塞来昔布联合氟尿嘧啶对胰腺癌细胞株SW1990生长抑制作用及其机制研究

目的:研究选择性环氧化酶-2(COX-2)抑制剂塞来昔布联合氟尿嘧啶对胰腺癌细胞株SW1990生长的抑制作用,并对其机制进行初步探讨.方法:实验分为对照组、氟尿嘧啶组、塞来昔布组及两药联合组,将不同浓度的药物分剐作用于胰腺癌细胞株SW1990,MTT法检测各组细胞的生长抑制率,并探索产生最佳细胞生长抑制作用的药物浓度.流式细胞仪检测不同药物作用对肿瘤细胞周期的影响.RT-PCR检测各组细胞Survivin的表达情况.结果:MTT法显示氟尿嘧啶、塞来昔布均能抑制SW1990的生长,且细胞的存活率都随药物浓度的增加而降低.两药联合组对细胞生长的抑制作用更明显.流式细胞仪检测结果显示塞来昔布组、氟尿嘧啶组及两药联合组细胞较对照组G0/G1期细胞比例明显增加,S期和G2/M期细胞比例明显减少.RT-PCR结果显示氟尿嘧啶组、塞来昔布组、联合组都可下调Survivin的表达,以联合组最为明显.结论:塞来昔布联合氟尿嘧啶对胰腺癌SW1990细胞的生长具有抑制作用,其机制可能与下调Survivin的表达从而诱导细胞的凋亡和细胞周期的停滞有关.     

塞来昔布对直肠癌HCA-7 细胞放射敏感性的实验研究

目的:观察环氧合酶-2(COX-2)抑制剂塞来昔布对直肠癌HCA-7细胞株的放射敏感性及探讨其机制。方法:采用MTT法检测塞来昔布作用不同时间对直肠癌HCA-7细胞株增殖的影响,计算出塞来昔布的半数抑制浓度IC50;HCA-7细胞克隆形成实验用于检测塞来昔布对HCA-7细胞的放射敏感性,并绘制存活曲线;流式细胞仪(FCM)测定塞来昔布对HCA-7的细胞周期的影响。结果:塞来昔布对HCA-7细胞株的抑制率随时间的延长而升高,48h的IC50是40.19μmol/L;照射组+药物组的SF2、D0、Dq、SER较单纯照射组均有所下降。塞来昔布使HCA-7细胞发生G2和M期阻滞,并抑制S期的比例。结论:塞来昔布能增加直肠癌HCA-7细胞的放射敏感性。     

塞来昔布诱导HCT-116结肠癌细胞G2/M阻滞

目的:研究选择性COX-2抑制剂塞来昔布诱导结肠癌细胞株HCT-116细胞周期阻滞的作用及其可能的机制。方法:应用流式细胞仪检测塞来昔布对HCT-116细胞周期的影响,定量PCR检测细胞周期素cyclinB1及COX-2 mRNA表达水平,Western-Blot检测细胞周期素cyclinB1的蛋白水平。结果:塞来昔布诱导HCT-116细胞G2/M阻滞的作用呈剂量依赖性,塞来昔布在mRNA及蛋白水平下调HCT-116细胞的cyclinB1。结论:塞来昔布能在体外抑制HCT-116细胞的增殖,诱导G2/M的阻滞,其作用与下调细胞周期素cyclinB1有关。     

基于气相色谱-质谱法测定塞来昔布中磺酸酯类基因毒性杂质的残留量

为了建立一种测定塞来昔布原料药及其制剂中塞来昔布磺酸甲酯和塞来昔布磺酸乙酯残留量的气相色谱-质谱(gas chromatography-mass spectrometry,GC-MS)分析方法,采用碘化钠衍生-顶空进样,将两杂质衍生成碘甲烷和碘乙烷,DB624毛细管色谱柱(60 m×0.25 mm,1.4μm)分离,氦气为载气,质谱检测器检测。塞来昔布磺酸甲酯和塞来昔布磺酸乙酯均在10～500 ng·m L^-1浓度范围内线性关系良好;回收率在80.87%～106.52%,RSD小于10%;定量限均为10 ng·m L^-1。所有塞来昔布样品中均未检测出塞来昔布磺酸甲酯和塞来昔布磺酸乙酯杂质。该方法简便准确,可用于塞来昔布中塞来昔布磺酸甲酯和塞来昔布磺酸乙酯2个磺酸酯类基因毒性杂质的检测。     

