左旋紫草素对顺铂耐药人宫颈癌HeLa细胞的逆转作用研究

目的:探讨左旋紫草素(L-SHK)对顺铂(DDP)耐药人宫颈癌HeLa细胞(HeLa/DDP)的逆转作用及其可能机制。方法:以人宫颈癌HeLa细胞株为研究对象,以DDP诱导获得HeLa/DDP耐药细胞;采用CCK-8法测定HeLa/DDP细胞的耐药指数以及不同剂量L-SHK(0.125、0.25、0.5、1、2、4、8、16μmol/L)对该细胞的抑制率、半数抑制浓度(IC₅₀)和逆转倍数;采用流式细胞术检测低、中、高剂量L-SHK(0.3、0.6、1.2μmol/L)联合DDP对HeLa/DDP细胞周期及凋亡率的影响,采用Western blotting法检测低、中、高剂量L-SHK(0.3、0.6、1.2μmol/L)联合DDP对HeLa/DDP细胞凋亡相关蛋白[剪切型胱天蛋白酶3(Cleaved caspase-3)、Bcl-2、Bax]表达的影响。结果:所得HeLa/DDP细胞的耐药指数为11.8。L-SHK对HeLa/DDP细胞的抑制率有随剂量增加而逐渐升高的趋势。与单用DDP比较,DDP+低、中、高剂量L-SHK组细胞的IC₅₀值...     

Mechanisms of Cisplatin nephrotoxicity

Cisplatin is a widely used and highly effective cancer chemotherapeutic agent. One of the limiting side effects of cisplatin use is nephrotoxicity. Research over the past 10 years has uncovered many of the cellular mechanisms which underlie cisplatin-induced renal cell death. It has also become apparent that inflammation provoked by injury to renal epithelial cells serves to amplify kidney injury and dysfunction in vivo. This review summarizes recent advances in our understanding of cisplatin nephrotoxicity and discusses how these advances might lead to more effective prevention.     

地塞米松诱导肺癌细胞的顺铂耐药及其性别差异

目的：探讨地塞米松是否诱导肺癌细胞对顺铂耐药。方法：采用肺癌细胞株A1和26例肺癌患者手术标本分离的肺癌细胞。用不同浓度地塞米松体外诱导培养24 h后,加入不同浓度顺铂继续培养48 h,用MTT法检测细胞的存活率。结果：A1细胞株经地塞米松诱导后,对顺铂呈现典型的耐药,与地塞米松浓度呈剂量依赖关系;男性患者肺癌细胞1例呈现耐药（1/26,3.8%）,女性4例耐药（4/26,15.4%）,二者呈显著性差异（P〈0.01）。结论：体外实验结果表明,地塞米松对多数肺癌患者的肿瘤细胞不诱导顺铂抗性。女性患者的肺癌细胞中经地塞米松诱导后耐药比率高于男性患者。     

荜茇酰胺对人肺癌A549/DDP细胞耐药性的逆转作用

目的:研究荜茇酰胺对人肺癌A549/顺铂(DDP)细胞耐药性的逆转作用。方法:A549/DDP细胞经0、20、30μmol/L荜茇酰胺作用48 h后,用MTS法检测肿瘤细胞抑制率;流式细胞术检测肿瘤细胞凋亡、细胞周期、P-糖蛋白(P-gp)表达和肿瘤细胞内罗丹明Rht123含量的变化;Western blotting法检测多药耐药基因(MDR)1、多药耐药相关蛋白(MRP)1、DNA拓扑异构酶(Top)Ⅱ、谷胱甘肽S-转移酶(GST)-π、凋亡抑制蛋白Survivin、周期蛋白依赖性蛋白激酶(CDK)1和蛋白激酶(PK)Cζ蛋白表达;实时荧光聚合酶链反应(RT-PCR)法检测MDR1、MRP1、Top-II、GST-π、Survivin和CDK1 m RNA表达;酶标仪检测含半胱氨酸的天冬氨酸蛋白水解酶(Caspase)-3、8活性。结果:A549/DDP细胞经0、20、30μmol/L荜茇酰胺作用48 h后,DDP对肿瘤细胞增殖的抑制率明显升高;与0μmol/L比较,20、30μmol/L荜茇酰胺作用48 h后,DDP导致的细胞凋亡率和G2期/M期明显升高,P-gp表达明显减弱,Rh-123浓度明显增加,MDR1、MRP1、Top-II、GST-π、Survivin、CDK1和PKCζ蛋白表达明显减弱,MDR1、MRP1、Top-Ⅱ、GST-π、Survivin、CDK m RNA表达明显减弱,Caspase-3、8的活性明显增强。结论:荜茇酰胺可逆转人肺癌A549/DDP细胞DDP耐药性,可能与其调节多药耐药相关基因表达有关。     

