ATP-binding cassette transporters in progression and clinical outcome of pancreatic cancer: what is the way forward?

Pancreatic ductal adenocarcinoma(PDAC) is one of the most aggressive diseases and is characterized by high chemoresistance, leading to the lack of effective therapeutic approaches and grim prognosis. Despite increasing understanding of the mechanisms of chemoresistance in cancer and the role of ATPbinding cassette(ABC) transporters in this resistance, the therapeutic potential of their pharmacological inhibition has not been successfully exploited yet. In spite of the discovery of potent pharmacological modulators of ABC transporters, the results obtained in clinical trials have been so far disappointing, with high toxicity levels impairing their successful administration to the patients. Critically, although ABC transporters have been mostly studied for their involvement in development of multidrug resistance(MDR), in recent years the contribution of ABC transporters to cancer initiation and progression has emerged as an important area of research, the understanding of which could significantly influence the development of more specific and efficient therapies. In this review, we explore the role of ABC transporters in the development and progression of malignancies, with focus on PDAC. Their established involvement in development of MDR will be also presented. Moreover, an emerging role for ABC transporters as prognostic tools for patients' survival will be discussed, demonstrating the therapeutic potential of ABC transporters in cancer therapy.

ZBM30 suppresses atherosclerosis through up-regulating ATP-binding cassette A1 and G1

Atherosclerosis is the most common cause of cardiovascular diseases, such as myocardial infarction and stroke. The aim of this study was to investigate the effects of a novel compound ZBM30 on atherosclerosis in ApoE- deficient mice and its associated mechanism. ApoE-deficient mice （6 weeks old）, fed an atherogenic high-fat and high cholesterol diet for 8 weeks, were divided into three groups. Two groups were orally administrated ZBM30 （10, 30 nag ~ kg-1） daily for 12 weeks, while the control group was administered saline. Atherosclerotic lesions with en face aortas were evaluated by Sudan IV staining, and lesion areas in aortic sinuses were evaluated by oil red O staining. Necrotic core areas and fibrous cap areas in the lesion were evaluated by henaatoxylin and eosin （HE） staining and Masson＇ s trichronae staining in the aorta sinuses. The effects of ZBM30 on cholesterol accumulation in naacrophages and cholesterol transporters： ATP binding cassette A1 （ABCA1） and ATP binding cassette G1 （AB- CG1） were evaluated by oil red O assay, 3H-cholesterol efflux assay, Western blot, and real-time PCR on macro- phage cell lines： Raw 264.7 and THP-1. Inanauno-fluoresces was used to determine the ABCA1 expression in naac- rophage in aorta sinuses. Luciferase reporters of wild type and mutant types of ABCA1 promoter were constructed to determine the regulatory domain of ZBM30 on ABCA1 promoter. Results showed that, compared with the control group, en face lesions in ZBM30 group （ 10, 30 mg · kg^-1 ） were reduced 54.96 ± 10.06% and 71.50 ± 15.37% respectively, and aorta sinus lesions were reduced 41.85 ± 11.21% and 82.23 ± 8.25% respectively. Necrotic core areas in the ZBM30 group were markedly reduced and fibrous cap areas were not changed. Oil red O staining and 3 H-cholesterol efflux assays on Raw 264.7 cell line revealed that ZBM30 significantly attenuated the cholesterol accumulation in naacrophages by enhancing apolipoprotein AI and HDL mediated cholesterol efflux. Furthermore, ZBM30 induced the protein and naRNA expression of cholesterol transporters such as ABCA1 and ABCG1. Inanauno- fluoresces experiment revealed that ZBM30 induced the ABCA1 expression in naacrophage in the lesion, which is consistent with the results in vitro. Luciferase reporter assay revealed that ZBM30 exerted its effect on ABCA1 via liver X receptor （LXR） binding domain. In conclusion, ZBM30 suppresses atherosclerosis through up-regulating cholesterol efflux via ABCA1 and ABCG1 transporters in ApoE-deficient mice.

