MDR, multidrug resistance

MDR,多药耐药
  • 文章类型: Journal Article
    甲状腺癌,作为最常见的内分泌癌症之一,近年来发病率激增。这很可能是由于其传统诊断方式缺乏特异性和准确性,导致甲状腺结节的过度诊断。虽然有几种治疗选择,它们仅限于手术和131I放射治疗,这些治疗具有显著的副作用,因此不能满足恶性程度非常高的未分化甲状腺癌的治疗需求.利用光吸收的光学成像,折射和散射特性,不仅观察细胞的结构和功能,组织,器官,甚至整个有机体来协助诊断,但也可用于进行光学治疗,以实现甲状腺癌的靶向非侵入性和精确治疗。这些筛选的应用,诊断,和治疗,赋予光学成像在甲状腺癌手术导航领域的潜力。在过去的十年里,光学成像在甲状腺癌诊断和治疗中的研究逐年增长,但是没有发表关于这个主题的全面评论。这里,我们回顾了光学成像在甲状腺癌诊断和治疗中应用的关键进展,并讨论了该技术在临床应用中的挑战和潜力。
    Thyroid cancer, as one of the most common endocrine cancers, has seen a surge in incidence in recent years. This is most likely due to the lack of specificity and accuracy of its traditional diagnostic modalities, leading to the overdiagnosis of thyroid nodules. Although there are several treatment options available, they are limited to surgery and 131I radiation therapy that come with significant side effects and hence cannot meet the treatment needs of anaplastic thyroid carcinoma with very high malignancy. Optical imaging that utilizes optical absorption, refraction and scattering properties, not only observes the structure and function of cells, tissues, organs, or even the whole organism to assist in diagnosis, but can also be used to perform optical therapy to achieve targeted non-invasive and precise treatment of thyroid cancer. These applications of screening, diagnosis, and treatment, lend to optical imaging\'s promising potential within the realm of thyroid cancer surgical navigation. Over the past decade, research on optical imaging in the diagnosis and treatment of thyroid cancer has been growing year by year, but no comprehensive review on this topic has been published. Here, we review key advances in the application of optical imaging in the diagnosis and treatment of thyroid cancer and discuss the challenges and potential for clinical translation of this technology.
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  • 文章类型: Journal Article
    UNASSIGNED:本研究旨在确定埃塞俄比亚结核病患者中结核分枝杆菌和利福平耐药的频率和趋势。他们在2014年至2021年之间使用XpertMTB/RIF测定法进行了测试。
    UNASSIGNED:数据是回顾性地从患者登记处收集的。从国家结核病(TB)转诊实验室数据库中提取基于实验室的数据。2014年3月1日至2021年9月30日期间,来自全国各地的所有患者都转诊到国家结核病参考实验室(NTRL)进行结核病诊断,并使用XpertMTB/RIF测定法进行测试,包括在内。将提取的数据输入到MicrosoftExcel表中,并通过社会科学统计软件包(SPSS)版本23进行分析。
    UASSIGNED:在使用XpertMTB/RIF测定法测试的总共13772个人中,大多数(8223;59.7%)是男性,48.5%(6678)的个体年龄在15至39岁之间。在被检查的个体中,结核分枝杆菌(MTB)在17.0%(2347)中被检测到。在检测到的MTB病例中,近9.9%(233)为利福平耐药(RR-TB),而24(1.0%)为RR中间值。在所有RR-TB病例中,超过一半(125;53.6%)在男性中检测到,和105个新的结核病例。肺外(EPTB)患者的利福平耐药率(11.0%)高于肺(PTB)患者(9.6%)。
    未经评估:在研究环境中,TB和RR-TB的频率仍然很高。发现RR-TB与先前的抗结核药物治疗具有统计学上的显着关联。因此,在公认病例中提高治疗依从性有助于预防MTB和RR-TB病例.
    UNASSIGNED: This study aimed to determine the frequencies and trends of Mycobacterium tuberculosis and rifampicin resistance among presumptive tuberculosis patients in Ethiopia, who were tested using the Xpert MTB/RIF assay between 2014 and 2021.
