Crosslink among cyclin-dependent kinase 9,ATP binding cassette transporter G2 and Beclin 1 in colorectal cancer

Colorectal cancer(CRC)ranks third in the number of cancers mainly because of the inability to diagnose it at an early stage.The pathogenesis of CRC is complicated,which is the result of the complex interaction of multiple genetic and environmental factors.Currently,one of the main treatments for CRC is chemotherapy.But the primary cause of CRC treatment failure is drug resistance.The expression of cyclin-dependent kinase 9(CDK9)was correlated with elevated autophagy levels in colon cancer,and high expression of CDK9 indicates a poor prognosis in CRC.The incidence of autophagy and the expressions of Beclin 1 and ATP binding cassette transporter G2 are different in left and right colon cancer,and autophagy may be involved in the occurrence of chemotherapy resistance.In this article,the roles of CDK9,ATP binding cassette transporter G2 and Beclin 1 in CRC were elucidated,emphasizing the linkages among them and providing potential therapeutic targets of CRC.

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.

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.

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.

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.

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.

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.

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.

Protective Effect of Irbesartan on ATP Binding Cassette Transporter A1 in THP-1 Derived Macrophages

Objectives To explore the protective effect of irbesartan （lrb） under the interference with angiotensin II （Ang II） on ABCA1. Methods Electron microscopy was used to detect the morphous of foam cells. The expression of ABCA1 mRNA and its protein were determined by RT-PCR and Western blotting, respectively. The variance of cellular cholesterol content was measured by zymochemistry via-fluorospeetrophotometer. Results A positive facilitative effect of Ang II on the formation of foam cells was observed. Total cholesterol was increased significantly by Ang II, the expression of ABCA1 was down-regulated obviously by Ang II; Irb could protect ABCA1 against the lesion of Ang II; Total cellular cholesterol content was reduced significantly in Irb ＋ Ang II group; However, considerable alteration about the cholesterol content and the expression of ABCA1 were not observed in Irb group without incubation with Ang II. Conclusions Irb could protect ABCA1 against the lesion of Ang II, which may contribute to its anti-atherosclerotic properties. （ S Chin J Cardiol 2009; 10（4） ： 227 -233）

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.

A Possible Mechanism Linking Hyperglycemia and Reduced High-density Lipoprotein Cholesterol Levels in Diabetes

This study investigated the role of glucose in the biogenesis of high-density lipoprotein cholesterol(HDL-C).Mouse primary peritoneal macrophages were harvested and maintained in Dulbecco’s modified Eagle’s medium(DMEM) containing glucose of various concentrations.The cells were divided into 3 groups in terms of different glucose concentrations in the cultures:Control group(5.6 mmol/L glucose),high glucose concentration groups(16.7 mmol/L and 30 mmol/L glucose).ATP-binding cassette transporter A1(ABCA1) mRNA expression in the macrophages was detected by semi-quantitative RT-PCR 24,48 and 72 h after glucose treatment.The results showed that ABCA1 mRNA expression in the 16.7 mmol/L glucose group was not significantly different from that in the control group at all testing time points(P>0.05 for each).In the 30 mmol/L glucose group,macrophage ABCA1 mRNA expression was not changed significantly at 24 h(P=0.14),but was substantially decreased by 40.4% at 48 h(P=0.009) and by 48.1% at 72 h(P=0.015) as compared with that in the control group.It was concluded that ABCA1 is of vital importance for HDL-C biogenesis.High glucose may hamper HDL-C biogenesis by decreasing ABCA1 expression,which contributes to low HDL-C level in diabetes.

Regulation of Intestinal Cholesterol Absorption: A Disease Perspective

Hypercholesterolemia promotes atherosclerosis and precise regulation of cholesterol homeostasis is essential. Besides risk factor for cardiovascular disease, abnormalities in cholesterol metabolism have been associated with type 2 diabetes. Cholesterol homeostasis in the body is maintained by de novo synthesis. Furthermore, intestinal cholesterol absorption has recently been considered as an important control point in cholesterol homeostasis. Important insights have been gained into the mechanisms of transport of cholesterol from the intestinal lumen into the enterocytes. Several transporter proteins that appear to be key players in the control of the cholesterol absorption from the intestinal lumen have been identified. Here, we review intestinal cholesterol absorption and the mechanisms underlying alterations in cholesterol absorption under physiological conditions and in diseases such as diabetes mellitus.