Inhibiting NF-κB increases cholesterol efflux from THP-1 derived-foam cells treated with AngⅡ via up-regulating the expression of ATP-binding cassette transporter A1

Objective： To study the role of nuclear factor-kappa B（NF- κB） in cholesterol efflux from THP-1 derived-foam cells treated with Angiotensin Ⅱ（Ang Ⅱ ）. Methods：Cultured THP-1 derived-foam cells were treated with Ang Ⅱ or preincubated with tosyl-phenylalanine chloromethyl-ketone（TPCK） NF- κB inhibitor. The levels of activated NF- κB in the cells were examined by sandwich ELISA, Cellular cholesterol content was studied by electron microscopy scanning and zymochemistry via fluorospectrophotometer and cholesterol effiux was detected by scintillation counting technique. ABCA1 mRNA and protein were quantified by RT-PCR and Western blotting. Results：Addition of TPCK to the cells before Ang Ⅱ stimulation attenuated the response of NF- κB p65 nuclear translocation induced by Ang Ⅱ and showed no peak in foam cells group and caused a reduction in cholesterol content and an increase in cholesterol efflux by 24.1%（P〈 0.05） and 41.1%（P〈 0.05） respectively, when compared with Ang Ⅱ group. In accordance, the ABCA1 mRNA and protein were increased by 30% and 19%（P 〈 0.05） respectively, when compared with Ang Ⅱ group. Conclusion：Ang Ⅱ can downregulate ABCA1 in THP-1 derived-foam cells via NF- K B, which leads to less cholesterol effiux and the increase of cholesterol content with the consequence of the promotion of atherosclerosis.

ATP binding cassette C1 (ABCC1/MRP1)-mediated drug efflux contributes to disease progression in T-lineage acute lymphoblastic leukemia

Purpose: In acute lymphoblastic leukemia (ALL), multidrug resistance is often mediated by AT- Pase Binding Cassette (ABC) proteins, which principally involve ABCC1 (multidrug resistance protein 1, MRP1) and ABCB1 (multidrug resistance 1, MDR1). However, direct comparisons between the differential effects of ABCC1 and ABCB1 have been difficult, since identical cell lines with differential expression of these transporters have not been developed. Experimental Design: In this study, we developed and compared the biological profiles of Jurkat cell lines that selectively over-expressed ABCC1 and ABCB1. Vincristine (VCR) plays an important role in the treatment of T-lineage ALL (T-ALL), and is often the first drug given to newly-diagnosed patients. Because of its importance in treatment, we provide descalating, sub-lethal doses of VCR to Jurkat cells, and extended our observations to expression profiling of newly diagnosed patients with T-ALL. Results: We found that VCR-resistant cells over-expressed ABCC1 nearly 30-fold. The calcein AM assay confirmed that VCR-resistant cells actively extruded VCR, and that ABCC1-mediated drug resistance conferred a different spectrum of multidrug resistance than other T-ALL induction agents. siRNA experiments that blocked ABCC1 export confirmed that VCR resistance could be reversed in vitro. Analyses of T-lymphoblasts obtained from 100 newly diagnosed T-ALL patients treated on Children’s Oncology Group Phase III studies 9404 and AALL0434 that induction failure could be could be partially explained by the over-expression of ABCC1 and ABCB1. Conclusions: Taken together, these results suggest that over-expression of ABC transporters plays a contributing role in mediating treatment failure in T-ALL, and underscore the need to employ alternate treatment approaches in patients for whom induction failed or for those with relapsed disease.

