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.

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.

Knocking-Out OsPDR7 Triggers Up-Regulation of OsZIP9 Expression and Enhances Zinc Accumulation in Rice

Zinc(Zn) is an essential trace mineral that is required for plant growth and development. A number of protein transporters, which are involved in Zn uptake, translocation and distribution, are finely regulated to maintain Zn homeostasis in plant. In this study, we functionally characterized an ATP-binding cassette(ABC) transporter gene, OsPDR7, which is involved in Zn homeostasis. Os PDR7 encodes a plasma membrane-localized protein that is expressed mainly in the exodermis and xylem in the rice root.ospdr7 mutants resulted in higher Zn accumulation compared with the wild type. Heterogeneous expression of OsPDR7 in a yeast mutant rescued the Zn-deficiency phenotype, implying transport activity of OsPDR7 to Zn in yeast. However, no ZIP genes except for OsZIP9 showed change in expression profile in the ospdr7 mutants, which suggested that OsPDR7 maintains cellular Zn homeostasis through regulating Os ZIP9 expression. RNA-Seq analysis further revealed a set of differentially expressed genes between the wild type and ospdr7 mutants that allowed us to propose a possible OsPDR7-associated signaling network involving transporters, hormone responsive genes, and transcription factors. Our results revealed a novel transporter involved in the regulation of Zn homeostasis and will pave the way toward a better understanding of the fine-tuning of gene expression in the network of transporter genes.

Advances in drug resistance of triple negative breast cancer caused by pregnane X receptor

Breast cancer is the most common malignancy in women worldwide.Triplenegative breast cancer(TNBC),refers breast cancer negative for estrogen receptor,progesterone receptor and human epidermal growth factor receptor 2,characterized by high drug resistance,high metastasis and high recurrence,treatment of which is a difficult problem in the clinical treatment of breast cancer.In order to better treat TNBC clinically,it is a very urgent task to explore the mechanism of TNBC resistance in basic breast cancer research.Pregnane X receptor(PXR)is a nuclear receptor whose main biological function is to participate in the metabolism,transport and clearance of allobiological agents in PXR.PXR plays an important role in drug metabolism and clearance,and PXR is highly expressed in tumor tissues of TNBC patients,which is related to the prognosis of breast cancer patients.This reviews synthesized the important role of PXR in the process of high drug resistance to TNBC chemotherapeutic drugs and related research progress.

Mechanisms of drug resistance in colon cancer and its therapeutic strategies

Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATPbinding cassette(ABC) transporters and evasion of apoptosis, two representatives of transport-based and non-transport-based mechanisms of drug resistance, as well as their therapeutic strategies. Different ABC transporters were found to be up-regulated in colon cancer, which can facilitate the efflux of anticancer drugs out of cancer cells and decrease their therapeutic effects. Inhibition of ABC transporters by suppressing their protein expressions or co-administration of modulators has been proven as an effective approach to sensitize drug-resistant cancer cells to anticancer drugs in vitro. On the other hand, evasion of apoptosis observed in drug-resistant cancers also results in drug resistance to anticancer agents, especially to apoptosis inducers. Restoration of apoptotic signals by BH3 mimetics or epidermal growth factor receptor inhibitors and inhibition of cancer cell growth by alternative cell death pathways, such as autophagy, are effective means to treat such resistant cancer types. Given that the drug resistance mechanisms are different among colon cancer patients and may change even in a single patient at different stages, personalized and specific combination therapy is proposed to be more effective and safer for the reversal of drug resistance in clinics.

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.

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.

小鼠CD45^-/CD31^+肺侧群细胞诱导分化的研究

目的探讨在体外诱导分化肺侧群细胞(SP)的特性。方法取小鼠肺组织,流式细胞术分选小鼠白细胞分化抗原(CD)45^-/CD31^+肺SP;免疫荧光检测分选肺SP三磷酸腺苷结合转运蛋白G超家族成员2(ABCG2)的表达;逆转录聚合酶链反应(RT-PCR)检测肺SP中ABCG2、酪氨酸激酶2(Tie2)及血管性血友病因子(vWF)的表达。细胞体外分化诱导14 d后,免疫荧光检测细胞vWF的表达;RT-PCR检测分化诱导前后细胞中ABCG2和vWF的表达。结果流式细胞术成功分选出CD45^-/CD31^+肺SP细胞,免疫荧光检测其表达ABCG2;RT-PCR检测SP表达ABCG2和Tie2,不表达vWF。主群细胞表达vWF;分化诱导前的肺SP表达ABCG2;分化诱导后的肺SP表达vWF。结论 CD45^-/CD31^+肺SP是血管内皮细胞的祖细胞,具有干细胞分化特性。在体外培养可分化为血管内皮细胞。

