Pitavastatin

匹伐他汀
  • 文章类型: Journal Article
    背景:尽管有有效的策略,EGFR突变肺癌的耐药性仍是一个挑战.代谢重编程是肿瘤耐药的主要机制之一。一类被称为“他汀类药物”的药物抑制脂质胆固醇代谢,广泛用于心血管疾病患者。先前的研究也证明了其在接受EGFR-TKI治疗的肺癌患者中改善治疗效果的能力。因此,他汀类药物对肺癌靶向耐药的影响仍有待研究。
    方法:长时间接触吉非替尼导致从亲本敏感细胞系(PC9)中出现耐药肺癌细胞系(PC9GR),表现出传统的EGFR突变。CCK-8测定用于评估各种浓度的匹伐他汀对细胞增殖的影响。进行RNA测序以检测差异表达的基因及其相关途径。为了检测蛋白质的表达,进行蛋白质印迹。通过异种移植小鼠模型在体内评估匹伐他汀的抗肿瘤活性。
    结果:低剂量维持诱导PC9吉非替尼耐药菌株。细胞培养和动物相关研究验证了匹伐他汀对肺癌细胞增殖的抑制作用,促进细胞凋亡,抑制了EGFR-TKIs的获得性耐药。KEGG通路分析表明,相对于PC9细胞,在PC9GR细胞中hippo/YAP信号通路被激活,匹伐他汀对YAP的表达有抑制作用。用YAPRNA干扰,pAKT,pBAD和BCL-2表达降低,而BAX表达则增加。因此,YAP下调显著增加吉非替尼耐药肺癌细胞的凋亡并降低其存活率。SC79增加pAKT后,吉非替尼诱导的YAP下调细胞凋亡减少,细胞存活率提高。机械上,匹伐他汀的这些作用与YAP途径有关,从而抑制下游AKT/BAD-BCL-2信号通路。
    结论:本研究为临床应用降脂药物匹伐他汀增强肺癌患者对EGFR-TKI药物的敏感性、缓解耐药提供了分子依据。
    BACKGROUND: Despite effective strategies, resistance in EGFR mutated lung cancer remains a challenge. Metabolic reprogramming is one of the main mechanisms of tumor drug resistance. A class of drugs known as \"statins\" inhibit lipid cholesterol metabolism and are widely used in patients with cardiovascular diseases. Previous studies have also documented its ability to improve the therapeutic impact in lung cancer patients who receive EGFR-TKI therapy. Therefore, the effect of statins on targeted drug resistance to lung cancer remains to be investigated.
    METHODS: Prolonged exposure to gefitinib resulted in the emergence of a resistant lung cancer cell line (PC9GR) from the parental sensitive cell line (PC9), which exhibited a traditional EGFR mutation. The CCK-8 assay was employed to assess the impact of various concentrations of pitavastatin on cellular proliferation. RNA sequencing was conducted to detect differentially expressed genes and their correlated pathways. For the detection of protein expression, Western blot was performed. The antitumor activity of pitavastatin was evaluated in vivo via a xenograft mouse model.
    RESULTS: PC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC9 cells, and the YAP expression was inhibited by pitavastatin administration. With YAP RNA interference, pAKT, pBAD and BCL-2 expression was decreased, while BAX expression as increased. Accordingly, YAP down-regulated significantly increased apoptosis and decreased the survival rate of gefitinib-resistant lung cancer cells. After pAKT was increased by SC79, apoptosis of YAP down-regulated cells induced by gefitinib was decreased, and the cell survival rate was increased. Mechanistically, these effects of pitavastatin are associated with the YAP pathway, thereby inhibiting the downstream AKT/BAD-BCL-2 signaling pathway.
    CONCLUSIONS: Our study provides a molecular basis for the clinical application of the lipid-lowering drug pitavastatin enhances the susceptibility of lung cancer to EGFR-TKI drugs and alleviates drug resistance.