Coarse-Grained Free-Energy Simulations of Conformational State Transitions in an Adenosine 5′-Triphosphate-binding Cassette Exporter

ATP-binding cassette exporters transport many substrates out of cellular membranes via alternating between inward-facing and outward-facing conformations. Despite extensive research efforts over the past decades, understanding of the molecular mechanism remains elusive. As these large-scale conformational movements are global and collective, we have previously performed extensive coarse-grained molecular dynamics simulations of the potential of mean force along the conformational transition pathway [J. Phys. Chem. B 119, 1295(2015)]. However, the occluded conformational state, in which both the internal and external gate are closed, was not determined in the calculated free energy profile. In this work, we extend the above methods to the calculation of the free energy profile along the reaction coordinate, d1-d2, which are the COM distances between the two sides of the internal(d1)and the external gate(d2). The potential of mean force is thus obtained to identify the transition pathway, along which several outward-facing, inward-facing, and occluded state structures are predicted in good agreement with structural experiments. Our coarse-grained molecular dynamics free-energy simulations demonstrate that the internal gate is closed before the external gate is open during the inward-facing to outward-facing transition and vice versa during the inward-facing to outward-facing transition. Our results capture the unidirectional feature of substrate translocation via the exporter, which is functionally important in biology. This finding is different from the previous result, in which both the internal and external gates are open reported in an X-ray experiment [Proc. Natl. Acad. Sci. USA 104,19005(2007)]. Our study sheds light on the molecular mechanism of the state transitions in an ATP-binding cassette exporter.

冠心病患者ABCG1、ANGPTL2启动子区甲基化与心力衰竭发生的关系研究

目的分析冠状动脉粥样硬化性心脏病(冠心病)患者三磷酸腺苷结合盒转运蛋白G1(ABCG1)、血管生成素样蛋白2(ANGPTL2)启动子区甲基化与心力衰竭(心衰)发生的关系。方法选取2020年3月至2022年3月于湖南省第二人民医院收治的冠心病患者120例。根据是否发生心衰,将患者分为合并心衰组(n=26)和不合并心衰组(n=94)。采用全自动生化仪检测血清总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)。采用心脏超声检查患者左室射血分数(LVEF)、左心室舒张末期内径(LVEDD)、左室收缩末期内径(LVESD)水平。特异性PCR检测ABCG1和ANGPTL2基因甲基化。采用实时荧光定量聚合酶链反应检测ABCG1和ANGPTL2基因mRNA表达水平。Logistic回归分析探讨影响冠心病患者发生心衰的因素。结果两组患者LDL-C、LVEF、LVEDD、LVESD、ABCG1、ANGPTL2基因启动子区甲基化等方面比较,差异具有统计学意义(P<0.05)。LVESD、LVEF、ABCG1甲基化和ANGPTL2甲基化是冠心病患者发生心衰的危险因素。ABCG1甲基化、ANGPLT2甲基化患者中LVESD水平均高于未甲基化患者(P<0.05)。ABCG1甲基化、ANGPLT2甲基化患者中LVEF水平均低于未甲基化患者(P<0.05)。合并组ABCG1、ANGPTL2基因甲基化的患者mRNA的表达量明显低于非甲基化患者(P<0.05)。结论ABCG1和ANGPTL2基因甲基化是冠心病患者发生心衰的危险因素,检测上述两基因甲基化状态可为诊治冠心病心衰提供理论支持。

Overexpression of the steroidogenic acute regulatory protein increases the expression of ATP-binding cassette transporters in microvascular endothelial cells(bEnd.3)

Objective:To determine the effect of steroidogenic acute regulatory protein(StAR) overexpression on the levels of adenosine triphosphate(ATP)-binding cassette transporter A1(ABCA1) and ATP-binding cassette transporter G1(ABCG1) in an endothelial cell line(bEnd.3).Methods:The StAR gene was induced in bEnd.3 cells with adenovirus infection.The infection efficiency was detected by fluorescence activated cell sorter(FACS) and fluorescence microscopy.The expressions of StAR gene and protein levels were detected by real-time polymerase chain reaction(PCR) and Western blot.The gene and protein levels of ABCA1 and ABCG1 were detected by real-time PCR and Western blot after StAR overexpression.Results:The result shows that StAR was successfully overexpressed in bEnd.3 cells by adenovirus infection.The mRNA and protein expressions of ABCA1 and ABCG1 were greatly increased by StAR overexpression in bEnd.3 cells.Conclusion:Overexpression of StAR increases ABCA1 and ABCG1 expressions in endothelial cells.