肿瘤的多药耐药机制及逆转剂的研究进展

肿瘤多药耐药性(Multidrug Resistance,MDR)指癌细胞对于许多结构不相关的化疗药物表现出的交叉抵抗现象,是肿瘤难治疗、易复发的主要原因之一,故多药耐药机制便成为当前肿瘤化疗的研究热点.许多肿瘤的耐药细胞中存在着多药耐药基因(mdr-1)和多药耐药相关蛋白基因(mrp)的高表达,而这些基因的表达又受到某些基因及蛋白的调节,如P53、P-gp等.另外,DNA甲基化也与肿瘤的多药耐药性有关.本文就近几年来有关肿瘤细胞多药耐药机制的研究进展以及针对这些耐药性研发的不同逆转方法进行综述.     

血竭总黄酮抗血栓作用及机制研究

目的 探讨血竭总黄酮的抗血栓的作用及机制.方法 建立血瘀模型,用ELISA法测定血浆VWF及CMP-140含量;测定血小板粘附率及ADP、Adr诱导的血小板聚集率;对大鼠实验性静脉血栓的影响.结果 血竭总黄酮显著降低血瘀大鼠血浆中的VWF及CMP-140含量;能有效降低大鼠血小板粘附率;对ADP、PAF诱导的血小板聚集有明显抑制作用;对大鼠实验性静脉血栓有较强的抑制作用.结论 血竭总黄酮具有较好的抗血栓作用,且显示出多途径、多靶点的特征.     

Resistance to fosfomycin: Mechanisms,Frequency and Clinical Consequences

Fosfomycin has been used for the treatment of infections due to susceptible and multidrug-resistant (MDR) bacteria. It inhibits bacterial cell wall synthesis through a unique mechanism of action at a step prior to that inhibited by β-lactams. Fosfomycin enters the bacterium through membrane channels/transporters and inhibits MurA, which initiates peptidoglycan (PG) biosynthesis of the bacterial cell wall. Several bacteria display inherent resistance to fosfomycin mainly through MurA mutations. Acquired resistance involves, in order of decreasing frequency, modifications of membrane transporters that prevent fosfomycin from entering the bacterial cell, acquisition of plasmid-encoded genes that inactivate fosfomycin, and MurA mutations. Fosfomycin resistance develops readily in vitro but less so in vivo. Mutation frequency is higher among Pseudomonas aeruginosa and Klebsiella spp. compared with Escherichia coli and is associated with fosfomycin concentration. Mutations in cAMP regulators, fosfomycin transporters and MurA seem to be associated with higher biological cost in Enterobacteriaceae but not in Pseudomonas spp. The contribution of fosfomycin inactivating enzymes in emergence and spread of fosfomycin resistance currently seems low-to-moderate, but their presence in transferable plasmids may potentially provide the best means for the spread of fosfomycin resistance in the future. Their co-existence with genes conferring resistance to other antibiotic classes may increase the emergence of MDR strains. Although susceptibility rates vary, rates seem to increase in settings with higher fosfomycin use and among multidrug-resistant pathogens.     