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  • 文章类型: Journal Article
    肺癌是全球癌症相关死亡的最常见原因,由多种因素引起,包括高脂肪饮食(HFD)。CD36,一种脂肪酸受体,与代谢相关的疾病密切相关,包括心血管疾病和癌症。然而,CD36在HFD加速非小细胞肺癌(NSCLC)中的作用尚不清楚.在体内,我们饲喂C57BL/6J野生型(WT)和CD36敲除(CD36-/-)小鼠正常食物或HFD在有或没有匹伐他汀的2周前皮下注射LLC1细胞。体外,用游离脂肪酸(FFA)处理A549和NCI-H520细胞以模拟HFD情况以探索潜在机制。我们发现HFD在体内促进LLC1肿瘤生长,FFA增加A549和NCI-H520细胞的细胞增殖和迁移。降脂药匹伐他汀抑制了增强的细胞或肿瘤生长,减少脂质积累。更重要的是,我们发现,NSCLC患者的血浆可溶性CD36(sCD36)水平高于健康患者.与WT小鼠相比,在CD36-/-小鼠中LLC1细胞的增殖被大大抑制,在HFD组中被匹伐他汀进一步抑制。在分子水平上,我们发现CD36抑制,用匹伐他汀或质粒,通过AKT/mTOR途径降低增殖和迁移相关蛋白的表达。一起来看,我们证明匹伐他汀或其他抑制剂抑制CD36表达可能是NSCLC治疗的可行策略.
    Lung cancer is the most common cause of cancer-related deaths worldwide and is caused by multiple factors, including high-fat diet (HFD). CD36, a fatty acid receptor, is closely associated with metabolism-related diseases, including cardiovascular disease and cancer. However, the role of CD36 in HFD-accelerated non-small-cell lung cancer (NSCLC) is unclear. In vivo, we fed C57BL/6J wild-type (WT) and CD36 knockout (CD36-/-) mice normal chow or HFD in the presence or absence of pitavastatin 2 weeks before subcutaneous injection of LLC1 cells. In vitro, A549 and NCI-H520 cells were treated with free fatty acids (FFAs) to mimic HFD situation for exploration the underlying mechanisms. We found that HFD promoted LLC1 tumor growth in vivo and that FFAs increased cell proliferation and migration in A549 and NCI-H520 cells. The enhanced cell or tumor growth was inhibited by the lipid-lowering agent pitavastatin, which reduced lipid accumulation. More importantly, we found that plasma soluble CD36 (sCD36) levels were higher in NSCLC patients than those in healthy ones. Compared to that in WT mice, the proliferation of LLC1 cells in CD36-/- mice was largely suppressed, which was further repressed by pitavastatin in HFD group. At the molecular level, we found that CD36 inhibition, either with pitavastatin or plasmid, reduced proliferation- and migration-related protein expression through the AKT/mTOR pathway. Taken together, we demonstrate that inhibition of CD36 expression by pitavastatin or other inhibitors may be a viable strategy for NSCLC treatment.
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  • 文章类型: Journal Article
    氨基糖苷类抗生素对内耳毛细胞的不可逆损伤有助于感觉神经性听力损失的形成。匹伐他汀(PTV),一种3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂,据报道可以发挥神经保护作用。然而,其在氨基糖苷类诱导的听力损失中的作用尚不清楚.这项研究的目的是调查有益的影响,以及PTV对新霉素诱导的耳毒性的作用机制。我们发现PTV显着减少了新霉素刺激后小鼠耳蜗外植体的毛细胞损失,并促进了听觉HEI-OC1细胞的存活。我们还观察到,新霉素增加的听觉脑干反应阈值通过小鼠PTV预处理显着降低。此外,PTV通过抑制PERK/eIF2α/ATF4信号传导来减弱新霉素诱导的毛细胞内质网应激。此外,我们发现PTV抑制了RhoA/ROCK/JNK信号通路,在HEI-OC1细胞中被新霉素刺激激活。总的来说,我们的结果表明,PTV可能是一种有前景的抗氨基糖苷类所致耳毒性的治疗剂.