辐射对药物转运体以及药物代谢动力学的影响

辐射是以波或粒子形式向周围扩散的能量,包含电离辐射与非电离辐射,可引发机体多种生理病理改变,近年来其对体内药物吸收代谢的影响备受关注。药物转运体是介导药物跨膜转运的关键,在药物代谢全程发挥重要作用,其水平可影响药物体内代谢,进而改变药物系统暴露量与毒性。关注辐射对机体药物转运体的影响对合理用药意义重大。本文着重综述不同类型辐射对药物转运体以及药物代谢动力学的影响。

LMR、miR-21、HOPX与宫颈癌同步放化疗瘤体体积变化参数的关系及联合预测患者预后的价值

目的探讨宫颈癌同步放化疗患者血清淋巴细胞/单核细胞比值(LMR)、微小RNA-21(miR-21)、转录因子含同源结构域蛋白同源盒(HOPX)水平,分析其与瘤体体积变化参数[瘤体缩减率(TVRR)]相关性及其对患者预后的预测价值。方法选取2019年6月至2022年3月医院收治的108例行同步放化疗宫颈癌患者为研究对象,依据治疗结束后3个月内预后情况分为预后不良组(37例)、预后良好组(71例)。比较两组临床资料、TVRR及治疗后14 d血清LMR、miR-21、HOPX水平。分析血清LMR、miR-21、HOPX水平与临床病理特征、TVRR相关性。采用logistic回归分析预后相关影响因素。分析治疗后14 d血清各指标水平对预后预测效能。结果预后不良组治疗后14 d血清LMR、HOPX水平低于预后良好组,miR-21表达量高于预后良好组(P<0.05);血清LMR、HOPX与宫颈癌浸润深度、FIGO分期呈负相关,且与TVRR呈正相关,而miR-21与之相反(P<0.05);LMR、miR-21、HOPX与患者预后相关(P<0.05)。治疗后14 d血清LMR、miR-21、HOPX联合预测预后的曲线下面积(AUC)大于单一指标预测(P<0.05)。结论宫颈癌同步放化疗患者血清LMR、miR-21、HOPX水平与临床病理特征、TVRR密切相关,三者联合评估患者预后的价值最高。

GPRC5A调控的ABCB1表达对肺腺癌增殖的影响

目的ATP结合盒B亚家族成员1(ATP binding cassette subfamily B member 1,ABCB1)的异常表达在多种癌症的发生发展中发挥关键作用。然而,G蛋白偶联受体C家族5组A型(G protein coupled receptor family C group5 type A,GPRC5A)调控的ABCB1表达对肺腺癌增殖的影响仍不清楚。本研究探讨了GPRC5A调控的ABCB1表达对肺腺癌增殖的影响。方法我们采用RT-PCR、Western-blot或免疫组化实验,分析ABCB1在肺腺癌细胞系、人肺腺癌组织以及GPRC5A基因敲除小鼠和野生型小鼠的气管上皮细胞和肺组织中的表达。采用细胞计数试剂盒-8(CCK-8)分析GPRC5A基因敲除小鼠气管上皮细胞对化疗药物的敏感性。采用皮下肿瘤形成实验探讨下调ABCB1表达是否可抑制体内肺腺癌增殖。采用免疫荧光和免疫沉淀实验研究GPRC5A和ABCB1之间潜在的调控关系。结果ABCB1在肺腺癌细胞系和人类肺腺癌组织中表达上调。GPRC5A基因敲除小鼠的气管上皮细胞及肺组织的ABCB1表达高于野生型小鼠。与GPRC5A野生型小鼠的气管上皮细胞相比,GPRC5A基因敲除小鼠的气管上皮细胞对塔立奇达和多柔比星更敏感。注射移植细胞28天后,接受ABCB1基因敲除细胞移植的GPRC5A-/-C57BL/6小鼠的肺肿瘤的体积和重量均明显低于野生型细胞移植小鼠(P=0.0043,P=0.0060)。此外,免疫荧光和免疫沉淀实验表明,GPRC5A通过直接结合方式调控ABCB1的表达。结论GPRC5A通过抑制ABCB1表达降低肺腺癌增殖。GPRC5A调节ABCB1表达的途径有待研究。

