基于MDR模型的喹诺酮类抗生素对蛋白核小球藻联合毒性作用评估

为考察新污染物中喹诺酮类抗生素混合物的联合毒性效应,以常见的氧氟沙星(Ofloxacin,OFXL)、环丙沙星(Ciprofloxacin,CIP)、诺氟沙星(Norfloxacin,NFXL)3种喹诺酮类抗生素为供试品,通过96 h急性毒性试验测定3种抗生素对蛋白核小球藻(Chlorella pyrenoidosa)生长抑制的单一毒性及二元和三元混合体系(共计20组)的联合毒性,通过等效线图法、浓度加和模型(CA)、独立作用模型(IA)、模型偏移率(MDR)和组合指数法评价二元和三元混合体系抗生素的相互作用类型。结果表明:①3种喹诺酮类抗生素对蛋白核小球藻在96 h均呈现明显的生长抑制,以半数效应浓度EC_(50)的负对数(pEC_(50))作为判断毒性大小的指标,毒性呈NFXL(pEC_(50)=-2.02)>CIP(pEC_(50)=-2.12)>OFXL(pEC_(50)=-2.23)的特征。②混合体系毒性相互作用类型以协同作用为主,毒性相互作用类型与混合体系组分浓度比、毒性效应区域和污染物浓度范围有关。混合体系中混合物组分浓度比最接近1∶1时,协同作用最强,毒性最大。③混合体系在低浓度范围(0%~30%)时,毒性相互作用类型以加和作用为主;在中高浓度范围(30%~100%)时,毒性相互作用随混合体系的不同而呈现出不同类型。研究显示,环境水体中喹诺酮类抗生素对蛋白核小球藻有一定的毒性效应,且抗生素二元、三元混合体系的协同毒性效应呈毒性增大的趋势。

Diarrheal Diseases: A Review on Gastroenteritis Bacteria Global Burden and Alternative Control of Multidrug-Resistant Strains

Diarrheal diseases represent a significant and pervasive health challenge for humanity. The aetiology of diarrheal diseases is typically associated with the presence of enteropathogens, including viruses, bacteria and parasites. The implementation of preventive measures, including the maintenance of good food hygiene, effective water sanitation, and the development of rotavirus vaccines, has resulted in a notable reduction in the prevalence of the disease. However, the emergence of bacterial multidrug resistance due to the past or present inappropriate use of antibiotics has rendered bacterial infections a significant challenge. The objective of this review is threefold: firstly, to provide an overview of diarrheal diseases associated with bacteria;secondly, to offer a concise analysis of bacterial multidrug resistance on a global scale;and thirdly, to present the potential of filamentous fungi as an alternative solution to the challenge posed by multidrug-resistant strains. Campylobacter spp. is the most dangerous bacteria, followed by Shigella spp. and Vibrio cholerae in all age groups combined. However, Shigella spp. was the deadliest in children under five years of age and, together with E. coli, are the most antibiotic-resistant bacteria. With their highly developed secondary metabolism, fungi are a reservoir of natural bioactive compounds.

Efficacy and Safety of Combined Bedaquiline and Delamanid Use among Patients with Multidrug-Resistant Tuberculosis in Beijing,China

Objectives The combined use of bedaquiline and delamanid(BDQ-DLM)is limited by an increased risk of prolonging the QTc interval.We retrospectively evaluated patients who received DLM/BDQcontaining regimens at a TB-specialized hospital.We aimed to present clinical efficacy and safety data for Chinese patients.Methods This case-control study included patients with multidrug-resistant tuberculosis(MDR-TB)treated with BDQ alone or BDQ plus DLM.Results A total of 96 patients were included in this analysis:64 in the BDQ group and 32 in the BDQ+DLM group.Among the 96 patients with positive sputum culture at the initiation of BDQ alone or BDQ combined with DLM,46 patients(71.9%)in the BDQ group and 29(90.6%)in the BDQ-DLM group achieved sputum culture conversion during treatment.The rate of sputum culture conversion did not differ between the two groups.The time to sputum culture conversion was significantly shorter in the BDQ-DLM group than in the BDQ group.The most frequent adverse event was QTc interval prolongation;however,the frequency of adverse events did not differ between the groups.Conclusion In conclusion,our results demonstrate that the combined use of BDQ and DLM is efficacious and tolerable in Chinese patients infected with MDR-TB.Patients in the BDQ-DLM group achieved sputum culture conversion sooner than those in the BDQ group.