    Irreversible injury to inner ear hair cells induced by aminoglycoside antibiotics contributes to the formation of sensorineural hearing loss. Pitavastatin (PTV), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been reported to exert neuroprotective effects. However, its role in aminoglycoside-induced hearing loss remains unknown. The objectives of this study were to investigate the beneficial effects, as well as the mechanism of action of PTV against neomycin-induced ototoxicity. We found that PTV remarkably reduced hair cell loss in mouse cochlear explants and promoted auditory HEI-OC1 cells survival after neomycin stimulation. We also observed that the auditory brainstem response threshold that was increased by neomycin was significantly reduced by pretreatment with PTV in mice. Furthermore, neomycin-induced endoplasmic reticulum stress in hair cells was attenuated by PTV treatment through inhibition of PERK/eIF2α/ATF4 signaling. Additionally, we found that PTV suppressed the RhoA/ROCK/JNK signal pathway, which was activated by neomycin stimulation in HEI-OC1 cells. Collectively, our results showed that PTV might serve as a promising therapeutic agent against aminoglycoside-induced ototoxicity.
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  • 文章类型: Journal Article
    尿液中的挥发性有机化合物(VOCs)是乳腺癌的潜在生物标志物。以前,我们的研究小组通过分析小鼠尿液中的VOCs来研究乳腺癌,并确定了一组能够监测肿瘤进展的VOCs.然而,一个未解决的问题是,随着时间的推移,是否可以类似地利用VOC来监测抗肿瘤治疗的疗效.在这里,用匹伐他汀在高(8mg/kg)和低(4mg/kg)浓度下治疗荷瘤小鼠的亚群,通过固相微萃取(SPME)和气相色谱-质谱(GC-MS)分析尿液。先前使用X射线和micro-CT分析进行的研究表明,以8mg/kg的剂量给予匹伐他汀对乳腺肿瘤具有保护作用,而4mg/kg治疗不能抑制肿瘤诱导的损伤。使用化学计量学分析将接受匹伐他汀治疗的小鼠的VOC与先前分析的健康对照和荷瘤小鼠进行比较。这表明,在健康对照的方向上,用高浓度匹伐他汀治疗的小鼠与未治疗的荷瘤小鼠有显著差异。用低浓度处理的小鼠显示出相对于健康对照的显著差异,并且反映了荷瘤未处理的小鼠。这些结果表明,随着时间的推移,尿VOC可以准确且无创地预测匹伐他汀治疗的疗效。
    Volatile organic compounds (VOCs) in urine are potential biomarkers of breast cancer. Previously, our group has investigated breast cancer through analysis of VOCs in mouse urine and identified a panel of VOCs with the ability to monitor tumor progression. However, an unanswered question is whether VOCs can be exploited similarly to monitor the efficacy of antitumor treatments over time. Herein, subsets of tumor-bearing mice were treated with pitavastatin at high (8 mg/kg) and low (4 mg/kg) concentrations, and urine was analyzed through solid-phase microextraction (SPME) coupled with gas chromatography-mass spectrometry (GC-MS). Previous investigations using X-ray and micro-CT analysis indicated pitavastatin administered at 8 mg/kg had a protective effect against mammary tumors, whereas 4 mg/kg treatments did not inhibit tumor-induced damage. VOCs from mice treated with pitavastatin were compared to the previously analyzed healthy controls and tumor-bearing mice using chemometric analyses, which revealed that mice treated with pitavastatin at high concentrations were significantly different than tumor-bearing untreated mice in the direction of healthy controls. Mice treated with low concentrations demonstrated significant differences relative to healthy controls and were reflective of tumor-bearing untreated mice. These results show that urinary VOCs can accurately and noninvasively predict the efficacy of pitavastatin treatments over time.