New Insights into the Potential Cytotoxic Role of Bacillus cytotoxicus Cytotoxin K-1

The thermotolerant representative of the Bacillus cereus group, Bacillus cytotoxicus, reliably harbors the coding gene of cytotoxin K-1 (CytK-1). This protein is a highly cytotoxic variant of CytK toxin, initially recovered from a diarrheal foodborne outbreak that caused the death of three people. In recent years, the cytotoxicity of B. cytotoxicus has become controversial, with some strains displaying a high cytotoxicity while others show no cytotoxicity towards cell lines. In order to better circumscribe the potential pathogenic role of CytK-1, knockout (KO) mutants were constructed in two B. cytotoxicus strains, E8.1 and E28.3. The complementation of the cytK-1 KO mutation was implemented in a mutant strain lacking in the cytK-1 gene. Using the tetrazolium salt (MTT) method, cytotoxicity tests of the cytK-1 KO and complemented mutants, as well as those of their wild-type strains, were carried out on Caco-2 cells. The results showed that cytK-1 KO mutants were significantly less cytotoxic than the parental wild-type strains. However, the complemented mutant was as cytotoxic as the wild-type, suggesting that CytK-1 is the major cytotoxicity factor in B. cytotoxicus.     

白色念珠菌生物被膜形成和由其产生的耐药机制

白色念珠菌以生物被膜方式生长是相对于其悬浮生长状态而言的另一种独特的生长形式,其最具特征的表型是对多种抗真菌药物表现出高度耐药.本文对近年来白色念珠菌生物被膜形成的分子机制及其产生的耐药机制的研究进展进行综述.     

地奥心血康干预阿司匹林抵抗患者的临床试验

目的 观察地奥心血康对阿司匹林抵抗患者的干预效果并探讨其作用机制.方法 将60例阿司匹林抵抗患者随机分为加大阿司匹林用量组(对照组,拜阿司匹林300 mg/d)30例,地奥心血康组(治疗组,地奥心血康1.6 g,每日3次)30例.两组均连续用药4周.观察并对比血小板平均聚集率、血栓素B2(TXB2)、6-酮-前列腺素F1α(6-K-PGF1α)及药物安全性.结果 治疗组有效率显著高于对照组;治疗组治疗1个月后以花生四烯酸(AA)和二磷酸腺苷(ADP)诱导的血小板聚集率及其下降值均显著低于对照组.与治疗前比较,对照组和治疗组的TXB2均升高明显(P<0.01).治疗组的6-K-PGF1α与对照组相比升高(P<0.05),与治疗前比较,对照组降低明显(P<0.01).与治疗前比较,对照组和治疗组的TXB2/6-K-PGF1α均降低(P<0.01,P<0.05).治疗组药物不良反应发生率显著低于对照组.结论 地奥心血康治疗阿司匹林抵抗有较好的疗效及安全性,其机制可能与其可降低TXB2同时升高6-K-PGF1α降低TXB2/6-K-PGF1α的作用有关.     

Drug Resistance Reversal Potential of Ursolic Acid Derivatives against Nalidixic Acid‐ and Multidrug‐resistant Escherichia coli

As a part of our drug discovery program, ursolic acid was chemically transformed into six semi‐synthetic derivatives, which were evaluated for their antibacterial and drug resistance reversal potential in combination with conventional antibiotic nalidixic acid against the nalidixic acid‐sensitive and nalidixic acid‐resistant strains of Escherichia coli. Although ursolic acid and its all semi‐synthetic derivatives did not show antibacterial activity of their own, but in combination, they significantly reduced the minimum inhibitory concentration of nalidixic acid up to eightfold. The 3‐O‐acetyl‐urs‐12‐en‐28‐isopropyl ester (UA‐4) and 3‐O‐acetyl‐urs‐12‐en‐28‐n‐butyl ester (UA‐5) derivatives of ursolic acid reduced the minimum inhibitory concentration of nalidixic acid by eightfold against nalidixic acid‐resistant and four and eightfold against nalidixic acid‐sensitive, respectively. The UA‐4 and UA‐5 were further evaluated for their synergy potential with another antibiotic tetracycline against the multidrug‐resistant clinical isolate of Escherichia coli‐KG4. The results showed that both these derivatives in combination with tetracycline reduced the cell viability in concentration‐dependent manner by significantly inhibiting efflux pump. This was further supported by the in silico binding affinity of UA‐4 and UA‐5 with efflux pump proteins. These ursolic acid derivatives may find their potential use as synergistic agents in the treatment of multidrug‐resistant Gram‐negative infections.     