    UNASSIGNED: Data were collected retrospectively from patient registries. Laboratory-based data were extracted from the national tuberculosis (TB) referral laboratory database. All patients referred to the National Tuberculosis Reference Laboratory (NTRL) for TB diagnosis from all over the country between March 1, 2014 and September 30, 2021, and tested using the Xpert MTB/RIF assay, were included. The extracted data were entered into a Microsoft Excel sheet and analyzed by Statistical Package for Social Sciences (SPSS) version 23.
    UNASSIGNED: Among a total of 13 772 individuals tested using the Xpert MTB/RIF assay, the majority (8223; 59.7%) were males, and 48.5% (6678) of the individuals were aged between 15 and 39 years. Mycobacterium tuberculosis (MTB) was detected in 17.0% (2347) of the examined individuals. Of the detected MTB cases, nearly 9.9% (233) were rifampicin resistant (RR-TB), while 24 (1.0%) were RR-intermediate. Among all RR-TB cases, more than half (125; 53.6%) were detected in males, and 105 were new TB cases. Extrapulmonary (EPTB) patients had a greater rate of rifampicin resistance (11.0%) than pulmonary (PTB) patients (9.6%).
    UNASSIGNED: The frequency of TB and RR-TB remains high in the study setting. RR-TB was found to have a statistically significant association with previous anti-TB medication treatment. As a result, improving treatment adherence in recognized instances could assist in preventing MTB and RR-TB cases.
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  • 文章类型: Journal Article
    由各种微生物病原体引起的人类传染病,总的来说,每年都会影响大量的个体。这些迅速传播的微生物疾病仍然是各种健康相关领域的大问题,并且要承受负面的药物影响,抗微生物抗性病原微生物(病原细菌和病原真菌)已经发展了针对许多抗微生物药物类别的各种抗性过程。在COVID-19爆发期间,药物和多药耐药相关的病原微生物种类似乎出现了热潮。现有抗菌药物的优势并不完全有效,这限制了它们在临床环境中的应用。细菌产生的几种天然化学物质,植物,动物,海洋物种,和其他来源现在正在研究抗菌特性。这些从不同来源提取的天然抗微生物化合物已被证明对多种疾病有效,虽然植物仍然是最丰富的来源。这些化合物在减少与药物耐受性和耐药性发展有关的微生物疾病方面显示出希望。本文详细介绍了一些最重要和最有前途的天然化合物及其衍生物对各种人类传染性微生物的影响。不同的天然抗菌化合物的抑制作用,以及它们对一系列病原真菌和细菌生物体的抗菌作用的可能机制,提供。该审查将有助于完善当前的抗菌药物(抗真菌和抗菌药物),并建立新的治疗策略,以应对不断增加的人类细菌和真菌相关感染。
    Human infectious diseases caused by various microbial pathogens, in general, impact a large population of individuals every year. These microbial diseases that spread quickly remain to be a big issue in various health-related domains and to withstand the negative drug impacts, the antimicrobial-resistant pathogenic microbial organisms (pathogenic bacteria and pathogenic fungi) have developed a variety of resistance processes against many antimicrobial drug classes. During the COVID-19 outbreak, there seems to be an upsurge in drug and multidrug resistant-associated pathogenic microbial species. The preponderance of existing antimicrobials isn\'t completely effective, which limits their application in clinical settings. Several naturally occurring chemicals produced from bacteria, plants, animals, marine species, and other sources are now being studied for antimicrobial characteristics. These natural antimicrobial compounds extracted from different sources have been demonstrated to be effective against a variety of diseases, although plants remain the most abundant source. These compounds have shown promise in reducing the microbial diseases linked to the development of drug tolerance and resistance. This paper offers a detailed review of some of the most vital and promising natural compounds and their derivatives against various human infectious microbial organisms. The inhibitory action of different natural antimicrobial compounds, and their possible mechanism of antimicrobial action against a range of pathogenic fungal and bacterial organisms, is provided. The review will be useful in refining current antimicrobial (antifungal and antibacterial) medicines as well as establishing new treatment strategies to tackle the rising number of human bacterial and fungal-associated infections.