Two pyrrole acids isolated from Phyllanthus emblica L.and their bioactivities

An undescribed pyrrole acid,1-(4′-methoxy-4′-oxobutyl)-1 H-pyrrole-2,5-dicarboxylic acid(1)and one known pyr-role acid(2)were isolated from the fruits of Phyllanthus emblica.The structures of these compounds were elucidated via the comprehensive analyses of IR,HRESIMS,1D and 2D spectroscopic data.A series of biological assays revealed that compounds 1 and 2 could inhibit LPS-induced over-production of nitric oxide(NO),interleukin-6(IL-6),monocyte chemotactic protein 1(MCP-1)and tumor necrosis factor-α(TNF-α)by reducing the phosphorylation of extracellular regulated protein kinases(ERK)and c-Jun N-terminal kinases(JNK)in RAW 264.7 cells.Additionally,compounds 1 and 2 were found to reduce lipid deposition and increase the mRNA expression of ATP-binding cassette transporter A1 in oxidized low-density lipoprotein-treated RAW264.7 macrophages.

Genetics of Gallstone Disease and Their Clinical Significance: A Narrative Review

Gallstone(GS)disease is common and arises from a combination of genetic and environmental factors.Although genetic abnormalities specifically leading to cholesterol GSs are rare,there are clinically significant gene variants associated with cholesterol GSs.In contrast,most bilirubin GSs can be attributed to genetic defects.The pathogenesis of cholesterol and bilirubin GSs differs greatly.Cholesterol GSs are notably influenced by genetic variants within the ABC protein superfamily,including ABCG8,ABCG5,ABCB4,and ABCB11,as well as genes from the apolipoprotein family such as ApoB100 and ApoE(especially the E3/E3 and E3/E4 variants),and members of the MUC family.Conversely,bilirubin GSs are associated with genetic variants in highly expressed hepatic genes,notably UGT1A1,ABCC2(MRP2),ABCC3(MRP3),CFTR,and MUC,alongside genetic defects linked to hemolytic anemias and conditions impacting erythropoiesis.While genetic cases constitute a small portion of GS disease,recognizing genetic predisposition is essential for proper diagnosis,treatment,and genetic counseling.

匹伐他汀对稳定型冠心病患者巨噬细胞胆固醇外流功能的影响及机制研究

目的研究匹伐他汀对稳定型冠心病(冠状动脉粥样硬化性心脏病)患者单核细胞来源的巨噬细胞的胆固醇外流功能的影响及其机制。方法选取2019年1月至2021年1月北京积水潭医院心内门诊及病房的合并脂代谢异常的稳定型冠心病患者60例,采用简单随机化分组的方法分为匹伐他汀组和阿托伐他汀组(各30例),分别予以匹伐他汀2~4 mg/d或阿托伐他汀10~20 mg/d,治疗6个月。分别于治疗前及治疗6个月后抽取外周静脉血,测定血脂水平。分离单核细胞进行巨噬化培养,实时定量聚合酶链反应法测定三磷酸腺苷结合盒转运蛋白A1(ABCA1)及三磷酸腺苷结合盒亚家族G1抗体(ABCG1)的mRNA表达水平,蛋白质印迹法检测ABCA1及ABCG1的蛋白表达水平。以^(3)H标记胆固醇分别测定经载脂蛋白A1及高密度脂蛋白(HDL)介导的胆固醇外流率变化。结果治疗6个月后,匹伐他汀组高密度脂蛋白胆固醇(HDL-C)水平[(1.34±0.15)mmol/L比(1.21±0.18)mmol/L],载脂蛋白A1和HDL介导的胆固醇外流率[(11.4±2.2)%比(8.6±1.7)%、(17.7±1.7)%比(12.8±1.6)%],巨噬细胞中检测到ABCA1及ABCG1 mRNA和蛋白表达水平均高于治疗前,差异均有统计学意义(均P<0.05)。而阿托伐他汀组治疗6个月后,HDL-C水平,载脂蛋白A1和HDL介导的胆固醇外流率,巨噬细胞中检测到ABCA1及ABCG1 mRNA和蛋白表达水平与治疗前比较,差异均无统计学意义(均P>0.05)。结论匹伐他汀治疗合并脂代谢异常的稳定型冠心病患者,在升高HDL-C水平的同时,可使ABCA1及ABCG1的表达上调,从而显著改善HDL介导的胆固醇外流功能。

