丹参酮类化合物对NB4细胞的增殖抑制与构效关系探讨

目的比较丹参酮类化合物对人急性早幼粒细胞白血病NB4细胞的体外增殖抑制作用,并探讨其分子结构与细胞毒性之间的关系。方法采用改良MTT法测定不同浓度的丹参酮类化合物与细胞共培养一定时间后对NB4细胞的增殖抑制作用;采用倒置显微镜观察其细胞形态。结果供试丹参酮类化合物均能有效抑制NB4细胞的增殖,其抑制作用呈明显的时间和剂量依赖性。与NB4细胞共培养24 h后,二氢丹参酮Ⅰ与丹参酮Ⅰ的IC50值分别为1.86、3.62μg·mL-1,丹参酮ⅡA和隐丹参酮的IC50值均大于10μg·mL-1;共培养48 h后二氢丹参酮Ⅰ、丹参酮Ⅰ、丹参酮ⅡA、隐丹参酮的IC50值分别为0.65、1.41、1.83、5.41μg·mL-1;72 h后的IC50值分别为0.28、0.33、0.45、2.59μg·mL-1。结论 4种丹参酮类化合物对NB4细胞均具有增殖抑制作用,作用强度大小依次为二氢丹参酮Ⅰ、丹参酮Ⅰ、丹参酮ⅡA、隐丹参酮,提示丹参酮类化合物的A环为芳环时可增强细胞毒性,C环的呋喃环结构可能影响其细胞毒性。     

Growth-inhibitory effects of the red alga Gelidium amansii on cultured cells

The objective of this study was to investigate the effects of Gelidium amansii, an edible red agar cultivated off the northeast coast of Taiwan, on the growth of two lines of cancer cells, murine hepatoma (Hepa-1) and human leukemia (HL-60) cells, as well as a normal cell line, murine embryo fibroblast cells (NIH-3T3). The potential role of G. amansii on the induction of apoptosis was also examined. The results indicated that all extracts from G. amansii, including phosphate-buffered saline (PBS) and methanol extracts from dried algae as well as the dimethyl sulfoxide (DMSO) extract from freeze-dried G. amansii agar, inhibited the growth of Hepa-1 and NIH-3T3 cells, but not the growth of HL-60 cells. Annexin V-positive cells were observed in methanol and DMSO extract-treated, but not PBS extract-treated Hepa-1 and NIH-3T3 cells, suggesting that the lipid-soluble extracts of G. amansii induced apoptosis. In summary, extracts of G. amansii from various preparations exhibited antiproliferative effects on Hepa-1 and NIH-3T3 cells, and apoptosis may play a role in the methanol and DMSO extract-induced inhibitory effects. However, the antiproliferative effects of PBS extracts was not through apoptosis. Moreover, the growth-inhibitory effects of G. amansii were not specific to cancer cells.     

异戊烯基香豆素类化合物抑制A549细胞增殖作用及其构效关系

目的 探讨异戊烯基香豆素类化合物对A549肺癌细胞增殖的影响,并对其构效关系及作用机制进行初步探讨。方法 将人肺癌细胞A549进行体外培养,采用不同浓度异戊烯基香豆素类化合物甘草香豆素（GCM）、甘草酚（GC）、补骨脂定（PSO）、香豆雌酚（COM）、7-去甲基软木花椒素（DE）、7, 2'', 4''-trihydroxy-5-methxy-3-penylcoumarin（TMP）和蛇床子素（OST）分别处理肺癌A549细胞36、72 h后,通过结晶紫染色法检测细胞增殖活性;采用蛋白免疫印迹法（Western blotting）检测细胞中TOPK、C-PARP、Bcl-2、Bax、p62、LC3B蛋白表达水平。结果 受试化合物对A549细胞增殖的抑制作用存在浓度和时间相关性;10 μmol/L的GCM、GC、PSO、COM、DE、TMP组Bcl-2表达均下降（P＜0.05）;A549细胞经10 μmol/L GCM、GC、PSO处理后,TOPK的表达显著降低,C-PARP、LC3 Ⅱ、p62的表达显著升高（P＜0.05）。结论 异戊烯基香豆素类化合物GCM、GC、PSO可显著抑制A549细胞的增殖活性,且其抗增殖活性可能与香豆素母核苯环上的异戊烯基结构取代和母核C-3位上苯环的取代及其环上游离的羟基有关;其抗A549细胞增殖的作用机制可能与促进细胞凋亡,诱导细胞发生不完全自噬并抑制自噬流有关。     

