CXCR4拮抗剂对三阴性乳腺癌MDA MB 231细胞增殖和凋亡的影响及机制研究

摘 要 目的：探讨趋化因子基质细胞衍生因子 1受体（CXCR4）拮抗剂（AMD3100）对三阴性乳腺癌MDA MB 231细胞增殖和凋亡的影响及机制。 方法: 设MCF10A细胞组、三阴性乳腺癌MDA MB 231细胞组、氟尿嘧啶组(8.0 μg·ml-1)、CXCR4拮抗剂低、高剂量组(4.0,8.0 μg·ml-1),测定各组癌细胞的细胞活力、单克隆形成数目、细胞凋亡率、穿膜孔数,及三阴性乳腺癌MDA MB 231细胞基质细胞衍生因子1（SDF 1）、CXCR4、半胱氨酸蛋白酶 3（caspase 3）、半胱氨酸蛋白酶 6（caspase 6）、血管内皮生长因子（VEGF ）mRNA、蛋白水平。 结果: 与MCF10A细胞组比较,MDA MB 231细胞组吸光度（A）值、存活率水平、细胞克隆形成数目、穿膜数、SDF 1、CXCR4、VEGF mRNA及蛋白表达水平显著升高,细胞凋亡率、caspase 3、caspase 6 mRNA及蛋白表达水平显著降低（P<0.05）。与MDA MB 231细胞组比较,氟尿嘧啶组、CXCR4拮抗剂低、高剂量组的A值、存活率水平、细胞克隆形成数目、穿膜数、SDF 1、CXCR4、VEGF mRNA及蛋白表达水平显著降低,细胞凋亡率、caspase 3、caspase 6 mRNA及蛋白表达水平显著升高（P<0.05）。与氟尿嘧啶组比较,CXCR4拮抗剂低剂量组的A值、存活率水平、细胞克隆形成数目、穿膜数、SDF 1、CXCR4、VEGF mRNA及蛋白表达水平显著升高,细胞凋亡率、caspase 3、caspase 6 mRNA及蛋白表达水平显著降低（P<0.05）;CXCR4拮抗剂高剂量组差异无统计学意义（P>0.05）。 结论: AMD3100能抑制三阴性乳腺癌MDA MB 231细胞增殖、侵袭,诱导其凋亡;其机制与AMD3100能特异性阻断三阴性乳腺癌MDA MB 231细胞 SDF 1、CXCR4 mRNA及蛋白的表达水平,导致其SDF 1/CXCR4信号传导受阻有关。     

小檗碱调节己糖激酶Ⅱ抑制乳腺癌细胞糖酵解的作用研究

摘 要 目的：研究小檗碱对乳腺癌细胞糖酵解的干预作用及对己糖激酶Ⅱ的影响。方法: 分别采用人乳腺癌MDA MB 231,MCF 7细胞株,通过MTT实验, 考察小檗碱对乳腺癌细胞增殖的抑制作用,检测小檗碱干预后乳腺癌细胞中葡萄糖消耗及乳酸含量,评价小檗碱对乳腺癌细胞糖酵解的影响;检测乳腺癌细胞中ATP及NAD+/NADH含量,评价乳腺癌细胞能量供应情况;通过检测己糖激酶Ⅱ活性及蛋白定量,明确小檗碱对乳腺癌细胞己糖激酶的影响。结果: 小檗碱对人乳腺癌细胞株MDA MB 231,MCF 7细胞增殖,具有明显抑制作用,并呈浓度依赖性;小檗碱可以明显降低不同乳腺癌细胞株中葡萄糖消耗及乳酸含量,中高剂量组相较于对照组差异有统计学意义(P<0.05);同时相较于对照组,中高剂量组可明显降低细胞ATP含量,升高NAD+/NADH含量(P<0.05);此外小檗碱可以抑制乳腺癌细胞己糖激酶Ⅱ活性及其蛋白含量。结论: 小檗碱可以明显抑制乳腺癌细胞增殖,并抑制乳腺癌细胞糖酵解,降低其能量供应,同时明显抑制乳腺癌细胞中己糖激酶Ⅱ的表达。     