Primary analysis and screening of microRNAs in gastric cancer side population cells

AIM: To explore the micro RNA(mi RNA) profiles and to determine the key mi RNAs within the side population(SP) cells of the gastric cancer cell line MKN-45. METHODS: We used fluorescence-activated cell sorting and Hoechst 33342 labeling to obtain SP cells from the human gastric carcinoma cell line MKN-45. The mi RNA expression profiles of the SP and major population(MP) cells were examined using a mi RNA gene chip, and key mi RNAs were obtained according to aberrant expression and the mi RNAs' possible targets as predicted by bioinformatics. RESULTS: Using a significance criterion of a 1.5-fold or greater difference in expression level, we observed an increase in the expression of 34 mi RNAs and a decrease in the expression of 34 mi RNAs when comparing SP to MP cells. Using quantitative real-time reverse transcription-polymerase chain reaction to test for differentially expressed mi RNAs combined with bioinformatics results, we found that the downregulated mi RNAs, such as hsa-mi R-3175 and hsa-mi R-203, and the upregulated mi RNAs, including hsa-mi R-130 a, hsa-mi R-324-5p, hsa-mi R-34 a, and hsa-mi R-25-star, may be important in maintaining and regulating the characteristics of SP cells. CONCLUSION: There are key mi RNAs expressed within the SP cells of the gastric cancer cell line MKN-45, andinclude hsa-mi R-3175, hsa-mi R-203, hsa-mi R-130 a, hsami R-324-5p, hsa-mi R-34 a, and hsa-mi R-25-star.

植物ABC转运蛋白及其在Al胁迫下的功能研究进展

ABC(ATP-Binding Cassette)转运蛋白家族是目前已知最大、功能最广泛的蛋白家族,能利用水解ATP的能量来参与生物体内多种物质的转运,这一基因家族成员在哺乳动物和微生物中已广泛鉴定,在植物中的研究是一个相对较新的研究领域。铝是酸性土壤作物生产的一个主要的限制因素,ABC转运蛋白在植物铝耐受性方面有重要作用。该文主要对ABC转运蛋白的特点、生物学功能及植物ABC转运蛋白在Al胁迫下的作用进行了综述,并分析其存在的问题,展望今后可能开展的研究方向。

ABC efflux transporters at blood-central nervous system barriers and their implications for treating spinal cord disorders

The barriers present in the interfaces between the blood and the central nervous system form a major hurdle for the pharmacological treatment of central nervous system injuries and diseases.The family of ATP-binding cassette(ABC)transporters has been widely studied regarding efflux of medications at blood-central nervous system barriers.These efflux transporters include P-glycoprotein(abcb1),‘breast cancer resistance protein'(abcg2)and the various‘multidrug resistance-associated proteins'(abccs).Understanding which efflux transporters are present at the blood-spinal cord,blood-cerebrospinal fluid and cerebrospinal fluid-spinal cord barriers is necessary to determine their involvement in limiting drug transfer from blood to the spinal cord tissue.Recent developments in the blood-brain barrier field have shown that barrier systems are dynamic and the profile of barrier defenses can alter due to conditions such as age,disease and environmental challenge.This means that a true understanding of ABC efflux transporter expression and localization should not be one static value but instead a range that represents the complex patient subpopulations that exist.In the present review,the blood-central nervous system barrier literature is discussed with a focus on the impact of ABC efflux transporters on:(i)protecting the spinal cord from adverse effects of systemically directed drugs,and(ii)limiting centrally directed drugs from accessing their active sites within the spinal cord.