分析塞来昔布与不同剂量艾瑞昔布治疗axSpA的效果及对骨代谢的影响

目的:探究塞来昔布和2种剂量艾瑞昔布治疗中轴脊柱关节炎(axSpA)的效果及对患者骨代谢的影响。方法:选取我院96例axSpA患者为研究对象,采用随机数字表法分为A组、B组、C组各32例。A组给予0.2 g/d艾瑞昔布治疗,B组给予0.4 g/d艾瑞昔布治疗C组给予0.4 g/d塞来昔布治疗。比较3组治疗前及治疗12周后疾病活动性[C反应蛋白(CRP)、红细胞沉降率(ESR)、Bath强直性脊柱炎疾病活动指数(BASDAI)]、躯体活动度(踝间距、腰椎侧弯度)、功能状态[Bath强直性脊柱炎功能指数(BASFI)、加拿大脊柱骨关节研究协会评分系统(SPARCC)]、骨代谢[血清骨形成发生蛋白-2(BMP-2)、血管内皮生长因子(VEGF)、Dickkopf相关蛋白1(DKK-1)]差异,并记录3组治疗期间不良反应发生情况。结果:治疗12周后,3组疾病活动性(CRP、ESR、BASDAI)、功能状态(BASFI、SPARCC)、骨代谢(BMP-2、VEGF、DKK-1)均较治疗前降低(P<0.05),躯体活动度(踝间距及左右侧腰椎侧弯度)则较治疗前升高(P<0.05);但B组及C组组间比较,差异无统计学意义(P>0.05),而A组上述指标变化幅度低于B组及C组(P<0.05)。3组治疗期间不良反应发生情况比较,差异均无统计学意义(P>0.05)。结论:较高剂量(0.4 g/d)艾瑞昔布疗效明显优于较低剂量(0.2 g/d),不良反应也未增加,且0.4 g/d艾瑞昔布及同剂量塞来昔布治疗axSpA具有相似的疗效及安全性,适用于临床治疗。     

双氯芬酸钠与塞来昔布治疗类风湿关节炎的疗效及对心血管的影响研究

目的:探讨双氯芬酸钠和塞来昔布治疗类风湿关节炎的临床疗效及用药安全性。方法:将我院2011年1月-2012年1月门诊收治的98例类风湿性关节炎患者随机分为对照组和观察组,每组49例。对照组给予双氯芬酸钠治疗,观察组给予塞来昔布治疗,观察两组临床治疗效果及心血管不良事件的发生情况。结果:观察组总有效率为91.84%显著高于对照组的75.51%,两组比较差异具有统计学意义(P0.05);观察组ESR及CRP分别为(110.65±7.28)mm/h和(10.42±0.98)mg/L显著低于治疗前和对照组,比较差异具有统计学意义(P0.05);观察组心血管不良事件发生率为8.16%显著低于对照组的20.41%,两组比较差异具有统计学意义(P0.05)。结论:塞来昔布治疗类风湿关节炎具有较好的临床疗效,可有效改善患者疼痛、僵硬或功能受限等症状,且心血管不良事件发生率低,值得临床进一步推广和应用。     

双氯芬酸钠与塞来昔布治疗类风湿关节炎的疗效及对心血管的影响研究

目的：探讨双氯芬酸钠和塞来昔布治疗类风湿关节炎的临床疗效及用药安全性。方法：将我院2011 年1 月-2012 年1 月门诊收治的98 例类风湿性关节炎患者随机分为对照组和观察组,每组49 例。对照组给予双氯芬酸钠治疗,观察组给予塞来昔布治疗,观察两组临床治疗效果及心血管不良事件的发生情况。结果：观察组总有效率为91.84%显著高于对照组的75.51%,两组比较差异具有统计学意义（P〈0.05）;观察组ESR及CRP 分别为（110.65± 7.28）mm/h 和（10.42± 0.98）mg/L显著低于治疗前和对照组,比较差异具有统计学意义（P〈0.05）;观察组心血管不良事件发生率为8.16%显著低于对照组的20.41%,两组比较差异具有统计学意义（P〈0.05）。结论：塞来昔布治疗类风湿关节炎具有较好的临床疗效,可有效改善患者疼痛、僵硬或功能受限等症状,且心血管不良事件发生率低,值得临床进一步推广和应用。     