Apatinib reduces liver cancer cell multidrug resistance by modulating NF-κB signaling pathway

Objectives:This investigation aimed to elucidate the inhibitory impact of apatinib on the multidrug resistance of liver cancer both in vivo and in vitro.Methods:To establish a Hep3B/5-Fu resistant cell line,5-Fu concentrations were gradually increased in the culture media.Hep3B/5-Fu cells drug resistance and its alleviation by apatinib were confirmed via flow cytometry and Cell Counting Kit 8(CCK8)test.Further,Nuclear factor kappa B(NF-κB)siRNA was transfected into Hep3B/5-Fu cells to assess alterations in the expression of multidrug resistance(MDR)-related genes and proteins.Nude mice were injected with Hep3B/5-Fu cells to establish subcutaneous xenograft tumors and then categorized into 8 treatment groups.The treatments included oxaliplatin,5-Fu,and apatinib.In the tumor tissues,the expression of MDRrelated genes was elucidated via qRT-PCR,immunohistochemistry,and Western blot analyses.Results:The apatinibtreated mice indicated slower tumor growth with smaller size compared to the control group.Both the in vivo and in vitro investigations revealed that the apatinib-treated groups had reduced expression of MDR genes GST-pi,LRP,MDR1,and p-p65.Conclusions:Apatinib effectively suppresses MDR in human hepatic cancer cells by modulating the expression of genes related to MDR,potentially by suppressing the NF-κB signaling pathway.

Identification of FDA-Approved Drugs as Modulators of Multidrug Resistance Protein 2 (MRP2/ABCC2) Expression Levels in MRP2-Overexpressing Cells: Preliminary Data

Multidrug Resistance Protein 2 (MRP2) is an ATP-dependent transmembrane protein that plays a pivotal role in the efflux of a wide variety of physiological substrates across the plasma membrane. Several studies have shown that MRP2 can significantly affect the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles of many therapeutic drugs and chemicals found in the environment and diet. This transporter can also efflux newly developed anticancer agents that target specific signaling pathways and are major clinical markers associated with multidrug resistance (MDR) of several types of cancers. MDR remains a major limitation to the advancement of the combinatorial chemotherapy regimen in cancer treatment. In addition to anticancer agents, MRP2 reduces the efficacy of various drug classes such as antivirals, antimalarials, and antibiotics. The unique role of MRP2 and its contribution to MDR makes it essential to profile drug-transporter interactions for all new and promising drugs. Thus, this current research seeks to identify modulators of MRP2 protein expression levels using cell-based assays. A unique recently approved FDA library (372 drugs) was screened using a high-throughput In-Cell ELISA assay to determine the effect of these therapeutic agents on protein expression levels of MRP2. A total of 49 FDA drugs altered MRP2 protein expression levels by more than 50% representing 13.17% of the compounds screened. Among the identified hits, thirty-nine (39) drugs increased protein expression levels whereas 10 drugs lowered protein expression levels of MRP2 after drug treatment. Our findings from this initial drug screening showed that modulators of MRP2 peregrinate multiple drug families and signify the importance of profiling drug interactions with this transporter. Data from this study provides essential information to improve combinatorial drug therapy and precision medicine as well as reduce the drug toxicity of various cancer chemotherapies.