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  • 文章类型: Journal Article
    抗菌素耐药性的出现是一项重大的全球卫生挑战,并成为决策者的当务之急。在埃塞俄比亚,缺乏从一种健康角度提出多药耐药模式的科学研究。因此,一项系统评价和荟萃分析旨在确定人类细菌多药耐药性的汇总患病率,动物,食物,和环境来源。
    在本系统综述和荟萃分析中,在PubMed和Google学者中使用不同的关键字进行了电子搜索。在埃塞俄比亚所有地区进行的研究,从2015年到2020年在同行评审期刊上发表,包括英语全文。荟萃分析是在STATA版本14上进行的。使用随机效应模型分析了每种细菌的多药耐药性的汇总患病率;CochranQ统计量和I2统计量用于分析异质性,并在p<0.01时被认为是显着的。
    81项研究纳入系统评价和荟萃分析;53项人体研究,八项动物研究,和16个环境/食物研究。荟萃分析包括来自革兰氏阳性细菌的6种和来自革兰氏阴性细菌的13种。金黄色葡萄球菌53%(95CI:42-64%),凝固酶阴性葡萄球菌68%(95CI:53-82),假单胞菌属。73%(95CI:48-93%),大肠杆菌70%(95CI:61-78%),柠檬酸杆菌属。71%(95CI:54-87%),克雷伯菌属。68%(54-80%),肠杆菌属。67%(48-83%)和沙门氏菌。65%(95CI:48-81%)是来自两种或更多种来源的常见多重耐药细菌。
    在埃塞俄比亚,在大多数人类细菌物种中,MDR的合并患病率很高,动物,食物,和环境来源。葡萄球菌,肠杆菌科和假单胞菌的大多数成员,是涉及所有来源的标准MDR细菌种群。因此,应实施综合政策和干预措施,以减少MDR细菌的出现和传播,从而获得更好的动物和人类健康结果。
    UNASSIGNED: The emergence of antimicrobial resistance is a major global health challenge and becoming an urgent priority for policymakers. There is a paucity of scientific studies presenting the multidrug resistance pattern from one health perspective in Ethiopia. Therefore, a systematic review and meta-analysis aimed to determine the pooled prevalence of multidrug resistance in bacteria from human, animal, food, and environmental sources.
    UNASSIGNED: In this systematic review and meta-analysis, an electronic search was made in PubMed & Google scholar using different keywords. The studies conducted in all areas of Ethiopia, published from 2015 to 2020 in peer-reviewed journals, English full-length papers were included. The meta-analysis was done on STATA version 14. The pooled prevalence of multidrug resistance for each bacterium was analysed using the random-effects model; Cochran Q statistics and the I 2 statistic was used to analyse heterogeneity and considered significant at p < 0.01.
    UNASSIGNED: 81 studies were included in the systematic review and meta-analysis; 53 human studies, eight animal studies, and 16 environments/food studies. The meta-analysis included six species from gram-positive bacteria and 13 from gram-negative bacteria. S. aureus 53% (95%CI: 42-64%), Coagulase negative Staphylococci 68%(95%CI:53-82), Pseudomonas spp. 73%(95%CI:48-93%), E. coli 70% (95%CI:61-78%), Citrobacter spp. 71%(95%CI:54-87%), Klebsiella spp. 68% (54-80%), Enterobacter spp. 67% (48-83%) and Salmonella spp. 65% (95%CI:48-81%) were the common multidrug-resistant species of bacteria from two or more sources.
    UNASSIGNED: In Ethiopia, the pooled prevalence of MDR is high in most bacterial species from humans, animals, food, and environmental sources. Staphylococcus, most members of the Enterobacteriaceae and Pseudomonas, are the standard MDR bacterial population involving all sources. Therefore, integrated policy and intervention measures should be implemented to reduce the emergence and spread of MDR bacteria for better animal and human health outcomes.