乳腺癌患者超说明书用药方案的评价分析

摘 要 目的：对乳腺癌患者治疗方案中符合说明书和超说明书用药分别进行有效率、安全性、经济性评价。 方法: 根据药品说明书将1 206例次住院乳腺癌患者分为超说明书用药组和符合说明书用药组。依据《中国抗癌协会乳腺癌诊治指南与规范（2017版）》和《NCCN乳腺癌临床实践指南（2017版）》进行治疗方案评价,有效性评价按照实体瘤的反应评价标准（RECIST）评价,不良事件评价按照CTACE4.03标准,经济性评价包括住院费、药费和抗肿瘤药物费用分析。 结果: 超说明书用药组有效率高于符合说明书用药组（100% vs. 83.53%,P<0.05）;超说明书用药组的低蛋白血症、白细胞降低、中性粒细胞降低、碱性磷酸酶升高、γ 谷氨酰胺转肽酶升高、胆红素升高发生率高于符合说明书用药组（P<0.05或P<0.01）;符合说明书用药组患者抗肿瘤药物费用、总药费、住院费均明显低于超说明书用药组（P<0.01）。 结论: 超说明书用药组的有效率高于符合说明书用药组,但治疗费用和不良反应发生率均明显高于符合说明书用药组。     

降低曲妥珠单抗使用时间对HER-2阳性乳腺癌患者影响的系统评价

摘 要 目的：系统评价降低曲妥珠单抗使用时间对人类表皮生长因子受体2（HER-2）阳性乳腺癌患者的影响。方法：计算机检索PubMed、Embase、the Cochrane Library（2018年5期）、Clinicaltrial.gov、SinoMed、CNKI、WanFang Data和VIP数据库，搜集曲妥珠单抗不同给药疗程治疗HER-2阳性乳腺癌患者的随机对照试验（RCTs），检索时限均为建库至2018年5月。由两位研究人员独立进行文献筛选、数据提取和偏倚风险评价后，采用RevMan 5.3软件进行Meta分析。 结果：共纳入4个RCTs，包括9 466例患者，Meta分析结果显示，与对照组（6个月组）相比，试验组（12个月组）因心脏毒性提前停药[Peto OR=2.49，95%CI（1.83，3.39），P＜0.000 01]、心功能障碍[Peto OR=1.50，95%CI（1.23，1.83），P＜0.000 1]、LVEF＜50% [Peto OR=1.39，95%CI（1.14，1.70），P=0.001]的发生率更高，差异有统计学意义。两组在有效率与死亡率方面的差异无统计学意义（P＞0.05）。结论：当前证据表明，缩短曲妥珠单抗的使用时间，并未降低治疗效果，但却可以降低心脏毒性。受纳入研究数量和质量的影响，上述结论尚需大样本高质量临床研究予以证实。     

氢吗啡酮静脉自控镇痛对乳腺癌术后疼痛的控制作用及对患者血清5-HT和hs-CRP的影响

摘 要 目的： 探讨氢吗啡酮静脉自控镇痛（PCIA）对乳腺癌术后疼痛的控制作用和安全性,及其对患者血清5 羟色胺（5-HT）和超敏C反应蛋白（hs-CRP）的影响。 方法: 行改良根治术治疗的乳腺癌患者100例随机分为舒芬太尼组和氢吗啡酮组各50例。术后舒芬太尼组给予舒芬太尼PCIA,氢吗啡酮组给予氢吗啡酮PCIA。分别应用视觉模拟评分法(VAS)、Ramsay评分于术后2,6,12,18,24 h评估观察患者镇痛和镇静效果,记录两组患者24h PCIA泵自动进药量、按压次数、实际有效进药次数,以及两组药品不良反应发生情况;分别于术后2h和术后24h检测血清5-HT和hs-CRP水平。结果: 氢吗啡酮组患者术后12h、18h和24h 的VAS评分和Ramsay评分均明显低于舒芬太尼组(P＜0.05);术后24 h自动进药量、按压次数、实际有效进药次数均明显低于舒芬太尼组(P＜0.05)。两组患者术后24 h血清5-HT和hs-CRP水平均较前显著升高(P＜0.05),而氢吗啡酮组术后24 h血清5-HT和hs-CRP水平低于舒芬太尼组(P＜0.05)。两组患者不良反应发生率差异无统计学意义（P＞0.05）。 结论: 乳腺癌术后应用氢吗啡酮PCIA,具有良好的镇痛和镇静作用,且能有效降低5-HT、hs-CRP水平,安全性较好。     