盐酸氨基葡萄糖联合塞来昔布对膝关节骨性关节炎的临床疗效观察

目的:观察盐酸氨基葡萄糖联合塞来昔布治疗膝关节骨性关节炎的效果及对不同程度关节炎Lequesne评分的影响,为关节炎的临床治疗提供参考。方法:选取2012年6月至2014年3月我院收治的膝关节骨性关节炎患者60例,根据治疗方法不同,将所选患者分为观察组和对照组,每组30例。对照组患者给予盐酸氨基葡萄糖单药治疗,观察组患者给予盐酸氨基葡萄糖和塞来昔布联合治疗。观察两种治疗方案的不良反应发生率,比较两组患者治疗前后的Lequesne评分。结果:对照组患者不良反应的发生率为26.67%,观察组为23.33%,差异无统计学意义(P0.05)。两组患者治疗后的Lequesne评分均低于治疗前,且观察组患者Lequesne评分显著低于对照组,差异具有统计学意义(P0.05)。观察组不同程度膝关节骨性关节炎患者的Lequesne评分均显著低于对照组,差异具有统计学意义(P0.05)。结论:盐酸氨基葡萄糖联合塞来昔布治疗膝关节骨性关节炎具有良好的临床效果,应进一步推广应用。     

塞来昔布对慢性低O_2高CO_2大鼠肺动脉高压的影响及其机制研究

目的：探讨塞来昔布对慢性低O2高CO2大鼠肺动脉高压的作用。方法：将SD大鼠分为正常对照组,慢性低O2高CO2组,慢性低O2高CO2＋塞来昔布组。用电镜、放免等方法,观察各组大鼠肺动脉平均压、颈动脉平均压、肺细小动脉显微结构、血浆和肺匀浆血栓素B2（TXB2）及6-酮-前列腺素F1α（6-keto-PGF1α）含量的变化。结果：①慢性低O2高CO2组平均肺动脉压（mPAP）比正常组显著升高,塞来昔布组的mPAP比慢性低O2高CO2组显著升高,3组间平均颈动脉压（mCAP）比较差异无显著性。②慢性低O2高CO2组与正常对照组相比血浆和肺匀浆TXB2浓度、TXB2/6-keto-PGF1α比值显著增高,6-keto-PGF1α浓度显著下降;塞来昔布组与慢性低O2高CO2组相比血浆和肺匀浆TXB2浓度无明显变化、TXB2/6-keto-PGF1α显著升高,6-keto-PGF1α显著下降。③光镜下慢性低O2高CO2组与正常组相比,肺细小动脉管壁面积/管总面积（WA/TA）和肺细小动脉中膜厚度（PAMT）均显著增高。塞来昔布组与慢性低O2高CO2组相比WA/TA和PAMT显著增高。④电镜下慢性低O2高CO2组大鼠肺细小动脉内皮细胞吞饮小泡增多,血管壁增厚,中膜平滑肌细胞增生,纤维细胞增多,肺泡II型上皮细胞微绒毛脱落;塞来昔布组中膜平滑肌细胞增大、增多,胞浆肌丝丰富,平滑肌细胞间隙增宽,肺泡隔胶原纤维增生明显。结论：塞来昔布可能有加重慢性低O2高CO2性肺动脉高压和肺血管结构重建倾向,过度抑制COX-2,使TXA2/PGI2比值升高可能是其作用机制之一。     

液相色谱-串联质谱法同时测定大鼠血浆中阿霉素和塞来昔布

目的:建立同时测定大鼠血浆中阿霉素和塞来昔布的液相色谱-串联质谱(LC/MS/MS)方法,研究这两种药物联合应用的药代动力学.方法:大鼠尾静脉注射阿霉素和塞来昔布,眼眶取血并抗凝,离心分离血浆,采用乙酸乙酯提取血浆中的阿霉素和塞来昔布,N2吹干乙酸乙酯,残留物用50μL甲醇溶解,取20μL用于LC/MS/MS分析.结果:用LC/MS/MS法检测大鼠血浆中阿霉素和塞来昔布的线性范围为1-800ng/mL,日内、日间精密度(RSD)均小于15%,检测血浆低、中、高三个浓度(8、50、500ng/mL)阿霉素的回收率分别为101.2%、95.1%和91.4%,检测血浆低、中、高三个浓度(8、50、500ng/mL)塞来昔布的回收率分别为105.6%、106.8%和93.7%.大鼠尾静脉注射5.8mg/kg阿霉素和3.8mg/kg塞来昔布的半衰期分别为2.3 h和3.6h,曲线下面积分别为670 ng·h·mL-1和1480ng·h·mL-1.结论:建立的方法灵敏、准确、快速,适甩于阿霉素和塞来昔布的药代动力学研究.     

Apoptosis: molecular mechanisms

Apoptosis is a genetically programmed cell death that is required for morphogenesis during embryogenic development and for tissue homeostasis in adult organisms. In most cases, apoptosis involves cytochrome c release from mitochondria. In the cytosol, cytochrome c combines with APAF-1 in the presence of ATP to activate caspase-9 that, in turn, activates effectors caspases such as caspase-3. Bcl-2 and related proteins control cytochrome c release from the mitochondria whereas IAP (for Inhibitor of APoptosis) molecules modulate the activity of caspases. Plasma membrane receptors such as Fas (CD95, APO-1), characterized by a so-called "death domain" in their cytoplasmic domain, can activate the caspase cascade through adaptator molecules such as FADD (Fas-Associated protein with a Death Domain). Dysregulation of the apoptotic machinery plays a role in the pathogenesis of various diseases and molecules involved in cell death pathways are potential therapeutic targets in immunologic, neurologic, cancer, infectious and inflammatory diseases.     