肾移植受者代谢标志物与血脂水平的相关性研究

目的分析肾移植受者血脂代谢、高脂血症、他克莫司药物代谢中共表达的基因及其与血脂水平的相关性。方法从比较毒理基因组学数据库(CTD)中筛选出共表达的基因。收集25例肾移植受者的一般资料,检测ATP结合盒亚家族A成员1(ABCA1)、过氧化物酶体增殖物激活受体γ(PPAR-γ)、糖基磷脂酰肌醇锚定高密度脂蛋白结合蛋白1(GPIHBP1)的表达情况。对肾移植受者进行跟踪随访,收集术后1、3、6、12个月空腹血糖、糖化血红蛋白、甘油三酯、总蛋白、白蛋白、球蛋白、胆固醇、高密度脂蛋白、低密度脂蛋白、他克莫司血药浓度,并分析受者高脂血症的发生情况。分析ABCA1、GPIHBP1、PPAR-γ与临床指标的相关性,及其与相关指标对肾移植术后高脂血症的诊断效能。结果共筛选出3个共表基因ABCA1、PPAR-γ、GPIHBP1。ABCA1与术后6个月胆固醇、术后3个月他克莫司血药浓度成正相关,与术后3个月空腹血糖呈负相关(均为P<0.05);GPIHBP1与术前胆固醇、术前甘油三酯呈负相关,与术后3个月他克莫司血药浓度呈正相关(均为P<0.05)。PPAR-γ与术前球蛋白、术前低密度脂蛋白呈负相关(均为P<0.05)。ABCA1、GPIHBP1、PPAR-γ联合术前球蛋白及术后1、6个月血糖水平诊断肾移植术后高甘油三酯血症的效果较好(AUC=0.900)。ABCA1、GPIHBP1、PPAR-γ联合术后1、6个月他克莫司血药浓度及术后6个月血糖水平诊断肾移植术后高胆固醇血症的效果较好(AUC=0.931)。结论ABCA1、GPIHBP1、PPAR-γ与肾移植术后血脂、他克莫司血药浓度等指标存在不同程度的相关关系,但用于预测肾移植术后高脂血症尚无确切依据。提升机体免疫力、规范的血糖管理可能是控制高脂血症的有益因素。

Novel understanding of ABC transporters ABCB1/MDR/P-glycoprotein, ABCC2/MRP2, and ABCG2/BCRP in colorectal pathophysiology