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  • 文章类型: Journal Article
    多药耐药(MDR)仍然是骨肉瘤(OS)成功治疗的关键瓶颈。木犀草素是一种类黄酮化合物,已被证实可增加许多肿瘤对抗肿瘤药物的敏感性。然而,它在逆转OS的MDR中的作用以及潜在的潜在机制在很大程度上仍然未知。在这项研究中,我们证明了木犀草素在OS细胞和异种移植模型中增强细胞对多柔比星和顺铂的化学敏感性,它可以增加miR-384水平并下调PTN表达。此外,靶标分析证实miR-384直接调节PTN表达,随后的机制分析证实miR-384可以通过抑制PTN/β-catenin/MDR1信号轴抑制OS细胞的MDR。进一步的分析显示用木犀草素处理敏感的MG63细胞有效地将miR-384包装到分泌的外泌体中,并且外泌体可以改善多柔比星抗性MG63/DOX细胞中的多柔比星应答。我们的研究证实,木犀草素通过miR-384调节PTN表达对OS细胞发挥MDR逆转作用,并且通过靶向PTN/β-catenin/MDR1轴,它可能是一种有前途的化疗耐药OS治疗剂。
    Multidrug resistance (MDR) remains a critical bottleneck in successful treatment of osteosarcoma (OS). Luteolin is a flavonoid compound that has been verified to increase the sensitivity to antineoplastic drugs in many tumors. However, its roles in reversing MDR of OS and the potential underlying mechanisms remain largely unknown. In this study, we demonstrated that luteolin enhances cellular chemosensitivity to doxorubicin and cisplatin both in OS cells and xenograft models, and it could increase the miR-384 level and downregulate the PTN expression. Additionally, target analysis confirmed that miR-384 directly modulates PTN expression, and subsequent mechanistic analysis verified that miR-384 could inhibit the MDR of OS cells through suppressing the PTN/β-catenin/MDR1 signaling axis. Further analysis revealed treatment of sensitive MG63 cells with luteolin effectively packaged miR-384 into secreted exosomes and the exosomes could improve doxorubicin response in doxorubicin-resistant MG63/DOX cells. Our study confirmed that luteolin exerts MDR reversal effect against OS cells by regulating PTN expression via miR-384 and it may be a promising therapeutic agent for chemoresistant OS via its targeting of the PTN/β-catenin/MDR1 axis.
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  • 文章类型: Journal Article
    纳米技术在医学应用中,特别是在肿瘤学中作为药物输送系统,最近显示了有希望的结果。然而,尽管这些进展在临床前阶段很有希望,这项技术的临床应用具有挑战性。为临床翻译创造具有更高治疗功效的药物递送系统,纳米粒子的物理化学特性,如尺寸,形状,弹性(柔性/刚性),表面化学,可以指定表面电荷以优化给定应用的效率。因此,跨学科研究人员专注于生产生物相容性材料,生产技术,或有效装载的新配方,和高稳定性。设计参数的影响可以在体外研究,在体内,或者使用计算模型,目的是了解它们如何影响纳米粒子生物物理学及其与细胞的相互作用。本综述总结了癌症纳米药物的生产和设计以实现临床转化和商业化的进展和技术。我们还强调了该领域现有的挑战和机遇。
    Nanotechnology in medical applications, especially in oncology as drug delivery systems, has recently shown promising results. However, although these advances have been promising in the pre-clinical stages, the clinical translation of this technology is challenging. To create drug delivery systems with increased treatment efficacy for clinical translation, the physicochemical characteristics of nanoparticles such as size, shape, elasticity (flexibility/rigidity), surface chemistry, and surface charge can be specified to optimize efficiency for a given application. Consequently, interdisciplinary researchers have focused on producing biocompatible materials, production technologies, or new formulations for efficient loading, and high stability. The effects of design parameters can be studied in vitro, in vivo, or using computational models, with the goal of understanding how they affect nanoparticle biophysics and their interactions with cells. The present review summarizes the advances and technologies in the production and design of cancer nanomedicines to achieve clinical translation and commercialization. We also highlight existing challenges and opportunities in the field.
