共查询到20条相似文献,搜索用时 15 毫秒
1.
Ma X Shah YM Guo GL Wang T Krausz KW Idle JR Gonzalez FJ 《The Journal of pharmacology and experimental therapeutics》2007,322(1):391-398
Rifaximin, a rifamycin analog approved for the treatment of travelers' diarrhea, is also beneficial in the treatment of multiple chronic gastrointestinal disorders. However, the mechanisms contributing to the effects of rifaximin on chronic gastrointestinal disorders are not fully understood. In the current study, rifaximin was investigated for its role in activation of the pregnane X receptor (PXR), a nuclear receptor that regulates genes involved in xenobiotic and limited endobiotic deposition and detoxication. PXR-humanized (hPXR), Pxr-null, and wild-type mice were treated orally with rifaximin, and rifampicin, a well characterized human PXR ligand. Rifaximin was highly concentrated in the intestinal tract compared with rifampicin. Rifaximin treatment resulted in significant induction of PXR target genes in the intestine of hPXR mice, but not in wild-type and Pxr-null mice. However, rifaximin treatment demonstrated no significant effect on hepatic PXR target genes in wild-type, Pxr-null, and hPXR mice. Consistent with the in vivo data, cell-based reporter gene assay revealed rifaximin-mediated activation of human PXR, but not the other xenobiotic nuclear receptors constitutive androstane receptor, peroxisome proliferator-activated receptor (PPAR)alpha, PPARgamma, and farnesoid X receptor. Pretreatment with rifaximin did not affect the pharmacokinetics of the CYP3A substrate midazolam, but it increased the C(max) and decreased T(max) of 1'-hydroxymidazolam. Collectively, the current study identified rifaximin as a gut-specific human PXR ligand, and it provided further evidence for the utility of hPXR mice as a critical tool for the study of human PXR activators. Further human studies are suggested to assess the potential role of rifaximin-mediated gut PXR activation in therapeutics of chronic gastrointestinal disorders. 相似文献
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Human organic anion transporting polypeptide-C (SLC21A6) is a major determinant of rifampin-mediated pregnane X receptor activation 总被引:11,自引:0,他引:11
Tirona RG Leake BF Wolkoff AW Kim RB 《The Journal of pharmacology and experimental therapeutics》2003,304(1):223-228
Rifampin, a member of the rifamycin class of antibiotics, is well known for its ability to induce drug-metabolizing enzymes and transporters, through activation of the pregnane X receptor. Available data suggest rifampin entry into hepatocytes may be transporter-mediated. Accordingly, it is therefore plausible that modulation of the achievable intracellular concentration of rifampin by drug uptake transporters would influence the degree of induction. In this study, we expressed an array of known hepatic uptake transporters to show the key hepatic rifampin uptake transporters are liver-specific members of the organic anion transporting polypeptide family (OATP). Indeed, both OATP-C and OATP8 seemed capable of mediating rifampin uptake into HeLa cells. OATP-C, however, seemed to have far greater affinity and capacity for rifampin transport. In addition, several allelic variants of OATP-C known to be present among European and African Americans were found to have markedly decreased rifampin transport activity. In cell-based, transactivation assays, OATP-C expression was associated with increased cellular rifampin retention as well as potentiation of PXR reporter gene activity. This is the first demonstration of an uptake transporter such as OATP-C, in modulating PXR function, and sheds important new insight into our understanding of the molecular determinants of PXR-mediated inductive processes. 相似文献
4.
Immune-mediated modulation of breast cancer growth and metastasis by the chemokine Mig (CXCL9) in a murine model 总被引:1,自引:0,他引:1
Walser TC Ma X Kundu N Dorsey R Goloubeva O Fulton AM 《Journal of immunotherapy (Hagerstown, Md. : 1997)》2007,30(5):490-498
Current immunotherapies are limited by several factors, including the failure to recruit sufficient numbers of immune effector cells to tumors. The chemokine monokine induced by gamma-interferon (Mig; CXCL9) attracts activated T cells and natural killer (NK) cells bearing the chemokine receptor CXCR3. We investigated Mig as an immunotherapeutic agent in a syngeneic murine model of metastatic breast cancer. We transfected the highly malignant murine mammary tumor cell line 66.1 to stably express murine Mig cDNA. Immune-competent mice injected with Mig-expressing tumor cells developed smaller local tumors and fewer lung metastases, and they survived longer than mice injected with vector-control tumor cells. Mig-mediated inhibition of local tumor growth was lost in the absence of host T cells. Mig-transduced tumors had increased numbers of CD4 T cells compared with vector-control tumors, consistent with the T-cell chemoattractant property of Mig, and many tumor-infiltrating host cells expressed CXCR3. NK cells had not been examined previously as a possible effector cell in Mig-based therapies. Our studies now show that NK cells are critical to the mechanism by which Mig limits metastasis. Inhibition of angiogenesis was not implicated as a mechanism of Mig-mediated therapy in this model. These studies support the hypothesis that by manipulating the Mig-CXCR3 gradient, it is possible to direct host immune effector cells to tumors, curtailing both local tumor growth and metastasis. These studies also implicate host NK cells as an additional effector cell critical for Mig-mediated control of metastasis. 相似文献
5.