New insights into renal lipid dysmetabolism in diabetic kidney disease

Lipid dysmetabolism is one of the main features of diabetes mellitus and manifests by dyslipidemia as well as the ectopic accumulation of lipids in various tissues and organs,including the kidney.Research suggests that impaired cholesterol metabolism,increased lipid uptake or synthesis,increased fatty acid oxidation,lipid droplet accumulation and an imbalance in biologically active sphingolipids(such as ceramide,ceramide-1-phosphate and sphingosine-1-phosphate)contribute to the development of diabetic kidney disease(DKD).Currently,the literature suggests that both quality and quantity of lipids are associated with DKD and contribute to increased reactive oxygen species production,oxidative stress,inflammation,or cell death.Therefore,control of renal lipid dysmetabolism is a very important therapeutic goal,which needs to be archived.This article will review some of the recent advances leading to a better understanding of the mechanisms of dyslipidemia and the role of particular lipids and sphingolipids in DKD.

Role of interleukin-1 and its antagonism of hepatic stellate cell proliferation and liver fibrosis in the Abcb4^(-/-) mouse model

AIM: To study the interleukin-1(IL-1) pathway as a therapeutic target for liver fibrosis in vitro and in vivo using the ATP-binding cassette transporter b4^(-/-)(Abcb4^(-/-)) mouse model.METHODS: Female and male Abcb4^(-/-) mice from 6 to 13 mo of age were analysed for the degree of cholestasis(liver serum tests), extent of liver fibrosis(hydroxyproline content and Sirius red staining) and tissue-specific activation of signalling pathways such as the IL-1 pathway [quantitative polymerase chain reaction(q PCR)]. For in vivo experiments, murine hepatic stellate cells(HSCs) were isolated via pronasecollagenase perfusion followed by density gradient centrifugation using female mice. Murine HSCs were stimulated with up to 1 ng/m L IL-1β with or without 2.5 μg/m L Anakinra, an IL-1 receptor antagonist, respectively. The proliferation of murine HSCs was assessed via the Brd U assay. The toxicity of Anakinra was evaluated via the fluorescein diacetate hydrolysis(FDH) assay. In vivo 8-wk-old Abcb4^(-/-) mice with an already fully established hepatic phenotype were treated with Anakinra(1 mg/kg body-weight daily intraperitoneally) or vehicle and liver injury and liver fibrosis were evaluated via serum tests, q PCR, hydroxyproline content and Sirius red staining. RESULTS: Liver fibrosis was less pronounced in males than in female Abcb4^(-/-) animals as defined by a lower hydroxyproline content(274 ± 64 μg/g vs 436 ± 80 μg/g liver, respectively; n = 13-15; P < 0.001; MannWhitney U-test) and lower m RNA expression of the profibrogenic tissue inhibitor of metalloproteinase-1(TIMP)(1 ± 0.41 vs 0.66 ± 0.33 fold, respectively; n = 13-15; P < 0.05; Mann-Whitney U-test). Reduced liver fibrosis was associated with significantly lower levels of F4/80 m RNA expression(1 ± 0.28 vs 0.71 ± 0.41 fold, respectively; n = 12-15; P < 0.05; Mann-Whitney U-test) and significantly lower IL-1β m RNA expression levels(1 ± 0.38 vs 0.44 ± 0.26 fold, respectively; n = 13-15; P < 0.001; Mann-Whitney U-test). No gender differences in the serum liver parameters [bilirubin; alanine aminotransferase(ALT); aspartate aminotransferase and alkaline phosphatase(AP)] were found. In vitro, the administration of IL-1β resulted in a significant increase in HSC proliferation [0.94 ± 0.72 arbitrary units(A.U.) in untreated controls, 1.12 ± 0.80 A.U. at an IL-1β concentration of 0.1 ng/m L and 1.18 ± 0.73 A.U. at an IL-1β concentration of 1 ng/m L in samples from n = 6 donor animals; P < 0.001; analyses of variance(ANOVA)]. Proliferation was reduced significantly by the addition of 2.5 μg/m L Anakinra(0.81 ± 0.60 A.U. in untreated controls, 0.92 ± 0.68 A.U. at an IL-1β concentration of 0.1 ng/m L, and 0.91 ± 0.69 A.U. at an IL-1β concentration of 1 ng/m L; in samples from n = 6 donor animals; P < 0.001; ANOVA) suggesting an anti-proliferative effect of this clinically approved IL-1 receptor antagonist. The FDH assay showed this dose to be non-toxic in HSCs. In vivo, Anakinra had no effect on the hepatic hydroxyprolinecontent, liver serum tests(ALT and AP) and profibrotic(collagen 1α1, collagen 1α2, transforming growth factor-β, and TIMP-1) and anti-fibrotic [matrix metalloproteinase 2(MMP2), MMP9 and MMP13 ] gene expression after 4 wk of treatment. Furthermore, the hepatic IL-1β and F4/80 m RNA expression levels were unaffected by Anakinra treatment.CONCLUSION: IL-1β expression is associated with the degree of liver fibrosis in Abcb4^(-/-) mice and promotes HSC proliferation. IL-1 antagonism shows antifibrotic effects in vitro but not in Abcb4^(-/-) mice.