MDRO肺炎感染患者SAA、PCT、Treg细胞及有关因子表达水平

目的探讨血清淀粉样蛋白A(serum amyloid A protein,SAA)、降钙素原(procalcitonin,PCT)、Treg细胞及有关因子在多重耐药菌(multidrug-resisitant organism,MDRO)肺炎感染患者中的表达水平及其与疗效的关联性。方法选取97例MDRO肺炎感染患者为研究对象,根据治疗14 d后的治疗效果分为有效组(73例)和无效组(24例),根据入院时肺炎严重指数(PSI)分为低危(34例)、中危(49例)、高危(14例)三个亚组。比较2组治疗前、治疗7 d后、治疗14 d后SAA、PCT、Treg细胞、超敏C反应蛋白(hs-CRP)、肿瘤坏死因子-α(TNF-α)水平,比较治疗前低危、中危、高危患者血清各指标水平及PSI评分,分析血清各指标水平与PSI评分的相关性。结果与无效组比较,治疗7、14 d后有效组SAA、PCT、hs-CRP、TNF-α水平较低,Treg细胞数较高,差异有统计学意义(P<0.05);治疗前,低危患者SAA、PCT、hs-CRP、TNF-α及PSI评分<中危患者<高危患者,Treg细胞数>中危患者>高危患者,差异有统计学意义(P<0.05);治疗前,SAA、PCT、hs-CRP、TNF-α水平与PSI评分呈正相关,Treg细胞数与PSI评分呈负相关(P<0.05);受试者操作特征(ROC)曲线显示治疗前SAA、PCT、Treg细胞、hs-CRP、TNF-α联合预测治疗无效的AUC大于各指标单独预测。结论MDRO肺炎感染患者SAA、PCT、hs-CRP、TNF-α、Treg细胞数量呈异常表达,且表达水平对预后具有重要影响,临床可监测其水平变化,联合预测预后的价值较高。

国际EPC热轧工程中MDR的应用

以国际EPC热轧工程项目为例,详细介绍项目进度计划管理中MDR的实际应用,重点探讨在大型项目设计阶段进度计划管理实施方面的一些方法和经验;指出国际项目必须精细化、精准化、可量化管理,为类似国际工程项目提供经验,以进一步提高企业的国际竞争力。

南京机场2015-2018年MDRS重要天气概率预报情况统计分析

本文对南京机场2015至2018年MDRS启动及重要天气概率预报情况进行了统计。南京机场的复杂天气以大雾和雷暴强降水为主,1月份也会出现较强的冰雪天气影响航班运行。就评估结果而言,预报命中的天气中,不准确率(预报误差超过4h)低于20%,预报效果较好,此外大雾天气预报的漏报率最高,而冰雪天气预报的准确率最高。

CYP3A7与MDR1基因多态性与镇痛效应的关系研究

目的 分析CYP3A7、MDR1基因多态性与镇痛效应之间的关系。方法 回顾性分析87例行腹部手术患者的一般临床资料,术后均采用舒芬太尼镇痛,对影响患者术后镇痛效应的相关因素进行分析。结果 87例行腹部手术的患者中,术后轻度疼痛(轻度疼痛组)45例、术后中重度疼痛(中重度疼痛组)42例。两组的年龄、性别、美国麻醉医师协会(ASA)分级以及CYP3A7基因多态性比较差异无统计学意义(P>0.05);两组MDR1 2677G>T/A基因多态性比较差异有统计学意义(P<0.05)。将轻度疼痛组与中重度疼痛组患者具有统计学意义的单因素纳入Logistic回归模型进行多因素分析,结果表明MDR1 2677G>T/A GG、GA、TA、AA为术后镇痛效应的影响因素(OR=0.998、1.078、1.044、1.038,P<0.05)。结论 MDR1基因多态性对患者术后镇痛效应可产生影响,临床在制定镇痛方案时应该综合考虑患者基因型等相关因素制定个体化的镇痛治疗方案。