Clinical effects of biapenem on febrile neutropenia in patients with hematological malignancy

BACKGROUND: Recent advances in the treatment of hematological malignancies often induce febrile neutropenia (FN) due to severe myelosuppression. The aim of this study was to evaluate the safety and efficacy of biapenem in such FN. METHODS: Candidate patients were admitted to our hospital and were treat of their hematological malignancy from February 2005 to March 2006. They gave written informed consent to enter this study in advance. When the diagnosis of FN was established among them, those patients received intravenous biapenem 0.6 g every 12 hours. This trail was approved by our institutional review board. RESULTS: A total of 54 consecutive patients were registered and 49 patients were evaluable for response. The median age was 61. The underlying diseases were acute lymphocytic leukemia in 6 cases, acute myelocytic leukemia in 21, multiple myeloma in 3, and non-Hodgkin's lymphoma in 19. The response rate was 78% (excellent response: 51%, good response: 27%, minor response: 6%, no response: 16%). In patients with neutrophil counts under 500/microl, the response rate was 73%. Infectious death or other serious adverse events were not observed. CONCLUSION: Biapenem is effective and safe for treating FN.     

姜黄素抑制淋巴瘤细胞周期蛋白水平的研究

目的:探讨姜黄素对淋巴瘤细胞株Raji细胞增殖和细胞周期的影响。方法:6.25~100μmol.L-1的姜黄素分别处理Raji细胞12~60h后,MTT法检测Raji细胞的生长活性;流式细胞仪(FCM)检测细胞凋亡;蛋白印迹法(W estern B lot)分析姜黄素作用前后,肿瘤细胞中周期蛋白E以及相应视网膜母细胞瘤基因Rb的表达。结果:姜黄素可呈时间及剂量依赖性抑制Raji细胞的增殖,抑制率为59.83%~91.46%。流式细胞仪检测Raji细胞,凋亡率为14.38%~61.18%。姜黄素刺激Raji细胞24h内周期蛋白E和视网膜母细胞瘤基因Rb蛋白表达显著增强(P<0.05),但随着姜黄素浓度增高而表达下调,呈剂量依赖性下调。结论:姜黄素能干扰细胞周期进程,其作用机制为诱导Raji细胞的凋亡,下调周期蛋白E的表达,从而抑制其相应视网膜母细胞瘤基因Rb的表达,可能是其作用机制之一。     

姜黄素前体化合物诱导膀胱癌细胞凋亡的研究

目的观察姜黄素前体化合物诱导膀胱癌细胞凋亡的生物学效应,并探讨其可能的机制。方法N-马来酰-L-缬氨酸酯姜黄素、N-马来酰-甘氨酸酯姜黄素分别作用于人膀胱癌EJ细胞、肾小管上皮HKC细胞6~24 h后,采用台盼蓝活细胞拒染法检测细胞生长活性,透射电镜观察细胞超微结构改变,DNA片段化原位荧光标记技术、流式细胞术检测细胞凋亡及比率。结果10μmol.L-1~40μmol.L-1的N-马来酰-L-缬氨酸酯姜黄素、N-马来酰-甘氨酸酯姜黄素作用6~24 h后,EJ细胞生长抑制率分别为6.11%~66.23%(P<0.05)、8.96%~68.21%(P<0.05),呈浓度、时间依赖性;部分癌细胞出现凋亡形态学改变,DNA直方图上可见“亚G1峰”,12 h细胞凋亡率分别为10.13%~23.36%(P<0.05)、12.42%~28.56%(P<0.05)。两种前体化合物对HKC细胞生长的抑制作用较同浓度姜黄素降低(P<0.05)。结论姜黄素前体化合物能在体外有效诱导膀胱癌EJ细胞凋亡,降低对正常二倍体细胞生长的抑制作用,为深入研制肿瘤靶向性化疗药物提供了新的途径。     