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  • 文章类型: Journal Article
    我国利福平耐药结核病(RR-TB)的病例逐年增加,RR-TB的死亡被认为是由于抗结核药物的副作用导致的QTc间期延长。因此,在RR-TB患者中,需要将细胞因子用作QTc间期延长的早期标志物.
    本研究旨在分析接受较短治疗方案的RR-TB患者中炎性细胞因子与QTc间期的相关性。
    本研究采用病例对照研究,时间序列为2019年9月至2020年2月,在印度尼西亚的一家结核病转诊医院进行。使用ELISA方法测量血液样本中的细胞因子水平,使用心电图机自动记录QTc间期。使用的统计分析是卡方检验,曼·惠特尼测试,独立性t检验,和Spearman秩检验,p<0.05。
    在TNF-α值(6.8pg/ml;r=0.207;p=0.281)的强化期,炎性细胞因子与QTc延长之间没有显着相关性,IL-1β(20.13pg/ml;r=0.128;p=0.509),和IL-6(43.17pg/ml;r=-0.028;p=0.886)。同时,在延续阶段,TNF-α的值(4.79pg/ml;r=0.046;p=0.865),IL-1β(7.42pg/ml;r=-0.223;p=0.406),和IL-6(40.61pg/ml;r=-0.147;p=0.586)。
    炎性细胞因子(TNF-α,IL-1β,和IL-6)不能用于识别接受较短方案的RR-TB患者的QTc间期延长。
    UNASSIGNED: The cases of Rifampicin-Resistant Tuberculosis (RR-TB) in our country have increased every year and RR-TB deaths are thought to be caused by prolongation of the QTc interval due to side effects of anti-tuberculosis drugs. Thus, cytokines are needed to be used as early markers of prolongation of the QTc interval in RR-TB patients.
    UNASSIGNED: This study aims to analyze the correlation of inflammatory cytokines on QTc interval in RR-TB patients who received shorter regimens.
    UNASSIGNED: This study uses a case-control study with a time series conducted in the period September 2019 to February 2020 in one of the referral hospitals for Tuberculosis in Indonesia. Cytokines levels from blood samples were measured using the ELISA method, while QTc intervals were automatically recorded using an electrocardiography machine. The statistical analysis used was the Chi-square test, Man Whitney test, Independence t-test, and Spearman-rank test with p < 0.05.
    UNASSIGNED: There was no significant correlation between inflammatory cytokines and QTc prolongation in intensive phase which TNF-α value (6.8 pg/ml; r = 0.207; p = 0.281), IL-1β (20.13 pg/ml; r = 0.128; p = 0.509), and IL-6 (43.17 pg/ml; r = -0.028; p = 0.886). Meanwhile, in the continuation phase, the values for TNF-α (4.79 pg/ml; r = 0.046; p = 0.865), IL-1β (7.42 pg/ml; r = -0.223; p = 0.406), and IL- 6 (40.61 pg/ml; r = -0.147; p = 0.586).
    UNASSIGNED: inflammatory cytokines (TNF-α, IL-1β, and IL-6) cannot be used to identify QTc interval prolongation in RR-TB patients who received shorter regimens.