MDR-PTB患者CT征象及治疗转归的危险因素分析

目的分析耐多药肺结核(MDR-PTB)患者的计算机断层扫描(CT)征象及治疗转归的危险因素。方法回顾性分析2019年2月至2022年3月在陕西省结核病防治院接受治疗的84例MDR-PTB患者临床资料,其中男53例,女31例,年龄(38.52±6.707)岁。经标准化学治疗24个月后按临床治疗转归分为治疗有效组(完成治疗、治愈,57例)与治疗无效组(治疗失败,27例),同期选择84例非MDR-PTB患者为参照组。采用t检验对比参照组与MDR-PTB组治疗前的CT征象,采用χ^(2)检验对比MDR-PTB治疗有效组与治疗无效组临床资料,采用多因素logistic回归分析MDR-PTB患者治疗转归的影响因素。结果MDR-PTB组厚壁空洞、多发空洞、肺损毁、胸膜增厚、肺内播散、肺实变、钙化影、条索影、全肺受累发生率分别为53.57%(45/84)、57.14%(48/84)、9.52%(8/84)、66.67%(56/84)、72.62%(61/84)、58.33%(49/84)、59.52%(50/84)、53.57%(45/84)、29.76%(25/84),参照组分别为19.05%(16/84)、15.48%(13/84)、1.19%(1/84)、16.67%(14/84)、50.00%(42/84)、30.95%(26/84)、17.86%(15/84)、23.81%(20/84)、7.14%(6/84),差异均有统计学意义(均P<0.05);MDR-PTB组斑片影、间质病变及胸腔积液发生率分别为69.05%(58/84)、11.90%(10/84)、60.71%(51/84),参照组分别为61.90%(52/84)、9.52%(8/84)、55.95%(47/84),差异均无统计学意义(均P>0.05)。治疗有效组年龄<60岁、初治、初始痰涂片细菌等级≤2+、初始痰培养细菌等级≤2+、规范用药、治疗6个月后痰培养阴性、无多发空洞、无厚壁空洞、无全肺受累、无胸膜增厚、无肺实变、无钙化影率分别为61.40%(35/57)、66.67%(38/57)、70.18%(40/57)、73.68%(42/57)、78.95%(45/57)、71.93%(41/57)、52.63%(30/57)、56.14%(32/57)、87.72%(50/57)、40.35%(23/57)、49.12%(28/57)、49.12%(28/57),治疗无效组分别为25.93%(7/27)、37.04%(10/27)、44.44%(12/27)、33.33%(9/27)、48.15%(13/27)、40.74%(11/27)、22.22%(6/27)、25.93%(7/27)、33.33%(9/27)、15.52%(5/27)、25.93%(7/27)、22.22%(6/27),差异均有统计学意义(均P<0.05)。logistic回归分析结果显示,年龄、复治、初始痰培养细菌等级3级及以上、多发空洞、厚壁空洞、全肺受累均是MDR-PTB患者治疗转归的危险因素(均P<0.05),治疗6个月后痰培养阴性、规范用药均是患者治疗转归的保护因素(均P<0.05)。结论MDR-PTB患者CT征象具有病灶分布广、形态多样性等特点,其治疗转归受到多种因素的影响,临床应重视对相关因素的干预,改善患者的治疗转归。

米诺环素联合头孢哌酮舒巴坦对MDR-AB感染重症肺炎患者肺功能及炎性因子的影响

目的 观察米诺环素联合头孢哌酮舒巴坦对多重耐药鲍曼不动杆菌(MDR-AB)感染重症肺炎患者肺功能及炎性因子的影响。方法 选取2020年1月—2023年6月武夷山市立医院收治的MDR-AB感染重症肺炎患者135例,根据随机数字表法分为联合组(68例)和对照组(67例)。在常规治疗基础上,对照组予头孢哌酮舒巴坦治疗,联合组在对照组基础上予米诺环素治疗,2组均治疗2周。比较2组疗效、细菌清除率,治疗前后肺功能[第1秒用力呼气容积(FEV_(1))、用力肺活量(FVC)、FEV_(1)/FVC]、炎性因子[白介素-8(IL-8)、C反应蛋白(CRP)、降钙素原(PCT)]及不良反应。结果 联合组总有效率为97.06%,高于对照组的86.57%(χ^(2)=4.964,P=0.026);联合组细菌总清除率为73.53%,高于对照组的56.72%(χ^(2)=4.204,P=0.040)。治疗2周后,2组FEV_(1)、FVC、FEV_(1)/FVC高于治疗前,且联合组高于对照组(P<0.05或P<0.01);2组IL-8、CRP、PCT水平低于治疗前,且联合组低于对照组(P<0.05或P<0.01)。联合组与对照组不良反应总发生率比较差异无统计学意义(14.71%vs.10.45%,χ^(2)=0.556,P=0.456)。结论 米诺环素联合头孢哌酮舒巴坦治疗MDR-AB感染重症肺炎疗效显著,可促进细菌清除,改善患者肺功能,减轻炎性反应,且安全性较高。

Multidrug-Resistant of Escherichia coli and Salmonella spp. Strains in Chicken Feces Intended for Consumption in Open Spaces of Ouagadougou, Burkina Faso