肥胖对外周血白细胞胆固醇逆转运相关基因表达的影响

目的 研究肥胖者外周血白细胞胆固醇逆转运相关基因表达的情况.方法 采用实时荧光定量PCR方法,测定肥胖组和对照组外周血白细胞胆固醇逆转运相关基因ABCA1、ABCG1和ApoA1 mRNA表达水平.结果 肥胖组ABCG1mRNA表达水平较对照组显著降低（0.536±0.271比6.243±1.511,P＜0.05）,ApoA1mRNA表达水平较对照组升高（0.385±0.188比0.206±0.062,P＜0.05）.单因素相关分析显示,ABCG1mRNA表达与体重指数BMI呈负相关（r=-0.403,P=0.012）.多元线性回归分析提示,ABCG1mRNA表达与体重指数BMI呈独立相关性（β=-0.488,P=0.004）.结论 肥胖者外周血白细胞ABCG1mRNA表达下调,且ABCG1mRNA与体重指数BMI呈负相关,这可能是肥胖导致动脉粥样硬化发生、发展的机制之一.

蠲痹历节清方对高尿酸血症大鼠肾脏中部分尿酸转运蛋白的影响

目的:探讨肾脏尿酸盐转运子1(Urate Transporter 1,URAT1)、三磷酸腺苷结合盒转运蛋白G2(ATP-binding Cassette Superfamily G Member 2,ABCG2)、葡萄糖转运蛋白9(Glucose Transporter 9,GLUT9)等尿酸转运蛋白在蠲痹历节清方降低血尿酸(Serum Uric Acid,SUA)中的机制。方法:将雄性SD大鼠随机分为空白组、模型组、苯溴马隆组(5 mg/kg)及蠲痹历节清方低、中、高剂量组(11,22,44 g/kg)。除空白组外,其余各组均建立高尿酸血症模型;苯溴马隆组和蠲痹历节清方组分别予相应浓度混悬液进行灌胃干预。最后收集大鼠腹主动脉血和双肾组织,采用全自动生化仪检测各组大鼠腹主动脉中血尿酸含量,采用实时荧光定量聚合酶链式反应(Real-time PCR)和蛋白免疫印迹法(Western Blot)检测各组大鼠肾脏中URAT1、GLUT9、ABCG2 mRNA和蛋白的表达。结果:与空白组相比,模型组血尿酸水平明显增加,差异有统计学意义(P<0.05);空白组与模型组血尿酸水平存在明显差异,提示造模成功。与空白组比较,模型组URAT1及GLUT9的mRNA和蛋白表达均显著升高,差异有统计学意义(P<0.05);ABCG2的mRNA和蛋白的表达则显著下降,差异有统计学意义(P<0.05)。与模型组比较,蠲痹历节清方各剂量组和苯溴马隆组URAT1及GLUT9的mRNA和蛋白表达均明显下降,差异有统计学意义(P<0.05);ABCG2的mRNA和蛋白的表达则显著升高,差异有统计学意义(P<0.05)。与蠲痹历节清方高剂量组比较,中、低剂量组URAT1及GLUT9的mRNA和蛋白表达均明显升高,差异有统计学意义(P<0.05);ABCG2的mRNA和蛋白的表达则明显下降,差异有统计学意义(P<0.05)。结论:蠲痹历节清方可通过抑制肾脏中URAT1、GLUT9 mRNA及蛋白表达,促进ABCG2的mRNA和蛋白的表达,来调节尿酸的分泌,减少尿酸的重吸收,增加尿酸的排泄,进而降低血尿酸水平,且随着剂量的升高,其降尿酸的作用逐渐增强。

Attempts to remodel the pathways of gemcitabine metabolism: Recent approaches to overcoming tumours with acquired chemoresistance

Gemcitabine is a cytidine analogue frequently used in the treatment of various cancers.However,the development of chemoresistance limits its effectiveness.Gemcitabine resistance is regulated by various factors,including aberrant genetic and epigenetic controls,metabolism of gemcitabine,the microenvironment,epithelial-to-mesenchymal transition,and acquisition of cancer stem cell properties.In many situations,results using cell lines offer valuable lessons leading to the first steps of important findings.In this review,we mainly discuss the factors involved in gemcitabine metabolism in association with chemoresistance,including nucleoside transporters,deoxycytidine kinase,cytidine deaminase,and ATP-binding cassette transporters,and outline new perspectives for enhancing the efficacy of gemcitabine to overcome acquired chemoresistance.