Immunogenic tumor cell death induced by chemoradiotherapy: molecular mechanisms and a clinical translation

Chemoradiotherapy can induce immunogenic cell death, triggering danger signals such as high-mobility group box 1 protein, and resulting in T-cell immunity. This concept can potentially be harnessed for clinical therapy to enhance tumor-specific immunity. There is however limited information to translate this theory directly in a clinical setting. In this review, we will discuss and summarize molecular and cellular mechanisms underlying immunogenic tumor cell death induced by chemoradiotherapy, with emphasis on a clinical translation.     

Renal cell apoptosis induced by nephrotoxic drugs: cellular and molecular mechanisms and potential approaches to modulation

Apoptosis plays a central role not only in the physiological processes of kidney growth and remodeling, but also in various human renal diseases and drug-induced nephrotoxicity. We present in a synthetic fashion the main molecular and cellular pathways leading to drug-induced apoptosis in kidney and the mechanisms regulating it. We illustrate them using three main nephrotoxic drugs (cisplatin, gentamicin, and cyclosporine A). We discuss the main regulators and effectors that have emerged as key targets for the design of therapeutic strategies. Novel approaches using gene therapy, antisense strategies, recombinant proteins, or compounds obtained from both classical organic and combinatorial chemistry are examined. Finally, key issues that need to be addressed for the success of apoptosis-based therapies are underlined.     

The molecular mechanisms of vulpinic acid induced programmed cell death in melanoma

Molecular Biology Reports - Malignant melanoma is an aggressive skin tumor with a rapidly increasing incidence and there is not yet a successful treatment strategy. Vulpinic acid (VA) is derived...     

Apoptosis induced by selenium in human glioma cell lines

Several studies have shown that selenium can inhibit tumorigenesis in tissues. However, little is known about the mechanism and the effect of selenium on DNA, especially in brain tumor cells. In this study we examined the biological effect of selenium on human glioma cell lines (A172 and T98G). Selenium exhibited an antiproliferative effect on these cell lines (and induced the typical ladder pattern of DNA fragmentation commonly found in apoptosis), which were prevented by catalase. Few effects of selenium on NTI4 fibroblasts were found. These findings demonstrate that selenium may induce, by apoptosis, cell death of human glioma cell lines, which are resulting from free radical oxygen forming.     

Function and molecular mechanisms of neuroendocrine cells in prostate cancer

Benign prostate contains luminal epithelial cells, basal cells and a minor component of neuroendocrine cells whose function may be to regulate the growth, differentiation and secretory function of the prostate gland. Neuroendocrine (NE) cells are also present in prostate cancer (PC), and many studies have shown that their number increases in high-grade and high-stage tumors, particularly in hormonally treated and hormone-refractory (androgen independent) PC. Unlike the non-neuroendocrine secretory-type PC cells, NE cells lack androgen receptor and are likely androgen independent. Therefore it is conceivable that hormonal therapy for advanced or metastatic prostate cancer, which consists of inhibiting androgen production or blocking androgen function, will not eliminate NE cancer cells. Instead, these cells may be enriched after the therapy and they may establish paracrine networks to stimulate androgen-independent proliferation of PC, leading to tumor recurrence. This article reviews the major functions of NE cells in PC, including stimulation of cancer proliferation and invasion, apoptosis resistance and angiogenesis. It also discusses molecular pathways involved in NE differentiation and the effectors of the NE cells.     

HIV介导的细胞凋亡

细胞凋亡是多细胞生物的一种生理性细胞死亡 ,它和坏死性细胞死亡是两种不同的细胞死亡形式 ,细胞凋亡是细胞内在的有规律的机制引起的 ,它可由细胞内部因素和外部刺激所诱导 ,细胞凋亡有其固有的形态特点 ,这种“自杀”行动对机体的正常发育和新陈代谢都是必要的 ,有助于维持组织稳态 ,对于机体是有利的。如细胞凋亡异常将会给机体带来各种病理后果。另外由于细胞凋亡的可诱导性 ,就为疾病的治疗提供了一条新思路。近年来发现 ,ＨＩＶ病毒也参与了细胞凋亡的诱导和抑制 ,在这些过程中相关的病毒基因的表达和相应蛋白质的合成起着关键性的作…