Resistant bacteria can be transmitted to humans through feces or contaminated meat from local chickens. Bacterial strains were isolated from the intestinal contents of 400 local chicken samples from various sales sites. These strains were then characterized using bacteriological and biochemical methods to identify resistant strains. In a study conducted in Ouagadougou, we systematically collected chicken fecal samples from 20 locations across the city, followed by isolation and identification of Salmonella spp. using specific enrichment and culture methods, as well as Escherichia coli. Bacterial strains were characterized using antibiotic resistance profiles were determined through agar diffusion tests, revealing sensitivity or resistance to a range of antibiotics based on established scientific criteria. The results showed that out of the 400 samples collected, 81.25% and 63.5% were contaminated by Escherichia coli and Salmonella spp., respectively. Among these, 86.15% of identified Escherichia coli and 50.78% of Salmonella spp. displayed resistance to at least one tested antibiotic. Among 280 Escherichia coli isolates identified resistant to at least one antibiotic, 31.07% were resistant to cefotaxime (CTX), 20.35% to ceftazidime (CAZ), 21.07% to ceftriaxone (CTR), 75% to amoxicillin clavulanic acid (AMC), 23.57% aztreoname (ATM) and 27.14% were resistant to imipenem (IMP). In the case of the 129 Salmonella spp. isolates resistant to at least one tested antibiotic, 34.88% were resistant to CTX;41.08% to CAZ;35.65% to CTR, 92% to AMC, 39.53% to ATM and finally 47.28% were resistant to IMP. Our study revealed high prevalence of resistance in bacterial strains isolated from local chickens sold outdoors in Ouagadougou. These findings raise significant public health concerns, due to the possible transmission of these resistant strains to humans through the consumption of contaminated meat, thus complicating the treatment of bacterial infections.

利奈唑胺联合多黏菌素B、亚胺培南治疗老年MDR-AB肺炎患者的效果

目的:观察利奈唑胺联合多黏菌素B、亚胺培南治疗老年多重耐药鲍氏不动杆菌(MDR-AB)肺炎患者的效果。方法:选取2022年1月至2023年1月该院收治的120例老年MDR-AB肺炎患者进行前瞻性研究,按照随机数字表法分为观察组与对照组各60例。对照组采用多黏菌素B联合亚胺培南治疗,观察组在对照组基础上加用利奈唑胺葡萄糖注射液治疗,比较两组治疗总有效率、血清炎性因子[白细胞介素(IL)-6、IL-8、肿瘤坏死因子(TNF-α)]水平、外周血T细胞亚群指标(CD3^(+)、CD4^(+)、CD8^(+)、CD4^(+)/CD8^(+))水平、肺功能指标[用力肺活量(FVC)、最大呼气中段流量(MMF)、呼气峰流速(PEF)]水平和不良反应发生率。结果:观察组治疗总有效率为95.00%,明显高于对照组的83.33%,差异有统计学意义(P<0.05);治疗后,观察组FVC、MMF、PEF、CD3^(+)、CD4^(+)和CD4^(+)/CD8^(+)水平高于对照组,IL-6、IL-8、TNF-α和CD8^(+)水平低于对照组,差异均有统计学意义(P<0.05);两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论:利奈唑胺联合多黏菌素B、亚胺培南治疗老年MDR-AB肺炎患者可提高治疗总有效率和肺功能指标水平,改善T细胞亚群指标水平,以及降低炎性因子水平,效果优于多黏菌素B联合亚胺培南治疗。

Establishment of a mdr1 Multidrug Resistant Model of Orthotopic Transplantation of Liver Carcinoma on Nude Mice

To develop a new method of inducing mdrl multidrug resistance by establishinga nude mice model of orthotopic transplantation of liver carcinoma by sporadic abdominalchemotherapy at intervals. Methods: Hepatocellular carcinoma HepG2 cell was cultured and injectedsubcutaneously to form the tumor-supplying mice. The tumor bits from the tumor-supplying mice wereimplanted under the envelope of the mice liver and induced by abdominal chemotherapy withPharmorubicin. Physical examination, ultrasonography, spiral CT and operative inspection were usedto examine tumor progression. RT-PCR and immunohistochemistry were adopted to detect the expressionof mdr1-mRNA and its encoded protein P-gp protein (P-gp). Results: There was no operative dead, therate of implanting tumor successfully was 88% (22/25), the rate of implanting secondly successfullywas 100% (3/3), and the rate of inducing successfully was 80% (16/20). The expression of mdrl-mRNAand the P-gp in the inducing group was 23 folds and 13 folds in the control group respectively.Conclusion: We have established an in vivo model of mdr using nude mice transplanted with orthotopicliver neoplasm coupled to chemotherapy.

