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991.
Hanan Galski Tamar Oved-Gelber Masha Simanovsky Philip Lazarovici Michael M. Gottesman Arnon Nagler 《Biochemical pharmacology》2013
The TNF-related apoptosis-inducing ligand (TRAIL or Apo2L) preferentially cause apoptosis of malignant cells in vitro and in vivo without severe toxicity. Therefore, TRAIL or agonist antibodies to the TRAIL DR4 and DR5 receptors are used in cancer therapy. However, many malignant cells are intrinsically resistant or acquire resistance to TRAIL. It has been previously proposed that the multidrug transporter P-glycoprotein (Pgp) might play a role in resistance of cells to intrinsic apoptotic pathways by interfering with components of ceramide metabolism or by modulating the electrochemical gradient across the plasma membrane. In this study we investigated whether Pgp also confers resistance toward extrinsic death ligands of the TNF family. To this end we focused our study on HeLa cells carrying a tetracycline-repressible plasmid system which shuts down Pgp expression in the presence of tetracycline. Our findings demonstrate that expression of Pgp is a significant factor conferring resistance to TRAIL administration, but not to other death ligands such as TNF-α and Fas ligand. Moreover, blocking Pgp transport activity sensitizes the malignant cells toward TRAIL. Therefore, Pgp transport function is required to confer resistance to TRAIL. Although the resistance to TRAIL-induced apoptosis is Pgp specific, TRAIL itself is not a direct substrate of Pgp. Pgp expression has no effect on the level of the TRAIL receptors DR4 and DR5. These findings might have clinical implications since the combination of TRAIL therapy with administration of Pgp modulators might sensitize TRAIL resistant tumors. 相似文献
992.
993.
Suriguga Xiao-Fei LiYang Li Chun-Hong YuYi-Ran Li Zong-Chun Yi 《Toxicology and applied pharmacology》2013
Catechol is widely used in pharmaceutical and chemical industries. Catechol is also one of phenolic metabolites of benzene in vivo. Our previous study showed that catechol improved erythroid differentiation potency of K562 cells, which was associated with decreased DNA methylation in erythroid specific genes. Catechol is a substrate for the catechol-O-methyltransferase (COMT)-mediated methylation. In the present study, the role of COMT in catechol-enhanced erythroid differentiation of K562 cells was investigated. Benzidine staining showed that exposure to catechol enhanced hemin-induced hemoglobin accumulation and induced mRNA expression of erythroid specific genes in K562 cells. Treatment with catechol caused a time- and concentration-dependent increase in guaiacol concentration in the medium of cultured K562 cells. When COMT expression was knocked down by COMT shRNA expression in K562 cells, the production of guaiacol significantly reduced, and the sensitivity of K562 cells to cytotoxicity of catechol significantly increased. Knockdown of COMT expression by COMT shRNA expression also eliminated catechol-enhanced erythroid differentiation of K562 cells. In addition, the pre-treatment with methyl donor S-adenosyl-l-methionine or its demethylated product S-adenosyl-l-homocysteine induced a significant increase in hemin-induced Hb synthesis in K562 cells and the mRNA expression of erythroid specific genes. These findings indicated that O-methylation catalyzed by COMT acted as detoxication of catechol and involved in catechol-enhanced erythroid differentiation of K562 cells, and the production of S-adenosyl-l-homocysteine partly explained catechol-enhanced erythroid differentiation. 相似文献
994.
目的:探讨VEGF165-BMSCs复合NanoBCP陶瓷支架材料异位成骨的可能性.方法:将VEGF165转染至BMSCs,并将其接种于已制备的多孔NanoBCP支架材料培养后植入裸鼠皮下,进行组织学观察和分析.结果:转染后的BMSCs表达VEGF165mRNA和蛋白,NanoBCP材料比BCP的表面和孔隙内有更多的新骨形成,并发现有血管和多核巨细胞的分布.结论:NanoBCP孔隙结构良好,具有一定的生物可降解性,用于骨组织工程支架材料异位成骨性能良好,具有潜在的应用价值. 相似文献
995.
996.
Cristina Martín-Sabroso Daniel Filipe Tavares-Fernandes Juan Ignacio Espada-García Ana Isabel Torres-Suárez 《International journal of pharmaceutics》2013
In this work a protocol to validate analytical procedures for the quantification of drug substances formulated in polymeric systems that comprise both drug entrapped into the polymeric matrix (assay:content test) and drug released from the systems (assay:dissolution test) is developed. This protocol is applied to the validation two isocratic HPLC analytical procedures for the analysis of dexamethasone phosphate disodium microparticles for parenteral administration. Preparation of authentic samples and artificially “spiked” and “unspiked” samples is described. Specificity (ability to quantify dexamethasone phosphate disodium in presence of constituents of the dissolution medium and other microparticle constituents), linearity, accuracy and precision are evaluated, in the range from 10 to 50 μg mL−1 in the assay:content test procedure and from 0.25 to 10 μg mL−1 in the assay:dissolution test procedure. The robustness of the analytical method to extract drug from microparticles is also assessed. The validation protocol developed allows us to conclude that both analytical methods are suitable for their intended purpose, but the lack of proportionality of the assay:dissolution analytical method should be taken into account. 相似文献
997.
