 ± 70.1 mg/dL versus 124.4 ± 26.7 mg/dL, P = 0.017). CONCLUSION: Pravastatin treatment did not affect IR or fasting glucose level in hyperglycemic patients. Therefore, we suggest pravastatin can be prescribed to hypercholesterolemic patients with hyperglycemia.

Pravastatin induces cell cycle arrest and decreased production of VEGF and bFGF in multiple myeloma cell line / Pravastatina induz parada no ciclo celular e diminuição na produção de VEGF e bFGF em linhagem de Mieloma Multiplo

Abstract Multiple myeloma (MM) is a B cell bone marrow neoplasia characterized by inflammation with an intense secretion of growth factors that promote tumor growth, cell survival, migration and invasion. The aim of this study was to evaluate the effects of pravastatin, a drug used to reduce cholesterol, in a MM cell line.Cell cycle and viability were determinate by Trypan Blue and Propidium Iodide. IL6, VEGF, bFGF and TGFβ were quantified by ELISA and qRT-PCR including here de HMG CoA reductase. It was observed reduction of cell viability, increase of cells in G0/G1 phase of the cell cycle and reducing the factors VEGF and bFGF without influence on 3-Methyl-Glutaryl Coenzyme A reductase expression.The results demonstrated that pravastatin induces cell cycle arrest in G0/G1 and decreased production of growth factors in Multiple Myeloma cell line.

Resumo O Mieloma Múltiplo é uma neoplasia de linfócitos B da medula óssea, caracterizada por inflamação com uma intensa secreção de fatores de crescimento que promovem o aumento do volume do tumor, sobrevivência celular, migração e invasão. O objetivo deste estudo foi avaliar os efeitos da pravastatina, uma droga usada para reduzir o colesterol, em um linhagem de MM. O ciclo celular e viabilidade foram determinadas por Trypan Blue e iodeto de propídio. IL6, VEGF, bFGF e TGF foram quantificadas por ELISA e qRT-PCR, incluindo aqui de HMG CoA redutase. Observou-se a redução da viabilidade das células, aumento de células na fase G0/G1 do ciclo celular e redução no VEGF e bFGF, sem influência na expressão da enzima 3-Metil-Glutaril Coenzima A redutase. Os resultados demonstraram que a pravastatina induz parada no ciclo celular em G0/G1 e diminuição da produção de fatores de crescimento em várias linhas de células de Mieloma.

Effect of different concentrations of pravastatin treatment on macrophage polarity in mice / 重庆医学

Objective To study the effect of different concentrations of pravastatin treatment on macrophage polarity in mice .Methods The mice bone marrow sources of macrophages were cultured in vitro ,with the 0μmol/L sodium pravastatin group as control ,by giving 10 ,25 ,50μmol/L sodium pravastatin to conduct the drug intervention for 24 h .The enzyme linked immunosor-bent assay (ELISA) was used to detect the secretion of interleukin 10 (IL-10) and IL-12;the flow cytometry instrument was used to detect cell membrane CD16/32 ,CD206 expression;real time quantitative polymerase chain reaction (RT-qPCR) was adopted to detect toll-like receptor 4 (TLR4) ,myeloid differentiation factor 88 (MyD88) ,interferon regulatory factor 5 (IRF5) mRNA expres-sion .Results After the intervention of pravastatin sodium on macrophages ,as the pravastatin sodium concentration increase ,the expression of IL-12 and CD16/32 was decline ,while the expression of IL-10 and CD206 was risen ,which was accompanied by TLR4 ,MyD88 ,IRF5 mRNA expression down regulatyion ,and a dose dependent manner .Conclusion Sodium pravastatin promote the polarization of macrophages toward an anti-inflammatory macrophage phenotype (M2) ,this effect may be related with the anti-inflammatory effect of sodium pravastatin .