金黄散外敷联合吲哚美辛治疗急性痛风性关节炎临床观察

摘 要 目的：观察金黄散外敷联合吲哚美辛治疗急性痛风性关节炎（AGA）的临床疗效和安全性。方法：58例初发AGA患者随机分为两组。对照组给予吲哚美辛治疗,观察组在对照组基础上外敷金黄散。两组疗程均为7 d。观察两组患者的临床疗效、关节症状改善和实验室指标恢复情况及药品不良反应。结果：观察组总有效率为93.10%,明显高于对照组的72.41%(P＜0.05)。总体疗效比较,观察组优于对照组（P＜0.01）。治疗后,两组患者的关节疼痛、肿胀和活动受限评分及红细胞沉降率(ESR)、白细胞计数（WBC）和血尿酸（BUA）水平均较治疗前下降(P＜0.01);且观察组患者症状评分及实验室指标水平均优于对照组(P＜0.05 和P＜0.01)。两组药品不良反应症状均较轻微,发生率差异无统计学意义（P＞0.05）。结论：金黄散外敷联合吲哚美辛治疗AGA能有效改善关节症状,降低血尿酸及炎症指标水平,疗效显著。     

神经节苷酯辅助治疗急性脑梗死患者的疗效及对其血清hs-CRP、TNF-α的影响

摘 要 目的： 探讨神经节苷脂钠治疗急性脑梗死患者的疗效及对其血清高敏C反应蛋白（hs-CRP）、肿瘤坏死因子α（TNF-α）的影响。方法: 急性脑梗死患者216例随机分为观察组与对照组,每组108例。对照组患者予常规治疗,观察组患者在对照组基础上加用神经节苷脂注射液100 mg加入0.9%氯化钠注射液250 ml,ivd,qd。两组疗程均为14 d。评价两组临床疗效,比较两组患者治疗前后神经功能缺损程度评分（NDS）、日常生活活动量评分,以及血清hs-CRP和TNF-α水平变化。观察两组药品不良反应发生情况。结果: 观察组治疗总有效率为90.7%,明显高于对照组的71.3%（P＜0.05）。治疗后,观察组NDS评分较前明显降低,而ADL评分较前明显提高（P＜0.05）,且与对照组比较,差异均有统计学意义（P＜0.05）;而对照组患者治疗前后NDS及ADL评分无明显变化（P＞0.05）。两组患者治疗后血清hs-CRP和TNF-α水平均较治疗前明显降低（P＜0.05）,且观察组血清hs-CRP和TNF-α水平明显低于对照组（P＜0.05）。治疗期间两组患者均未见药品不良反应发生。结论: 神经节苷脂钠辅助治疗急性脑梗死疗效良好,能显著降低患者血清hs-CRP和TNF-α水平,改善患者NDS及ADL评分,且安全性好,值得在临床上进一步推广应用。     

保妇康栓治疗宫颈柱状上皮异位疗效及对子宫颈组织ICMI-1mRNA、TGF-β1m RNA及炎性细胞因子水平的影响

摘 要 目的： 探讨保妇康栓治疗宫颈柱状上皮异位的疗效及对子宫颈组织细胞间黏附分子1（ICMI 1）、转化生长因子SymbolbA@1（TGF SymbolbA@1）mRNA表达以及炎性细胞因子的影响。方法: 宫颈柱状上皮异位患者102例随机分为观察组和对照组,每组51例。观察组给予保妇康栓治疗,对照组给予冷冻治疗。均连续治疗7 d。观察两组临床疗效和不良反应情况,比较两组患者治疗前后子宫颈组织ICMI 1 mRNA和TGF SymbolbA@1 mRNA表达及血清炎性细胞因子水平变化。结果: 观察组总有效率为94.12%,明显优于对照组（P＜0.05）。两组治疗后ICMI 1 mRNA和TGF SymbolbA@1 mRNA均较治疗前明显降低（P＜0.05）,且观察组明显低于对照组（P＜0.05）。对照组治疗前后白介素 6（IL 6）和白介素 1（IL 1）无明显变化（P＞0.05）;观察组治疗后IL 6和IL 1较治疗前明显降低（P＜0.05）,且低于对照组（P＜0.05）。两组治疗前后月经期和月经周期无明显变化,未见不良反应发生。结论: 保妇康能有效治疗宫颈柱状上皮异位,降低宫颈柱状上皮异位患者子宫组织ICMI-1mRNA、TGF-β1m RNA表达以及血清炎性细胞因子水平。     