AIM: To evaluate ATP-binding cassette(ABC) transporters in colonic pathophysiology as they had recently been related to colorectal cancer(CRC) development. METHODS: Literature search was conducted on Pub Med using combinations of the following terms: ABC transporters, ATP binding cassette transporter proteins, inflammatory bowel disease, ulcerative, colitis, Crohns disease, colorectal cancer, colitis, intestinal inflammation, intestinal carcinogenesis, ABCB1/P-glycoprotein(P-gp/CD243/MDR1), ABCC2/multidrug resistance protein 2(MRP2) and ABCG2/breast cancer resistance protein(BCRP), Abcb1/Mdr1 a, abcc2/Mrp2, abcg2/Bcrp, knock-out mice, tight junction, membrane lipid function. RESULTS: Recently, human studies reported thatchanges in the levels of ABC transporters were early events in the adenoma-carcinoma sequence leading to CRC. A link between ABCB1, high fat diet and gut microbes in relation to colitis was suggested by the animal studies. The finding that colitis was preceded by altered gut bacterial composition suggests that deletion of Abcb1 leads to fundamental changes of hostmicrobiota interaction. Also, high fat diet increases the frequency and severity of colitis in specific pathogenfree Abcb1 KO mice. The Abcb1 KO mice might thus serve as a model in which diet/environmental factors and microbes may be controlled and investigated in relation to intestinal inflammation. Potential molecular mechanisms include defective transport of inflammatory mediators and/or phospholipid translocation from one side to the other of the cell membrane lipid bilayer by ABC transporters affecting inflammatory response and/or function of tight junctions, phagocytosis and vesicle trafficking. Also, diet and microbes give rise to molecules which are potential substrates for the ABC transporters and which may additionally affect ABC transporter function through nuclear receptors and transcriptional regulation. Another critical role of ABCB1 was suggested by the finding that ABCB1 expression identifies a subpopulation of pro-inflammatory Th17 cells which were resistant to treatment with glucocorticoids. The evidence for the involvement of ABCC2 and ABCG2 in colonic pathophysiology was weak. CONCLUSION: ABCB1, diet, and gut microbes mutually interact in colonic inflammation, a well-known risk factor for CRC. Further insight may be translated into preventive and treatment strategies.

High-density lipoprotein and atherosclerosis: Roles of lipid transporters

Various previous studies have found a negative cor-relation between the risk of cardiovascular events and serum high-density lipoprotein(HDL) cholesterol levels. The reverse cholesterol transport, a pathway of choles-terol from peripheral tissue to liver which has several potent antiatherogenic properties. For instance, the particles of HDL mediate to transport cholesterol from cells in arterial tissues, particularly from atherosclerotic plaques, to the liver. Both ATP-binding cassette trans-porters(ABC) A1 and ABCG1 are membrane cholesterol transporters and have been implicated in mediating cholesterol effluxes from cells in the presence of HDL and apolipoprotein A-I, a major protein constituent of HDL. Previous studies demonstrated that ABCA1 and ABCG1 or the interaction between ABCA1 and ABCG1 exerted antiatherosclerotic effects. As a therapeutic approach for increasing HDL cholesterol levels, much focus has been placed on increasing HDL cholesterol levels as well as enhancing HDL biochemical functions. HDL therapies that use injections of reconstituted HDL, apoA-I mimetics, or full-length apoA-I have shown dramatic effectiveness. In particular, a novel apoA-I mi-metic peptide, Fukuoka University ApoA-I Mimetic Pep-tide, effectively removes cholesterol via specific ABCA1 and other transporters, such as ABCG1, and has an an-tiatherosclerotic effect by enhancing the biological func-tions of HDL without changing circulating HDL choles-terol levels. Thus, HDL-targeting therapy has significant atheroprotective potential, as it uses lipid transporter-targeting agents, and may prove to be a therapeutic tool for atherosclerotic cardiovascular diseases.

ATP-binding cassette transporter enhances tolerance to DDT in Tetrahymena

The reuse of dichlorodiphenyltrichloroethane(DDT) as an indoor residual spray was permitted by the World Health Organization in 2007, and approximately 14 countries still use DDT to control disease vectors. The extensive exposure of insects to DDT has resulted in the emergence of DDT resistance, especially in mosquitoes, and the mechanism for this resistance in mosquitoes has been widely reported. Spraying can also introduce DDT directly into surface water, and DDT can subsequently accumulate in microorganisms, but the mechanism for the resistance to DDT degradation in microorganisms is unclear. Using whole-genome microarray analysis, we detected an abcb15 gene that was up-regulated in a specific manner by DDT treatment in T. thermophile. The deduced ABCB15 peptide sequence had two transmembrane domains(TMDs) and two nucleotide-binding domains(NBDs) to form the structure TMD-NBD-TMD-NBD, and each NBD contained three conserved motifs: Walker-A, C-loop, and Walker-B, which indicated the T. thermophila abcb15 was a typical ABC transporter gene. The expression of ABCB15 fused with a C-terminal green fluorescent protein was found to be on the periphery of the cell, suggesting that ABCB15 was a membrane pump protein. In addition, cells with abcb15 partially knocked down(abcb15-KD) grew slower than wild-type cells in the presence of 256 mg L-1 DDT, indicating the tolerance of abcb15-KD strain to DDT exposure was decreased. Thus, we suggest that in Tetrahymena, the membrane pump protein encoded by ABCT gene abcb15 can enhance the tolerance to DDT and protect cells from this exogenous toxin by efficiently pumping it to the extracellular space.