基于MDR的知识图谱语义关系及表示标准化模型研究

本文通过对国内外知识图谱标准化研究和发布情况的系统梳理与剖析,发现当前知识图谱标准化过程中缺乏对底层语义关系结构和表示的标准化。因此,本文首先在MDR(metadata registries)概念元模型的基础上,扩充了语义关系类型和关系表示,构建了一个标准的、可扩展的、通用的知识图谱语义关系元模型,为知识图谱中语义关系的构建提供了必备的语义要素,实现从传统数据语义结构向知识图谱语义结构的迁移。其次,为实现语义关系表示的标准化,以该标准化元模型为指导,构建知识图谱语义关系标准化本体栈,为知识图谱语义关系标准化提供了从语义关系结构到表示的标准构建体系。最后,以石油领域井下作业业务需求为背景,对其中涉及的语义关系进行注册,并据此实现了石油领域井下作业知识图谱中语义关系的标准化,验证了本文提出的知识图谱语义关系元模型的合理性和正确性,提出的知识图谱语义关系元模型具有创新性。

The Activity of Erianin and Chrysotoxine from Dendrobium chrysotoxum to Reverse Multidrug Resistance in B16/h MDR-1 Cells

The ability of two dihydrostilbene derivatives erianin and chrysotoxine from Dendrobium chrysotoxum to reverse multidrug resistant (MDR) cells was investigated using murine B16 melanoma cells transfected with the human MDR 1 gene and crossresistant to vinblastine and adriamycin (B16/h MDR 1 cells). Both of the two compounds were shown to increase the accumulation of adriamycin, the P glycoprotein (P gp) substrate, in B16/h MDR 1 transfectants.

PXR、MDR1、CYP3A5和CYP2B6在高级别浆液性卵巢癌组织中的表达及其意义

目的探讨孕烷X受体(PXR)、多药耐药蛋白1(MDR1)、细胞色素P4503A5(CYP3A5)和细胞色素P4502B6(CYP2B6)在高级别浆液性卵巢癌(high grade serous ovarian cancer,HGSOC)组织中的表达及其意义。方法选取2019年9月-2021年12月青岛市市立医院妇科收治的56例HGSOC患者作为试验组,据其对铂类药物的耐药情况分为耐药组(24例)和敏感组(32例),另外选取妇科同期收治的16例子宫肌瘤患者作为对照组。采用免疫组织化学、实时定量荧光PCR及蛋白印迹法对试验组患者HGSOC组织和对照组患者正常输卵管组织中PXR、MDR1、CYP3A5和CYP2B6的表达情况进行检测。结果与对照组相比较,试验组患者PXR、MDR1、CYP3A5、CYP2B6阳性表达率显著升高(χ^(2)=12.879~17.174,P<0.05),mRNA相对表达量显著升高(t=9.746~17.640,P<0.05),蛋白表达量显著升高(t=13.312~60.448,P<0.05);与敏感组相比,耐药组患者PXR、MDR1、CYP3A5、CYP2B6阳性表达率显著升高(χ^(2)=4.371~8.549,P<0.05),mRNA相对表达量显著升高(t=6.859~19.000,P<0.05),蛋白表达量显著升高(t=8.693~27.670,P<0.05)。HGSOC患者PXR与CYP3A5、CYP2B6的表达呈正相关(r=0.332、0.308,P<0.05),与MDR1的表达无明显相关性(P>0.05)。结论PXR、MDR1、CYP3A5、CYP2B6在HGSOC患者的肿瘤组织中呈高表达,其可能参与HGSOC的发生发展过程。PXR、MDR1、CYP3A5和CYP2B6的表达检测可用于判断HGSOC对化疗的敏感性,有助于为术后化疗提供指导意见。

Reversing multidrug resistance by RNA interference through the suppression of MDR1 gene in human hepatoma cells

AIM： To reverse the multidrug resistance （MDR） by RNA interference （RNAi）-mediated MDRI suppression in heparoma cells.METHODS： For reversing MDR by RNAi technology, two different short hairpin RNAs （shRNAs） were designed and constructed into pGenSil-1 plasmid, respectively. They were then transfected into a highly adriarnycin-resistant HepG2 hepatorna cell line （HepG2/ADM）. The RNAi effect on MDR was evaluated by real-time PCR, cell cytotoxicity assay and rhodarnine 123 （Rh123） efflux assy. RESULTS： The stably-transfected clones showed various degrees of reversal of MDR phenotype. Surprisingly, the MDR phenotype was completely reversed in two transfected clones. CONCLUSION： MDR can be reversed by the shRNAmediated MDRI suppression in HepG2/ADM cells, which provides a valuable clue to make multidrug-resistant hepatoma cells sensitive to anti-cancer drugs.