不同剂型桂枝葛根汤治疗颈性眩晕的疗效比较

摘 要 目的：观察不同剂型桂枝葛根汤治疗颈性眩晕的疗效差异,并初步探讨其作用机制。方法：96例颈椎病患者随机分为饮片组、配方颗粒组和葛根定眩胶囊组各32例,分别采用桂枝葛根汤饮片、配方颗粒和葛根定眩胶囊治疗14 d,比较3组患者的疗效和治疗前后血流动力学指标变化,酶联免疫法测定3组患者治疗前后IL-6及IL 1β的表达。结果：3组总有效率比较,差异无统计学意义（P＞0.05）。治疗后3 组患者眩晕和头痛评分均较治疗前明显改善（P＜0.01）,饮片组眩晕评分优于胶囊组（P＜0.05）。治疗后3组患者基底动脉和双侧椎动脉的Vs和Vm均较治疗前明显增加（P＜0.01),且配方颗粒组和胶囊组椎动脉的Vm低于饮片组（P＜0.05或P＜0.01）。治疗后,饮片组和配方颗粒组血清IL 6水平较治疗前明显降低(P<0.05),饮片组和胶囊组血清IL-1β水平较治疗前明显降低(P<0.05);胶囊组血清IL-6水平显著高于其他两组(P<0.05),饮片组血清IL 1β水平显著低于配方颗粒组和胶囊组(P<0.05)。结论：桂枝葛根汤三种剂型治疗颈性眩晕的总有效率相当,部分疗效指标饮片相比配方颗粒和胶囊更优。此作用可能与增加脑血流及抑制相关炎症因子IL-6及IL-1β的表达有一定关联。     

坦度螺酮联合奥卡西平治疗癫痫合并焦虑抑郁患者的症状改善观察及机制探讨

摘 要 目的：探讨坦度螺酮联合奥卡西平对癫痫合并焦虑抑郁患者的症状改善,以及对患者血清5-HT1A受体及额叶皮质水平的影响。方法：癫痫合并焦虑、抑郁患者80例随机分为对照组和观察组各40例,对照组常规给予奥卡西平片治疗;观察组在对照组基础上加用坦度螺酮胶囊治疗。治疗8周后,比较两组患者治疗前后汉密尔顿焦虑量表（HAMA）评分、汉密尔顿抑郁量表（HAMD）评分、血清5-HT1A受体水平、额叶皮质水平及药品不良反应发生率。结果：治疗8周后,两组患者HAMA、HAMD评分均较治疗前明显降低（P＜0.05）,且观察组显著低于对照组（P＜0.05）。两组男、女患者血清5-HT1A水平均较治疗前明显升高（P＜0.05）,且观察组男、女患者血清5-HT1A水平均高于对照组（P＜0.05）。对照组患者左额叶谷氨酸复合物（Glx）/肌酸（Cr）治疗前后比较差异无统计学意义（P＞0.05）,其他指标治疗前后比较差异均有统计学意义（P＜0.05）;观察组患者各项指标治疗前后比较差异均有统计学意义（P＜0.05）。且治疗后对照组患者左额叶Glx/Cr、胆碱复合物（Cho）/Cr及右额叶Cho/Cr、N-乙酰天门冬氨酸（NAA）/Cr水平低于观察组,右额叶Glx/Cr及左额叶NAA/Cr水平高于观察组（P＜0.05）。两组药品不良反应发生率比较,差异无统计学意义（P＞0.05）。结论：坦度螺酮联合奥卡西平对癫痫合并焦虑抑郁患者疗效肯定,安全性高,能有效改善患者血清5 HT1A受体及额叶皮质水平,减轻焦虑及抑郁症状,提高患者生活质量。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.