Hepatocellular transport proteins and their role in liver disease

MOLECULAR PHYSIOLLGY OF HEPATOCELLULAR TRANSPORT PROTEINS Basolaferal transport systems Na+-dependent bile salt uptake Uptake of bile salts into the liver was first isolated perfused rat liver[1],isolated hepatocyte cultures and basolateral plasma membrane vesicles [2,4].

Roles of sulfonylurea receptor 1 and multidrug resistance protein 1 in modulating insulin secretion in human insulinoma

BACKGROUND:Sulfonylurea receptor 1(SUR1)and multidrug resistance protein 1(MRP1)are two prominent members of multidrug resistance proteins associated with insulin secretion. The aims of this study were to investigate their expression in insulinomas and their sole and synergistic effects in modulating abnormal insulin secretion. METHODS:Fasting glucose,insulin and C-peptide were measured in 11 insulinoma patients and 11 healthy controls. Prolonged oral glucose tolerance tests were performed in 6 insulinoma patients.Insulin content,SUR1 and MRP1 were detected in 11 insulinoma patients by immunohistochemistry. SUR1 and MRP1 were also detected in 6 insulinoma patients by immunofluorescence. RESULTS:Insulinoma patients presented the typical demons-trations of Whipple’s triad.Fasting glucose of each insulinoma patient was lower than 2.8 mmol/L,and simultaneous insulin and C-peptide were increased in insulinoma patients. Prolonged oral glucose tolerance tests showed that insulin secretion in insulinoma patients were also stimulated by high glucose.Immunohistochemistry and immunofluorescence staining showed that SUR1 increased,but MRP1 decreased in insulinoma compared with the adjacent islets. CONCLUSIONS:The hypersecretion of insulin in insulinomas might be,at least partially,due to the enrichment of SUR1. In contrast,MRP1,which is down-regulated in insulinomas, might reflect a negative feedback in insulin secretion.

Role of apolipoproteins,ABCA1 and LCAT in the biogenesis of normal and aberrant high density lipoproteins

In this review, we focus on the pathway of biogenesis of HDL, the essential role of apoA-I, ATP binding cassette transporter A1（ABCA1）, and lecithin： cholesterol acyltransferase（LCAT） in the formation of plasma HDL; the generation of aberrant forms of HDL containing mutant apoA-I forms and the role of apoA-IV and apoE in the formation of distinct HDL subpopulations. The biogenesis of HDL requires functional interactions of the ABCA1 with apoA-I（and to a lesser extent with apoE and apoA-IV） and subsequent interactions of the nascent HDL species thus formed with LCAT. Mutations in apoA-I, ABCA1 and LCAT either prevent or impair the formation of HDL and may also affect the functionality of the HDL species formed. Emphasis is placed on three categories of apoA-I mutations. The first category describes a unique bio-engineered apoA-I mutation that disrupts interactions between apoA-I and ABCA1 and generates aberrant prep HDL subpopulations that cannot be converted efficiently to a subpopulations by LCAT. The second category describes natural and bio-engineered apoA-I mutations that generate preβ and small size a4 HDL subpopulations, and are associated with low plasma HDL levels. These phenotypes can be corrected by excess LCAT. The third category describes bio-engineered apoA-I mutations that induce hypertriglyceridemia that can be corrected by excess lipoprotein lipase and also have defective maturation of HDL.The HDL phenotypes described here may serve in the future for diagnosis, prognoses and potential treatment of abnormalities that affect the biogenesis and functionality of HDL.