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  • 文章类型: Journal Article
    据报道,他汀类药物可抑制自发性高血压大鼠的血管重塑。然而,他汀类药物匹伐他汀对高血压诱导的内皮炎症和损伤的可能作用仍有待完全阐明。本研究旨在评价匹伐他汀对HUVEC损伤和炎症的影响。HUVEC暴露于血管紧张素(Ang)II,有或没有匹伐他汀共同治疗,之后通过逆转录定量PCR和蛋白质印迹检测MAPK7表达。MAPK7表达在HUVEC中通过短发夹RNA转染而沉默,然后用或不用匹伐他汀进行AngII治疗。细胞活力,炎症,活性氧(ROS)的产生,一氧化氮(NO)的产生和细胞凋亡,然后通过使用细胞检测试剂盒-8,ELISA,商业相应的试剂盒和TUNEL染色,分别。Western印迹还用于确定内皮NO合酶和内皮素1的蛋白表达以及参与凋亡的蛋白。本研究的结果表明,MAPK7在AngII诱导的内皮细胞中的表达水平降低,用匹伐他汀治疗后逆转。匹伐他汀通过激活MAPK7逆转了AngII诱导的细胞活力降低,逆转了AngII诱导的HUVECs炎症因子和ROS水平增加以及凋亡。匹伐他汀治疗除了通过MAPK7激活增加AngII诱导的HUVEC中内皮NO合酶和内皮素-1的表达外,还增加了NO的产生。总的来说,本研究的结果表明,匹伐他汀治疗可以保留MAPK7的表达,从而减轻AngII诱导的血管内皮细胞炎症和损伤。因此,本研究结果可能有助于阐明匹伐他汀对血管内皮细胞炎症和损伤的作用机制。
    Statins have been reported to suppress vascular remodeling in rats with spontaneous hypertension. However, the possible effects of the statin pitavastatin on hypertension-induced endothelial inflammation and injury remain to be fully elucidated. The present study aimed to evaluate the effects of pitavastatin on HUVEC injury and inflammation. HUVECs were exposed to angiotensin (Ang) II with or without pitavastatin co-treatment, after which MAPK7 expression was detected via reverse transcription-quantitative PCR and western blotting. MAPK7 expression was additionally silenced in HUVECs via transfection with short hairpin RNA, followed by Ang II treatment with or without pitavastatin. Cell viability, inflammation, reactive oxygen species (ROS) production, nitric oxide (NO) production and cell apoptosis were then measured by using Cell Conting Kit-8, ELISA, commercial corresponding kits and TUNEL staining, respectively. Western blotting was also used to determine the protein expression of endothelial NO synthase and endothelin 1, and the proteins involved in apoptosis. Results of the present study demonstrated that the expression levels of MAPK7 in Ang II-induced endothelial cells were decreased, which was reversed following treatment with pitavastatin. Pitavastatin reversed the Ang II-induced reduction in cell viability and reversed the Ang II-induced increase in inflammatory factor and ROS levels and apoptosis in HUVECs by activating MAPK7. Treatment with pitavastatin also increased the production of NO in addition to increasing the expression of endothelial NO synthase and endothelin-1 in Ang II-induced HUVECs through MAPK7 activation. Collectively, results from the present study demonstrated that treatment with pitavastatin preserves MAPK7 expression to alleviate Ang II-induced vascular endothelial cell inflammation and injury. Therefore, findings of the present study may help to elucidate the mechanisms underlying the effects of pitavastatin on vascular endothelial cell inflammation and injury.
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  • 文章类型: Journal Article
    An increasing number of works have highlighted the importance of metal implants surface modification in enhancing bone defect healing through the synergistic osteogenesis-angiogenesis regulation. Studies have shown that pitavastatin has the effect of promoting osteogenesis and angiogenesis. However, how to prepare pitavastatin functionalized implants and how pitavastatin regulates the synergies of osteogenesis and angiogenesis around implants as well as the related mechanisms remain unclear. In the present study, multilayer films with osteogenic and angiogenic properties were constructed on pure titanium substrates via the layer-by-layer assembly of pitavastatin-loaded β-cyclodextrin grafted chitosan and gelatin. In vitro experiments demonstrated that locally applied pitavastatin could dramatically enhance osteogenic potential of mesenchymal stem cells (MSCs) and angiogenic potential of endothelial cells (ECs). Moreover, pitavastatin loaded multilayer films could regulate the paracrine signaling mediated crosstalk between MSCs and ECs, and indirectly increase the angiogenic potential of MSCs and osteogenic potential of ECs via multiple paracrine signaling. The results of subcutaneous and femur implantation confirmed that locally released pitavastatin had potentially triggered a chain of biological events: mobilizing endogenous stem cells and ECs to the implant-bone interface, in turn facilitating coupled osteogenesis and angiogenesis, and eventually enhancing peri-implant osseointegration. This study enlarges the application scope of pitavastatin and provides an optional choice for developing a multifunctional bioactive coating on the surfaces of mental implants.