D. Le Broc-Ryckewaert R. Carpentier E. Lipka S. Daher C. Vaccher D. Betbeder C. Furman 《International journal of pharmaceutics》2013
Taxanes, including paclitaxel, are anti-cancer drugs approved for the treatment of prostate cancer but which have limited clinical application due to their hydrophobicity, their low therapeutic index and the emergence of chemoresistance. These side effects may be avoided through the use of new drug delivery systems such as nanoparticles, and paclitaxel-loaded PLGA nanoparticles up to 200 nm in size have shown encouraging results. As it is known that size affects the tissular penetration and distribution of tumors via the enhanced permeability and retention effect, so nanoparticles smaller than 100 nm are potentially interesting vehicles for improving paclitaxel delivery and efficacy. 相似文献
998.
目的考察草果挥发油、白豆蔻挥发油、砂仁挥发油单独和组合使用对磷酸川芎嗪(ligustrazine phosphate,LP)黏胶分散型透皮贴剂在离体裸鼠皮肤的促渗作用。方法采用E 100、丁二酸等制备LP黏胶分散型透皮贴剂;采用改良的Franz扩散池进行裸鼠体外透皮吸收实验;采用HPLC法进行接受液中药物含量测定。结果加入挥发油及氮酮促渗剂的LP贴剂的12 h累积渗透量(Q12)都有所增加,质量浓度为3%草果挥发油、5%白豆蔻挥发油、7%砂仁挥发油、1.5%草果挥发油+2.5%白豆蔻挥发油、2.5%白豆蔻挥发油+3.5%砂仁挥发油及3%氮酮组的Q12分别是(0.972±0.121)、(0.953±0.243)、(0.876±0.138)、(0.932±0.192)、(0.667±0.171)、(0.862±0.139)mg cm-2;增渗倍数(ER)分别是1.638、1.596、1.489、1.596、1.149、1.489;与阴性对照组比较,3%草果挥发油、5%白豆蔻挥发油、1.5%草果挥发油+2.5%白豆蔻挥发油有明显的促渗作用(P〈0.01)。结论各种质量浓度单一及组合的挥发油对贴剂中LP都具有一定促渗作用,以3%草果挥发油的促渗作用最好。 相似文献
999.
《Expert opinion on pharmacotherapy》2013,14(5):795-811
Background: Hyperparathyroidism (HPT), characterised by increased parathyroid hormone (PTH) secretion and parathyroid hyperplasia, can be caused by physiologic defects in the parathyroid gland (primary HPT [PHPT]) or as a consequence of declining renal function (secondary HPT [SHPT]). Objective: To review the safety and efficacy of cinacalcet in the treatment of SHPT and PHPT. Methods: Studies indexed in NLM/PubMed investigating the safety, efficacy, and pharmacokinetics of cinacalcet for PHPT and SHPT and supporting preclinical evidence. Results/conclusion: Recent evidence has demonstrated the efficacy of the calcimimetic cinacalcet in the treatment of PHPT and SHPT. Compared with traditional therapies such as vitamin D sterols and phosphate binders, cinacalcet treatment can allow an increased proportion of patients with SHPT to improve Kidney Disease Outcomes Quality Initiative (KDOQI?) Bone Metabolism and Disease laboratory parameter target attainment. Recent evidence suggests that improvements in these biochemical parameters with cinacalcet can translate into improved morbidity and mortality. Cinacalcet lowers PTH and calcium in patients following renal transplantation, and also normalises serum calcium in patients with PHPT. Ongoing studies are focusing and future studies are likely to focus on the effect of cinacalcet on clinical outcomes and on novel strategies for the integration of cinacalcet with traditional therapies to improve serum PTH and mineral metabolism control. 相似文献
1000.
《Expert opinion on pharmacotherapy》2013,14(10):1475-1488
Introduction: Hyperphosphataemia is common in chronic kidney disease (CKD), particularly in the late stages and is associated with secondary hyperparathyroidism, abnormal bone mineralisation and increased cardiovascular morbidity/mortality. At present, there is a range of phosphate binders designed to keep serum phosphate at normal or near normal levels. Colestilan is a new binder that offers additional actions that may afford further benefits over simply lowering phosphate.Areas covered: This paper reviews the pharmacology and clinical data currently available in the use of colestilan to treat hyperphosphataemia in CKD stage 5 patients on dialysis.Expert opinion: Available phosphate binders lower serum phosphorus levels to a clinically relevant extent. The balance between the risks and the potential benefits associated with each agent must be considered when choosing a binder. Calcium-based binders can lead to hypercalcaemia and/or positive calcium balance and cardiovascular calcification. Like sevelamer, colestilan is not absorbed and there is no evidence of any risk of hypercalcaemia. In addition, a significant lowering of low-density lipoprotein-cholesterol, similar to simvastatin, a reduction in plasma uric acid and a reduction in high glycosylated haemoglobin values suggest additional beneficial actions that may convert to reductions in mortality. 相似文献