植物多糖抗抑郁作用机制和构效关系的研究进展

抑郁症已成为严重的全球健康问题。以化学药物为主的临床治疗方案呈现出不同程度的不良反应和耐药性。植物多糖来源丰富,是研究最广泛的一种多糖类物质,具有抗氧化、抗肿瘤、抗炎、抗衰老、抗抑郁等多种生物活性。植物多糖可以通过调节神经递质及其受体表达、炎症反应、下丘脑-垂体-肾上腺轴、神经营养因子、抗氧化应激损伤以及调节色氨酸代谢、肠道菌群发挥抗抑郁作用。植物多糖结构与抗抑郁功效关系的大多数研究仅仅停留在描述其单糖组成,单糖在植物多糖抗抑郁功效中发挥的作用还未涉及。因此就植物多糖的抗抑郁作用机制、相关信号通路以及构效关系进行综述,为用于抗抑郁植物多糖产品的开发提供参考。     

五种二苯乙烯类化合物对一氧化氮介导的血管舒张反应的影响及构效关系

目的研究5种二苯乙烯类化合物(白藜芦醇,RES;己烯雌酚,DES;二苯乙烯苷,THSG;反式二苯乙烯,TS和二苯乙烯苷水加成产物,SWA)对一氧化氮(NO)介导的舒张血管反应的影响,并探讨其作用与化学结构的关系.方法采用血管张力记录法,观察药物对大鼠主动脉血管环张力的作用,并测定药物对NO含量和对一氧化氮合酶(NOS)活性的影响.结果RES、DES、THSG、TS和SWA(1、3、10、30、100μmol·L-1)能剂量依赖性地舒张苯肾上腺素(10μmol·L-1)诱发的血管收缩反应,其效价强度,依次为THSG＞DES＞RES＞SWA=TS;与二甲亚砜比较,TS和SWA的作用不明显.L-Arg(1μmol·L-1)可增强RES、DES、THSG的舒张血管作用,而亚甲蓝(1μmol·L-1)却可削弱之.另外,RES、DES、THSG(10μmol·L-1)可增加血管总NO含量及NOS活性,其增加NOS活性作用的强度,依次为THSG＞DES＞RES＞SWA＞TS.结论RES、DES、THSG具有剂量依赖性依内皮性舒张血管作用,此作用与增加NO含量及NOS活性有关.它们结构中的乙烯双键对发挥舒张血管作用是必需的,苯环上的羟基的数量及位置决定着其作用强度.     

白杨素抗肿瘤衍生物的合成及其构效关系

目的合成一系列白杨素衍生物并结合体外实验探讨白杨素衍生物抗肿瘤作用的构效关系。方法以5,7-二羟基黄酮为原料,通过取代、水解、酰胺缩合等化学反应引入一些极性不同的小分子化合物,合成一系列白杨素的衍生物,然后采用MTT比色法检测白杨素及其衍生物对食管癌EC109细胞、肝癌HepG2细胞、宫颈癌Hela细胞的增殖抑制作用。结果化合物Ⅲa、Ⅲb、Ⅲc、Ⅲd、Ⅲf对抑制EC109增殖表现出的抗癌活性较白杨素有明显的提高,化合物Ⅲa、Ⅲd、Ⅲe、Ⅲf对抑制HepG2增殖表现出的抗癌活性较白杨素有明显的提高,其中Ⅲd和Ⅲf的抗肿瘤作用显著;白杨素及其衍生物对抑制Hela细胞的增殖均较高,但其衍生物抗肿瘤作用与白杨素相比没有提高。结论引入极性基团对白杨素的抗肿瘤活性有明显的提高,经过极性基团修饰后的白杨素衍生物能明显提高对EC109、HepG2细胞增殖抑制作用。     