ATP gatekeeper of Plasmodium protein kinase may provide the opportunity to develop selective antimalarial drugs with multiple targets

Malaria is one of the most devastating infectious diseases that caused millions of clinical cases annually despite decades of prevention efforts. Recent cases of Plasmodium falciparum resistance against the only remaining class of effective antimalarial(artemisinin) in South East Asia may soon pose a significant threat. Hence, the identification of new antimalarial compounds with a novel mode of action is necessary to curb this problem. Protein kinase has been implicated as a valid target for drug development in diseases such as cancer and diabetes in humans. A similar approach is now recognized for the treatment of protozoan-related disease including malaria. Few Plasmodium protein kinases that are not only crucial for their survival but also have unique structural features have been identified as a potential target for drug development. In this review, studies on antimalarial drug development exploiting the size of Plasmodium protein kinase ATP gatekeeper over the past 15 years are mainly discussed. The ATP-binding site of Plasmodium protein kinases such as Pf CDPK1, Pf CDPK4, Pf PKG, Pf PK7, and Pf PI4K showed great potential for selective and multi-target inhibitions owing to their smaller or unique ATP-gatekeeper amino acid subunits compared to that of human protein kinase. Hence it is a feasible solution to identify a new class of active antimalarial agents with a novel mode of action and longer clinical life-span.

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

P-glycoprotein(ABCB1),multidrug resistance protein-1(ABCC1)and breast cancer resistance protein(ABCG2)belong to the ATP-binding cassette(ABC)superfamily of proteins that play an important physiological role in protection of the body from toxic xenobiotics and endogenous metabolites.Beyond this,these transporters determine the toxicity profile of many drugs,and confer multidrug resistance(MDR)in cancer cells associated with a poor treatment outcome of cancer patients.It has long been hypothesized that inhibition of ABC drug efflux transporters will increase drug accumulation and thereby overcome MDR,but until now no approved inhibitor of these transporters is available in the clinic.In this review we present molecular strategies to overcome this type of drug resistance and discuss for each of these strategies their promising value or indicate underlying reasons for their limited success.

The classification of ATP-binding cassette subfamily A member 3 mutations using the cystic fibrosis transmembrane conductance regulator classification system

Importance: The ATP-binding cassette subfamily A member 3 (ABCA3) protein plays a vital role in surfactant homeostasis. Mutations in the ABCA3 gene lead to the development of interstitial lung disease. In the most severe manifestation, mutations can lead to a fatal respiratory distress syndrome in neonates. ABCA3 belongs to the same ATP-binding cassette transporter superfamily as the cystic fibrosis transmembrane conductance regulator (CFTR), the gene that causes cystic fibrosis. Objective: To classify ABCA3 mutations in a manner similar to CFTR mutations in order to take advantage of recent advances in therapeutics. Methods: Sequence homology between the CFTR protein and the ABCA3 protein was established. The region of CFTR that is a target for the new potentiator class of drugs was of particular interest. We performed a literature search to obtain all published mutations that were thought to be disease causing. We classified these mutations using the established CFTR classification system. When possible, we drew on previous experimental classification of ABCA3 mutations. Results: Although the proteins share the same overall structure, only a 19％identity was established between CFTR and ABCA3. The CFTR therapeutic target region has a 22％ homology with the corresponding ABCA3 region. Totally 233 unique protein mutations were identified. All protein mutations were classified and mapped to a schematic diagram of the ABCA3 protein. Interpretation: This new classification system for ABCA3, based on CFTR classification, will likely aid further research of clinical outcomes and identification of mutation-tailored therapeutics, with the aim for improving clinical care for patients with ABCA3 mutations.