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  • 文章类型: Journal Article
    背景:银杏是治疗高血脂的传统中药。银杏黄酮醇和萜内酯在非酒精性脂肪性肝病(NAFLD)中具有降脂作用。然而,银杏黄酮醇和萜内酯在NAFLD中的药代动力学尚未明确.
    目的:研究银杏叶提取物(EGB)和NAFLD对肝细胞有机阴离子转运多肽(Oatp)1b2的影响,并评估EGB活性成分在NAFLD大鼠体内的药代动力学。
    方法:雄性大鼠饲喂高脂饮食诱导NAFLD模型。在用3.6、10.8和32.4mg/kgEGB治疗2或4周后,在NAFLD大鼠中研究了EGB活性成分的药代动力学特征。研究了NAFLD和EGB对匹伐他汀全身暴露的影响,Oatp1b2的探针底物。在hOATP1B1-HEK293细胞中测试了银杏黄酮醇和萜内酯对OATP1B1介导的3H-ES摄取的抑制作用。
    结果:在口服3.6-32.4mg/kg的EGB后,NAFLD大鼠的银杏内酯和黄酮醇的血浆暴露呈剂量依赖性增加。银杏内酯A的半衰期,B,C,白果内酯(2-3小时)短于槲皮素,山奈酚,和异鼠李素(约20小时)。由于大鼠肝脏中Oatp1b2表达增加,NAFLD使血浆匹伐他汀暴露减少约50%。EGB的增加(从3.6到32.4mg/kg)使匹伐他汀的Cmax和AUC0-t增加了1.8-3.2和1.3-3.0倍,分别。在hOATP1B1-HEK293细胞中,山奈酚和异鼠李素有助于抑制OATP1B1介导的3H-ES摄取,IC50值为3.28±1.08μM和46.12±5.25μM,分别。
    结论:NAFLD和EGB可以单独或联合改变肝脏摄取转运体Oatp1b2的活性。在这项研究中发现的药代动力学草药-疾病-药物相互作用将有助于告知EGB或Oatp1b2底物的临床施用。
    BACKGROUND: Ginkgo biloba L. is a traditional Chinese medicine for hyper lipaemia. Ginkgo flavonols and terpene lactones are responsible for the lipid-lowering effect in non-alcoholic fatty liver disease (NAFLD). However, the pharmacokinetics of ginkgo flavonols and terpene lactones in NAFLD was not clarified.
    OBJECTIVE: To investigate the effects of Ginkgo biloba L. leaves extracts (EGB) and NAFLD on hepatocyte organic anion transporting polypeptide (Oatp)1b2, and to assess the pharmacokinetics of EGB active ingredients in NAFLD rats.
    METHODS: Male rats were fed with a high-fat diet to induce NAFLD models. The pharmacokinetic characteristics of EGB active ingredients were studied in NAFLD rats after two or four weeks of treatment with 3.6, 10.8, and 32.4 mg/kg EGB. The effects of NAFLD and EGB were investigated on the systemic exposure of pitavastatin, a probe substrate of Oatp1b2. The inhibitory effects of ginkgo flavonols and terpene lactones on OATP1B1-mediated uptake of 3H-ES were tested in hOATP1B1-HEK293 cells.
    RESULTS: The plasma exposure of ginkgolides and flavonols in NAFLD rats increased in a dose-dependent manner following oral administration of EGB at 3.6-32.4 mg/kg. The half-lives of ginkgolides A, B, C, and bilobalide (2-3 h) were shorter than quercetin, kaempferol, and isorhamnetin (approximately 20 h). NAFLD reduced the plasma pitavastatin exposure by about 50 % due to the increased Oatp1b2 expression in rat liver. Increased EGB (from 3.6 to 32.4 mg/kg) substantially increased the Cmax and AUC0-t of pitavastatin by 1.8-3.2 and 1.3-3.0 folds, respectively. In hOATP1B1-HEK293 cells, kaempferol and isorhamnetin contributed to the inhibition of OATP1B1-mediated uptake of 3H-ES with IC50 values of 3.28 ± 1.08 μM and 46.12 ± 5.25 μM, respectively.