Insights into future therapeutics for atopic dermatitis

Introduction: Atopic Dermatitis (AD) is a common chronic inflammatory skin disorder with a constellation of symptoms. Currently, there are numerous therapies in various phases of drug development that target the pathogenesis of AD.

Areas covered: Our paper aims to examine small molecule therapies and other novel agents registered for clinical trial in the phase II and mainly phase III stages of development. A literature search using PubMed as well as Clinicaltrials.gov was conducted. Clinical trial evidence of these novel agents was compiled and assessed. Both topical and oral novel therapies with diverse range of mechanistic action are currently being studied, with varying success. These include phosphodiesterase-4 inhibitors, boron molecules, Janus kinase inhibitors, cannabinoid receptors agonists, kappa-opioid receptor agonists. A variety of compounds with yet undisclosed or unknown mechanisms of action are also being studied.

Expert opinion: Further research through extensive clinical trials will allow for more information about these targeted therapies and their potential place in the treatment algorithm of AD. Due to the success of such therapies in treating a spectrum of chronic inflammatory diseases, we remain hopeful that the successful development of targeted therapy for AD lies ahead.     

苄普地尔衍生物的合成及对多药耐药性的逆转作用

设计并合成了5个苄普地尔（BEP）的衍生物，并对其逆转多药耐药性作用进行了初步研究。结构均经红外光谱、核磁共振氢谱和质谱确证。药理实验以Fura-2/AM法测定P_糖蛋白功能，结果显示Ⅰa～Ⅰe都具有逆转多药抗药性的活性，其中Ⅰc和Ⅰe的活性与BEP相当，Ⅰb显著高于BEP（P〈O．05）。     

Temozolomide: An Updated Overview of Resistance Mechanisms,Nanotechnology Advances and Clinical Applications

Temozolomide (TMZ), an oral alkylating prodrug which delivers a methyl group to purine bases of DNA (O6-guanine; N7-guanine and N3-adenine), is frequently used together with radiotherapy as part of the first-line treatment of high-grade gliomas. The main advantages are its high oral bioavailability (almost 100% although the concentration found in the cerebrospinal fluid was approximately 20% of the plasma concentration of TMZ), its lipophilic properties, and small size that confer the ability to cross the blood-brain barrier. Furthermore, this agent has demonstrated activity not only in brain tumors but also in a variety of solid tumors. However, conventional therapy using surgery, radiation, and TMZ in glioblastoma results in a median patient survival of 14.6 months. Treatment failure has been associated with tumor drug resistance. This phenomenon has been linked to the expression of O6-methylguanine-DNA methyltransferase, but the mismatch repair system and the presence of cancer stem-like cells in tumors have also been related to TMZ resistance. The understanding of these mechanisms is essential for the development of new therapeutic strategies in the clinical use of TMZ, including the use of nanomaterial delivery systems and the association with other chemotherapy agents. The aim of this review is to summarize the resistance mechanisms of TMZ and the current advances to improve its clinical use.     

过氧化物还原酶2及其潜在的临床应用价值研究进展

过氧化物还原酶2（peroxiredoxins,Prx2）是过氧化物还原酶家族的重要一员,在人体多种组织器官中都有表达,红细胞内含量极其丰富。Prx2在清除过氧化物、信号转导、分子伴侣等方面发挥着重要作用。Prx2结构和表达量的改变与多种疾病直接相关,是临床诊断及药物开发领域的新关注点。本文从Prx2的生理功能及其与不同疾病的相关性、不同存在形式、Prx2的检测手段3个方面进行综述,为进一步探究Prx2与疾病调控机制及其在疾病诊断和潜在临床应用的研究方面提供参考。