The temporal relationship between behavioral and hematological effects of inhaled benzene

The time-effect relationship of the behavioral and hematological changes caused by inhaled benzene was investigated in C57BL mice. Mice were exposed to air, or 100, 300, 1000, or 3000 ppm benzene in standard inhalation chambers employing dynamic vapor exposure techniques. Mice were exposed for 6 hr/day for the number of days necessary to achieve a minimum concentration X time (Ct) product of 3000 ppm-days. The intermittent exposure regimen of 6 hr/day was employed to simulate occupational exposure. The most sensitive behavioral index (milk-licking) was affected by the lowest concentration tested (100 ppm), while homecage food intake, hindlimb grip strength, and body weight were reduced only at 1000 and 3000 ppm. Some of these previously undocumented behavioral changes occurred as rapidly as hematological changes that have been considered hallmarks of benzene toxicity. A significant decrease in circulating lymphocytes occurred after exposure to all concentrations. Circulating red blood cells were variably affected by benzene, in that anemia resulted after 10 days exposure to 100 ppm and after 3 days exposure to 300 ppm but not after 3 days exposure to 1000 ppm or a single exposure of 3000 ppm. The data indicate a departure from Ct relationships, and suggest that exposure duration as well as daily dose may be an important factor in benzene toxicity.     

Oleanane-type triterpenoid saponins from the roots of Pulsatilla koreana and their apoptosis-inducing effects on HL-60 human promyelocytic leukemia cells

Twenty-four oleanane-type triterpenoid saponins were isolated from a methanol extract of the Pulsatilla koreana roots. Their structures were elucidated by comparing spectroscopic data to published values. Among them, compounds 8–12 and 20–24 significantly diminished the proliferation of HL-60 human promyelocytic leukemia cells with IC₅₀ values from 0.3 to 4.2 μM, whereas compounds 7 and 19 showed moderate cytotoxic activity. Furthermore, apoptotic characteristics such as chromatin condensation and increase in the population of sub-G1 hypodiploid cells were observed after the HL-60 cells were treated with these compounds.     

Endothelin receptor antagonists: an overview of their synthesis and structure-activity relationship

Endothelins (ETs) are potent vasoconstrictor peptides and are associated with several disease states like pulmonary hypertension, systemic hypertension and heart failure. Endothelin-1 (ET-1) is the first member of the family and it has the receptor subtypes known as ETA and ETB. The receptors ETA and ETB are attractive new therapeutic targets for diseases associated with elevated ET-1 levels. Several studies have thus led to the discovery of selective ETA receptor antagonists as well as non-selective ETA/ETB antagonists. The preclinical and clinical studies have clearly established that these antagonists are effective in the treatment of essential hypertension, pulmonary hypertension, heart failure and atherosclerosis. The advances in this area have resulted in the FDA approval of the orally active dual antagonist Bosentan for pulmonary hypertension in 2001. This review highlights the synthesis and structure-activity of the endothelin receptor antagonists and covers the literature in this area up to 2001.     