    CONCLUSIONS: NAFLD and EGB can alter the activity of hepatic uptake transporter Oatp1b2 individually or in combination. The pharmacokinetic herb-disease-drug interaction found in this research will help inform the clinical administration of EGB or Oatp1b2 substrates.
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  • 文章类型: Journal Article
    背景:视网膜的过度血管生成是许多眼部疾病中导致失明的不可逆原因的关键组成部分。匹伐他汀是一种降胆固醇药物,用于降低心血管疾病的风险。各种研究已经显示匹伐他汀对血管生成的影响,但是结论是矛盾的。尚未揭示匹伐他汀对视网膜血管生成的影响。这项研究使用视网膜微血管内皮细胞(RMEC)研究了临床相关浓度的匹伐他汀对视网膜血管生成的影响及其潜在机制。
    方法:使用体外视网膜血管生成模型测定匹伐他汀对视网膜血管生成的影响,内皮细胞迁移,附着力,扩散,和细胞凋亡测定。使用免疫印迹和应力纤维染色进行机制研究。
    结果:匹伐他汀以与血管内皮生长因子(VEGF)和脂多糖(LPS)相似的方式刺激RMEC的毛细血管网络形成。匹伐他汀还增加了RMEC迁移,对Matrigel的粘附力,增长,和生存。匹伐他汀与VEGF或LPS的组合在刺激RMEC的生物学活性方面比单独的VEGF或LPS更有效。提示匹伐他汀可以增强VEGF和LPS对视网膜血管生成的刺激作用。匹伐他汀以不依赖3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶的方式作用于RMEC。相比之下,匹伐他汀通过促进VEGF的分泌激活促血管生成微环境,并通过多种机制刺激视网膜血管生成,包括激活RhoA介导的途径,诱导粘着斑复合物的形成,ERK通路的激活。
    结论:我们的工作提供了关于匹伐他汀通过与甲羟戊酸途径无关的多种机制在视网膜中的促血管生成作用的临床前证据。
    BACKGROUND: Excessive angiogenesis of the retina is a key component of irreversible causes of blindness in many ocular diseases. Pitavastatin is a cholesterol-lowering drug used to reduce the risk of cardiovascular diseases. Various studies have shown the effects of pitavastatin on angiogenesis but the conclusions are contradictory. The effects of pitavastatin on retinal angiogenesis have not been revealed. This study investigated the effects of pitavastatin at clinically relevant concentrations on retinal angiogenesis and its underlying mechanisms using retinal microvascular endothelial cells (RMECs).
    METHODS: The effects of pitavastatin on retinal angiogenesis were determined using in vitro model of retinal angiogenesis, endothelial cell migration, adhesion, proliferation, and apoptosis assays. The mechanism studies were conducted using immunoblotting and stress fiber staining.
    RESULTS: Pitavastatin stimulated capillary network formation of RMECs in a similar manner as vascular endothelial growth factor (VEGF) and lipopolysaccharide (LPS). Pitavastatin also increased RMEC migration, adhesion to Matrigel, growth, and survival. The combination of pitavastatin with VEGF or LPS was more effective than VEGF or LPS alone in stimulating biological activities of RMECs, suggesting that pitavastatin can enhance the stimulatory effects of VEGF and LPS on retinal angiogenesis. Pitavastatin acted on RMECs in a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase-independent manner. In contrast, pitavastatin activated pro-angiogenic microenvironment via promoting the secretion of VEGF and stimulated retinal angiogenesis via multiple mechanisms including activation of RhoA-mediated pathways, induction of focal adhesion complex formation, and activation of ERK pathway.
    CONCLUSIONS: Our work provides a preclinical evidence on the pro-angiogenic effect of pitavastatin in retina via multiple mechanisms that are irrelevant to mevalonate pathway.