REVERSAL EFFECTS OF MIFEPRISTONE ON MULTIDRUG RESISTANCE(MDR) IN DRUG-RESISTANT BREAST CANCER CELL LINE MCF7/ADR IN VITRO AND IN VIVO

To explore the reversal effect of mifepristone on multidrug resistance (MDR) in drug-resistant human breast cancer cell line MCF7/ADR and its mechanisms. Methods: Expression of MDR1 and MDR-associated protein(MRP) mRNA in MCF7/ADR cells was detected using reverse transcription- polymerase chain reaction(RT-PCR). Western blotting was used to assay the protein levels of P-glycoprotein (P-gp) and MRP. Intracellular rhodamine 123 retention and [3H]vincristine (VCR) accumulation were measured by flow cytometry and liquid scintillation counter, respectively. MTT reduction assay was used to determine the sensitivity of cells to the anticancer agent, adriamycin (ADR). Additionally, a MCF7/ADR cell xenograft model was established to assess the reversal effect of mifeprisone on MDR in MCF7/ADR cells in vivo. Results: Miferpristone dose-dependently down- regulated the expression of MDR1 and MRP mRNA in MCF7/ADR cells, accompanied by a significant decrease in the protein levels of P-gp and MRP. After exposure to 5, 10, and 20 mmol/L mifepristone, MCF7/ADR cells showed a 3.87-, 5.81-, and 7.40-fold increase in the accumulation of intracellular VCR(a known substrate of MRP), and a 2.14-, 4.39-, and 5.53-fold increase in the retention of intracellular rhodamine 123(an indicator of P-gp function), respectively. MTT analysis showed that the sensitivity of MCF7/ADR cells to ADR was enhanced by 7.23-, 13.62-, and 20.96-fold after incubation with mifepristone as above-mentioned doses for 96 h. In vivo, mifepristone effectively restored the chemosensitivity of MCF7/ADR cells to ADR. After 8 weeks of administration with ADR(2 mg穔g-1穌-1) alone or in combination with mifepristone(50 mg穔g-1穌-1), the growth inhibitory rate of xenografted tumors in nude mice was 8.08% and 37.25%, respectively. Conclusion: Mifepristone exerts potent reversal effects on MDR in MCF7/ADR cells in vitro and in vivo through down- regulation of MDR1/P-gp and MRP expression and inhibition of P-gp- and MRP-dependent drug efflux, thus increasing the sensitivity to anticancer drug.

多药耐药性基因1(MDR1)基因多态性对丙戊酸钠治疗老年癫痫血药浓度的影响

目的探讨多药耐药性基因1(multidrug resistance 1 gene,MDR1)基因多态性对丙戊酸钠治疗老年癫痫血药浓度的影响。方法选择2021年10月1日—2022年10月1日于淮北矿工总医院诊治的老年癫痫患者86例为研究对象,采用多聚酶连锁反应限制性片段长度多态性(Polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)和测序技术确定MDR1 C3435T位点基因型分布情况,采用柱前衍生化法(HPLC法)测定丙戊酸血清药物浓度,分析MDR1 C3435T基因多态性与丙戊酸钠治疗老年癫痫血药浓度的相关性。结果不同MDR1 C3435T基因型患者丙戊酸钠血药浓度差异有统计学意义(P<0.05)。与CC基因型组比较,TT基因型组和CT基因型组的丙戊酸钠血药浓度均显著升高(P<0.05)。老年癫痫患者使用丙戊酸钠后,突变组胃肠道反应、嗜睡、肝功能异常、肾功能异常等总不良反应发生率显著高于CC基因型组(P<0.05)。结论MDR1 C3435T的TT基因型组和CT基因型组均可增加老年癫痫患者丙戊酸钠的血药浓度,但同时不良反应发生率更高。