依布硒啉及衍生物的药理作用和构效关系研究进展

目的对依布硒啉及衍生物的药理作用和构效关系的研究进展进行综述。方法查阅近年来国内外相关文献进行归纳总结。结果依布硒啉及衍生物具有抗氧化、抗肿瘤和抗微生物等活性;2位氮原子取代基团的变化将会产生不同的药理活性。结论依布硒啉及衍生物具有广泛的药理活性,对其进一步的研究和开发具有重要的意义。     

9种黄酮类化合物对肿瘤细胞的抑制活性及构效关系研究

目的研究9种黄酮类化合物对3种肿瘤细胞的增殖抑制作用及构效关系。方法采用四甲基偶氮唑蓝(MTT)法体外检测黄酮化合物对Bel-7402(人肝癌细胞)、Hela(人宫颈癌细胞)和HT-29(人结肠癌细胞)3种癌细胞模型的抗肿瘤活性。结果 9种黄酮化合物对3种肿瘤细胞具有抑制作用,其中木犀草素活性最显著(IC50:12.81,19.02,19.69),通过对9种黄酮化合物IC50值对比,发现黄酮母核、2,3位双键、5-OH和3′,4′-OH的存在对抑制肿瘤细胞的增殖具有显著的作用。结论黄酮化合物对肿瘤细胞的增殖抑制作用与其结构有一定的相关性,为以后黄酮化合物及其衍生物的研究提供参考。     

Synthesis and structure-activity relationship effects on the tumor avidity of radioiodinated phospholipid ether analogues

Radioiodinated phospholipid ether analogues have shown a remarkable ability to selectively accumulate in a variety of human and animal tumors in xenograft and spontaneous tumor rodent models. It is believed that this tumor avidity arises as a consequence of metabolic differences between tumor and corresponding normal tissues. The results of this study indicate that one factor in the tumor retention of these compounds in tumors is the length of the alkyl chain that determines their hydrophobic properties. Decreasing the chain length from C12 to C7 resulted in little or no tumor accumulation and rapid clearance of the compound in tumor-bearing rats within 24 h of administration. Increasing the chain length had the opposite effect, with the C15 and C18 analogues displaying delayed plasma clearance and enhanced tumor uptake and retention in tumor-bearing rats. Tumor uptake displayed by propanediol analogues NM-412 and NM-413 was accompanied by high levels of liver and abdominal radioactivity 24 h postinjection to tumor-bearing rats. Addition of a 2-O-methyl moiety to the propanediol backbone also retarded tumor uptake significantly. A direct comparison between NM-404 and its predecessor, NM-324, in human PC-3 tumor bearing immune-compromised mice revealed a dramatic enhancement in both tumor uptake and total body elimination of NM-404 relative to NM-324. On the basis of imaging and tissue distribution studies in several rodent tumor models, the C18 analogue, NM-404, was chosen for follow-up evaluation in human lung cancer patients. Preliminary results have been extremely promising in that selective uptake and retention of the agent in tumors is accompanied by rapid clearance of background radioactivity from normal tissues, especially those in the abdomen. These results strongly suggest that extension of the human trials to include other cancers is warranted, especially when NM-404 is radiolabeled with iodine-124, a new commercially available positron-emitting isotope. The relatively long physical half-life of 4 days afforded by this isotope appears well-suited to the pharmacodynamic profile of NM-404.     

人参皂苷衍生化及其抗肿瘤构效关系研究进展

人参皂苷为三萜类化合物,其某些衍生物在抑制肿瘤细胞生长或转移、诱导肿瘤细胞凋亡和分化、逆转肿瘤多药耐药等药理活性方面强于人参中主要的原生皂苷,人参皂苷衍生物作为抗肿瘤药物具有研究价值和开发前景。本文对人参皂苷衍生化的方法、主要衍生物及其抗肿瘤构效关系进行归纳总结,为新的抗肿瘤药物研究和开发提供参考。     

丹参酮类心脑血管保护作用与机制的研究进展

丹参主要成分包括酚酸类和丹参酮类。丹参酮类是一类脂溶性萜醌类天然产物,其中的丹参酮IIA衍生物丹参酮IIA磺酸钠已经广泛应用于临床。越来越多的研究显示,丹参酮类具有抗动脉粥样硬化、抗心血管重构、抗血栓、抗心律失常及抗缺血再灌注损伤等药理作用。本文对丹参酮类防治心脑血管疾病研究现状进行总结与展望,以期为该类化合物的进一步研究与临床应用提供理论依据。     