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  • 文章类型: Journal Article
    Pancreatic cancer is the seventh leading cause of cancer-related deaths globally. Metformin is the standard first-line of treatment for hyperglycemia in Type 2 diabetes, whereas pitavastatin is a cholesterol-lowering drug used to prevent cardiovascular diseases. Both these agents evidently exert anticancer effects on pancreatic cancer; however, it remains unclear whether cotreatment using them has additive or synergistic anticancer effects on pancreatic cancer. Thus, we herein used the ASPC-1 and PANC-1 cells and treated them with metformin and/or pitavastatin. We performed the cell viability assay, transwell migration assay, and cell cycle analysis using flow cytometry. Western blotting was used to determine protein levels. We found that cotreatment with metformin (30 mM) and pitavastatin (10 μM) significantly reduced cell viability; caused G0/G1 cell cycle arrest; upregulated the expression levels of Bax, PCNA, cleaved PARP-1, cleaved caspase-3, LC3 II, and p27 Kip1 /p21Cip1 ; and inhibited cell migration. The combination index value for cell viability indicated a synergistic interaction between metformin and pitavastatin. Moreover, cotreating the cells with metformin (30 mM) and pitavastatin (10 μM) could preserve mitochondrial function, activate AMPK, and inhibit PI3K/mTOR than treatment with metformin or pitavastatin alone. These findings clearly indicated that metformin plus pitavastatin had a synergistic anticancer effect on pancreatic cancer cells, potentially caused due to the activation of AMPK and inhibition of PI3K/mTOR signaling. Altogether, our results provide that use of metformin plus pitavastatin maybe serve as a chemotherapeutic agent for human pancreatic cancer in future.
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  • 文章类型: Journal Article
    已经证明匹伐他汀可以显着降低低密度脂蛋白(LDL)胆固醇(LDL-C),但其对脂蛋白亚组分和氧化低密度脂蛋白(oxLDL)的影响尚未确定。本研究的目的是研究匹伐他汀对未经治疗的冠状动脉粥样硬化(AS)患者的LDL和高密度脂蛋白(HDL)以及oxLDL亚组分的潜在影响。这项研究招募了36名受试者。其中,18例AS患者给予匹伐他汀2mg/d,持续8周,18例未治疗的健康受试者作为对照。血浆脂质分布,分别在基线和8周时测定脂蛋白亚组分和循环oxLDL。结果表明,匹伐他汀治疗确实不仅降低了LDL-C,总胆固醇(TC),甘油三酯(TG)和载脂蛋白B(ApoB)水平,和增加HDL胆固醇(HDL-C),但也降低了所有LDL亚组分的胆固醇浓度以及中间和小LDL亚组分的百分比。同时,匹伐他汀可降低血浆oxLDL水平。此外,匹伐他汀治疗后,oxLDL和LDL-C以及LDL亚组分之间的相关性更为密切.我们得出的结论是,中等剂量的匹伐他汀治疗不仅可以降低LDL-C和oxLDL的浓度,而且可以改善AS患者的LDL亚组分。
    It has been demonstrated that pitavastatin can significantly reduce low-density lipoprotein (LDL) cholesterol (LDL-C), but its impact on lipoprotein subfractions and oxidized low-density lipoprotein (oxLDL) has not been determined. The aim of the present study was to investigate the potential effects of pitavastatin on subfractions of LDL and high-density lipoprotein (HDL) as well as oxLDL in untreated patients with coronary atherosclerosis (AS). Thirty-six subjects were enrolled in this study. Of them, 18 patients with AS were administered pitavastatin 2 mg/day for 8 weeks and 18 healthy subjects without therapy served as controls. The plasma lipid profile, lipoprotein subfractions and circulating oxLDL were determined at baseline and 8 weeks respectively. The results showed that pitavastatin treatment indeed not only decreased LDL-C, total cholesterol (TC), triglycerides (TG) and apolipoprotein B (ApoB) levels, and increased HDL cholesterol (HDL-C), but also reduced the cholesterol concentration of all of the LDL subfractions and the percentage of intermediate and small LDL subfractions. Meanwhile, pitavastatin could decrease plasma oxLDL levels. Furthermore, a more close correlation was found between oxLDL and LDL-C as well as LDL subfractions after pitavastatin treatment. We concluded that a moderate dose of pitavastatin therapy not only decreases LDL-C and oxLDL concentrations but also improves LDL subfractions in patients with AS.
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