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  • 文章类型: Journal Article
    顺铂(CSP)是一种有效的抗癌药物,广泛用于治疗多形性胶质母细胞瘤(GBM)。然而,CSP在GBM中的临床疗效与低治疗比例相比,毒性,多药耐药(MDR)。因此,我们开发了一种通过负载顺铂的聚合物纳米平台(CSP-NP)在GBM中主动靶向顺铂的系统。
    CSP-NP通过改进的双乳液和纳米沉淀技术制备。CSP-NP的物理化学表征使用zetasizer进行,扫描电子显微镜(SEM),药物释放动力学,和药物含量分析。细胞毒性,诱导凋亡,和细胞周期特异性的CSP-NP在人GBM细胞系中的活性通过MTT法进行评估,荧光显微镜,和流式细胞术。通过荧光成像和流式细胞术测量细胞内药物摄取。通过基于流式细胞术的药物外排测定来评估CSP-NP抑制MDR转运蛋白的潜力。
    CSP-NP具有光滑的表面特性,具有离散的粒径以及所需的zeta电位,多分散指数,药物包封效率,和药物含量。CSP-NP已显示出“初始爆发效应”,随后具有持续的药物释放特性。CSP-NP在人GBM细胞中赋予剂量和时间依赖性细胞毒性并触发凋亡。有趣的是,CSP-NP显着增加摄取,内化,和抗癌药物的积累。此外,CSP-NP显著逆转人GBM细胞中的MDR转运蛋白(ABCB1和ABCG2)。
    顺铂的纳米颗粒系统似乎具有积极靶向顺铂的潜力,可作为人类GBM的有效和特异性治疗剂,从而消除了目前化疗的局限性。
    UNASSIGNED: Cisplatin (CSP) is a potent anticancer drug widely used in treating glioblastoma multiforme (GBM). However, CSP\'s clinical efficacy in GBM contrasted with low therapeutic ratio, toxicity, and multidrug resistance (MDR). Therefore, we have developed a system for the active targeting of cisplatin in GBM via cisplatin loaded polymeric nanoplatforms (CSP-NPs).
    UNASSIGNED: CSP-NPs were prepared by modified double emulsion and nanoprecipitation techniques. The physiochemical characterizations of CSP-NPs were performed using zeta sizer, scanning electron microscopy (SEM), drug release kinetics, and drug content analysis. Cytotoxicity, induction of apoptosis, and cell cycle-specific activity of CSP-NPs in human GBM cell lines were evaluated by MTT assay, fluorescent microscopy, and flow cytometry. Intracellular drug uptake was gauged by fluorescent imaging and flow cytometry. The potential of CSP-NPs to inhibit MDR transporters were assessed by flow cytometry-based drug efflux assays.
    UNASSIGNED: CSP-NPs have smooth surface properties with discrete particle size with required zeta potential, polydispersity index, drug entrapment efficiency, and drug content. CSP-NPs has demonstrated an \'initial burst effect\' followed by sustained drug release properties. CSP-NPs imparted dose and time-dependent cytotoxicity and triggered apoptosis in human GBM cells. Interestingly, CSP-NPs significantly increased uptake, internalization, and accumulations of anticancer drugs. Moreover, CSP-NPs significantly reversed the MDR transporters (ABCB1 and ABCG2) in human GBM cells.
    UNASSIGNED: The nanoparticulate system of cisplatin seems to has a promising potential for active targeting of cisplatin as an effective and specific therapeutic for human GBM, thus eliminating current chemotherapy\'s limitations.
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  • 文章类型: Journal Article
    由ATP结合盒亚家族B成员1(ABCB1)介导的多药耐药(MDR)显着阻碍了有效的癌症化疗。然而,目前,目前尚无ABCB1抑制药物在临床上被批准用于治疗MDR癌症,主要是由于抑制剂的特异性,毒性,和药物相互作用。这里,我们报道了三种聚氧孕烷(POPs)是夜蛾中最丰富的成分(M.tenacissima)是新型ABCB1调节前药,在体内进行肠道微生物群介导的生物转化以产生活性代谢物。无毒浓度的代谢物通过抑制ABCB1外排活性而不改变ABCB1蛋白表达,恢复了ABCB1过表达癌细胞的化学敏感性。进一步鉴定为ABCB1的特异性非竞争性抑制剂,在ABCB1药物腔内显示多个结合位点。这些持久性有机污染物没有表现出ABCB1/药物代谢酶相互作用,并且它们的重复给药产生了可预测的与紫杉醇的药代动力学相互作用,而在体内没有明显的毒性。我们进一步表明,这些POPs增强了紫杉醇在肿瘤中的积累,并克服了ABCB1介导的化学抗性。结果表明,这些持久性有机污染物有可能被开发为安全的,强力,以及逆转ABCB1介导的MDR的特异性前药。我们的工作还为在联合化疗中使用肌腱分枝杆菌提供了科学证据。