成人复杂核型恶性血液病特点分析

目的 探讨成人恶性血液病患者复杂核型的特征。方法 选择2013年1月至2016年12月安徽省立医院收治的48例成人复杂染色体核型血液病患者,回顾性分析其临床特点及染色体异常情况。结果 成人复杂核型恶性血液病患者以高龄为主,60岁以上占37.50%。所涉及病例中,髓系恶性血液病患者占比最高,为68.75%,其次为急性淋巴细胞白血病,占12.50%。染色体异常以长短臂加减（31例）,marker染色体（22例）,以及平衡移位（21例）多见。结论 成人复杂核型恶性血液病患者中高龄人群占比较高,复杂核型以特定的几种异常为主。     

Antimalarial activity of cassane- and norcassane-type diterpenes from Caesalpinia crista and their structure-activity relationship

Malaria is one of the most life-threatening infectious diseases worldwide and claims millions of people's lives each year. The appearance of drug-resistance Plasmodium falciparum has made the treatment of malaria increasingly problematic, and thus, it is a dire need to search the new alternatives of current drugs. In the present study, 44 cassane- and norcassane-type diterpenes isolated from Caesalpinia crista of Myanmar and Indonesia were evaluated for their antimalarial activity against the malaria parasite Plasmodium falciparum FCR-3/A2 clone in vitro. Most of the tested diterpenes displayed antimalarial activity, and norcaesalpinin E (28) showed the most potent activity with an IC50 value of 0.090 microM, more potent than the clinically used drug chloroquine (IC50, 0.29 microM). Based on the observed results, a structure-activity relationship has been established.     

Inhibitory effects of flavonoids on phosphodiesterase isozymes from guinea pig and their structure-activity relationships

The structure-activity relationships of flavonoids with regard to their inhibitory effects on phosphodiesterase (PDE) isozymes are little known. The activities of PDE1-5 were measured by a two-step procedure using cAMP with [(3)H]-cAMP or cGMP with [(3)H]-cGMP as substrates. In the present results, PDE1, 5, 2, and 4 isozymes were partially purified from guinea pig lungs in that order, and PDE3 was from the heart. The IC(50) values of PDE1-5 were greater than those reported previously for the reference drugs, vinpocetin, EHNA, milrinone, Ro 20-1724, and zaprinast, by 5-, 5-, 7-, 5-, and 3-fold, respectively. As shown in Table 2, luteolin revealed non-selective inhibition of PDE1-5 with IC(50) values in a range of 10-20 microM, as did genistein except with a low potency on PDE5. Daidzein, an inactive analogue of genistein in tyrosine kinase inhibition, showed selective inhibition of PDE3 with an IC(50) value of around 30 microM, as did eriodictyol with an IC(50) value of around 50 microM. Hesperetin and prunetin exhibited more-selective inhibition of PDE4 with IC(50) values of around 30 and 60 microM, respectively. Luteolin-7-glucoside exhibited dual inhibition of PDE2/PDE4 with an IC(50) value of around 40 microM. Diosmetin more-selectively inhibited PDE2 (IC(50) of 4.8 microM) than PDE1, PDE4, or PDE5. However, biochanin A more-selectively inhibited PDE4 (IC(50) of 8.5 microM) than PDE1 or PDE2. Apigenin inhibited PDE1-3 with IC(50) values of around 10-25 microM. Myricetin inhibited PDE1-4 with IC(50) values of around 10-40 microM. The same was true for quercetin, but we rather consider that it more-selectively inhibited PDE3 and PDE4 (IC(50) of < 10 microM). In conclusion, it is possible to synthesize useful drugs through elucidating the structure-activity relationships of flavonoids with respect to inhibition of PDE isozymes at concentrations used in this in vitro study.