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.

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.

Piperine prevents cholesterol gallstones formation in mice

Biliary cholesterol may contribute to the formation of cholesterol gallstones, regulation of these levels could be a useful therapeutic strategy for gallstones disease. Piperine （PA） is a potential cholesterol lowering a- gent. In this study, we assessed the effect and mechanism of PA in preventing cholesterol gallstones formation in- duced by feeding lithogenic diet containing high cholesterol levels to mice. C57BL/6 inbred mice were fed lithogen- ic or chow diets for 10 weeks, with or without PA （ 15, 30 and 60 mg ~ kg-1 ） or ursodeoxycholic acid （ UDCA, 60 mg ~ kg-1） administration. Cholesterol, phospholipids and crystals in bile, the lipid in serum, pathological chan- ges and proteins expression in liver were analyzed. The results showed that PA could decrease the cholesterol poten- cy and crystals in bile, reduce total cholesterol （TC）, triglycerides （TG） and increase high-density lipoprotein / low-density lipoprotein （HDL/LDL） levels in serum. Furthermore, PA treatment reduced liver lipid peroxidation and protected hepatobiliary cells from liver injury by decreasing malondialdehyde （MDA） and increasing superoxide dismutase （SOD）. In addition, PA inhibited the expression of ATP-binding cassette transporters G5/8 （ABCG5/ 8 ） and liver X receptor （LXR） in liver, and reduced cholesterol transport from the hepatocytes to the gallbladder. It may be the mechanism of PA in preventing cholesterol gallstones formation. PA as a potential drug for prevention cholesterol gallstones merits further investigation.

High nuclear ABCG1 expression is a poor predictor for hepatocellular carcinoma patient survival

Background:ATP-binding cassette transporter G1(ABCG1)regulates cellular cholesterol homeostasis and plays a significant role in tumor immunity.But,for hepatocellular carcinoma(HCC),the role of ABCG1 has not been investigated.Thus,the aim of this study was to evaluate the prognostic value and clinicopathological significance of ABCG1 in HCC.Methods:One hundred and four adult patients with HCC were enrolled,and ABCG1 expression in paired HCC specimens was determined by immunohistochemistry.All these patients were stratified by ABCG1 expression,Kaplan-Meier analysis was used to compare the overall survival(OS)and recurrence-free survival(RFS),and Cox regression analysis was used to determine independent predictors of tumor recurrence.Results:Upregulation of ABCG1 was observed in HCC samples compared to matched tumor-adjacent tissues.Patients with high nuclear ABCG1 expression had lower OS and RFS(P=0.012 and P=0.020,respectively).High nuclear ABCG1 expression was related to larger tumor size(P=0.004)and tumor recurrence(P=0.027).Although ABCG1 was expressed in the cytoplasm,cytosolic expression could not predict the outcome in patients with HCC.A new stratification pattern was established based on the heterogenous ABCG1 expression pattern:high risk(High^(nucleus)/Low^(cytosol)),moderate risk(High^(nucleus)/High^(cytosol) or Low^(nucleus)/Low^(cytosol)),and low risk(Low^(nucleus)/High^(cytosol)).This ABCG1-based risk stratification could distinguish the different OS and RFS in patients with HCC.Multivariate Cox regression analysis indicated that ABCG1 high risk was an independent predictor of poor RFS(P=0.015).Conclusions:High nuclear ABCG1 expression indicates poor prognosis in patients with HCC.Asymmetric distribution of ABCG1 in the nucleus and cytoplasm may have an important role in tumor recurrence.