    Multidrug resistance (MDR) mediated by ATP binding cassette subfamily B member 1 (ABCB1) is significantly hindering effective cancer chemotherapy. However, currently, no ABCB1-inhibitory drugs have been approved to treat MDR cancer clinically, mainly due to the inhibitor specificity, toxicity, and drug interactions. Here, we reported that three polyoxypregnanes (POPs) as the most abundant constituents of Marsdenia tenacissima (M. tenacissima) were novel ABCB1-modulatory pro-drugs, which underwent intestinal microbiota-mediated biotransformation in vivo to generate active metabolites. The metabolites at non-toxic concentrations restored chemosensitivity in ABCB1-overexpressing cancer cells via inhibiting ABCB1 efflux activity without changing ABCB1 protein expression, which were further identified as specific non-competitive inhibitors of ABCB1 showing multiple binding sites within ABCB1 drug cavity. These POPs did not exhibit ABCB1/drug metabolizing enzymes interplay, and their repeated administration generated predictable pharmacokinetic interaction with paclitaxel without obvious toxicity in vivo. We further showed that these POPs enhanced the accumulation of paclitaxel in tumors and overcame ABCB1-mediated chemoresistance. The results suggested that these POPs had the potential to be developed as safe, potent, and specific pro-drugs to reverse ABCB1-mediated MDR. Our work also provided scientific evidence for the use of M. tenacissima in combinational chemotherapy.
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  • 文章类型: Journal Article
    计算机辅助模式分析(C@PA)最近被提出作为预测多靶标ABC转运蛋白抑制剂的强大工具。这种计算方法的骨架是对已针对ABCB1,ABCC1和ABCG2评估的一组固定的报告小分子中频繁出现的分子特征的统计分析。因此,阐明了阴性和阳性模式,和二级阳性亚结构可以补充多靶指纹。将C@PA提升到非统计和探索性水平,结论的次级阳性模式用潜在的阳性亚结构进行扩展,以提高C@PA的预测能力并探索其稳健性.采用已知ABCB1、ABCC1和ABCG2三联抑制的命中率已知的ABCC1抑制剂的小集合化合物文库来虚拟地筛选延长的阳性模式。总的来说,846种潜在的广谱ABCB1、ABCC1和ABCG2抑制剂,从其中购买了10个并进行了生物学评估。我们的方法揭示了4种新型多靶点ABCB1,ABCC1和ABCG2抑制剂,生物命中率为40%,但抑制能力略低于原始C@PA。这是关于通过改善C@PA来发现针对最突出的ABC转运蛋白的新型广谱抑制剂的第一份报告。
    Computer-aided pattern analysis (C@PA) was recently presented as a powerful tool to predict multitarget ABC transporter inhibitors. The backbone of this computational methodology was the statistical analysis of frequently occurring molecular features amongst a fixed set of reported small-molecules that had been evaluated toward ABCB1, ABCC1, and ABCG2. As a result, negative and positive patterns were elucidated, and secondary positive substructures could be suggested that complemented the multitarget fingerprints. Elevating C@PA to a non-statistical and exploratory level, the concluded secondary positive patterns were extended with potential positive substructures to improve C@PA\'s prediction capabilities and to explore its robustness. A small-set compound library of known ABCC1 inhibitors with a known hit rate for triple ABCB1, ABCC1, and ABCG2 inhibition was taken to virtually screen for the extended positive patterns. In total, 846 potential broad-spectrum ABCB1, ABCC1, and ABCG2 inhibitors resulted, from which 10 have been purchased and biologically evaluated. Our approach revealed 4 novel multitarget ABCB1, ABCC1, and ABCG2 inhibitors with a biological hit rate of 40%, but with a slightly lower inhibitory power than derived from the original C@PA. This is the very first report about discovering novel broad-spectrum inhibitors against the most prominent ABC transporters by improving C@PA.
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