Clinical significance of urokinase-type plasminogen activator receptor (uPAR) expression in cancer 总被引:9,自引:0,他引:9
The involvement of the urokinase-type plasminogen activator (uPA) system in particular has been extensively studied in the pathogenesis of cancer. The molecular role of the uPA receptor (uPAR) is well characterized with its participation in cell migration and extracellular matrix (ECM) degradation. Over-expression of uPAR in cancer has been demonstrated in many studies and is considered an attractive target for anticancer agents. We and others have down-regulated uPAR expression in an attempt to inhibit cancer metastasis based on its molecular role. Uniquely, uPAR which is a glycosyl phosphatidylinositol anchored protein is not only bound to the cell surface but also has a soluble form, suPAR. There is now accumulated clinical and experimental evidence supporting the significant role of uPAR and its soluble counterpart in a number of solid cancers. The expression of uPAR can be associated with tumor cells or stromal cells or both. Differences observed in the expression of uPAR using immunohistochemistry (IHC) are likely explained by the use of different antibodies and techniques rather than true cellular differences and are reviewed here. This review summarizes the clinical relevance of uPAR and its soluble form in the prognosis and diagnosis of different cancers. 相似文献
6.
Pei-Du Jiang Ying-Lan ZhaoXiao-Qiang Deng Yong-Qiu MaoWei Shi Qing-Qing TangZheng-Guang Li Yu-Zhu ZhengSheng-Yong Yang Yu-Quan Wei 《Biomedicine & Pharmacotherapy》2010
Metastatic breast cancers are hard to treat and almost always fatal. Chloroquine diphosphate, a derivative of quinine, has long been used as a potent and commonly used medicine against different human diseases. We therefore investigated the effects of chloroquine diphosphate on a highly metastatic mouse mammary carcinoma cell line. In vitro treatment of 4T1 mouse breast cancer cells with chloroquine diphosphate resulted in significant inhibition of cellular proliferation and viability, and induction of apoptosis in 4T1 cells in a time- and dose-dependent manner. Further analysis indicated that induction of apoptosis was associated with the loss of mitochondrial membrane potential, release of cytochrome c, and activation of caspase-9 and caspase-3, and cleavage of poly(ADP-ribose) polymerase. The effect of chloroquine diphosphate was then examined using a mice model in which 4T1 cells were implanted subcutaneously. Chloroquine diphosphate (25 mg/kg and 50 mg/kg, respectively) significantly inhibited the growth of the implanted 4T1 tumor cells and induced apoptosis in the tumor microenvironment. Moreover, the metastasis of tumor cells to the lungs was inhibited significantly and the survival of the mice enhanced. These data suggested that chloroquine diphosphate might have chemotherapeutic efficacy against breast cancer including inhibition of metastasis. 相似文献
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The involvement of the pregnane X receptor in hepatic gene regulation during inflammation in mice 总被引:6,自引:0,他引:6
Teng S Piquette-Miller M 《The Journal of pharmacology and experimental therapeutics》2005,312(2):841-848
Inflammation and proinflammatory cytokines suppress the expression of several hepatic transporters and metabolic enzymes, often resulting in cholestatic liver disease. However, mechanism(s) of this down-regulation have not been fully elucidated. As the pregnane X receptor (PXR) is involved in inducing many of these hepatic proteins, it is possible that PXR is also involved in their down-regulation during inflammation. Thus, we compared the effect of inflammation on hepatic gene regulation in wild-type (PXR(+/+)) versus PXR-null (PXR(-/-)) mice. Treatment of PXR(+/+) but not PXR(-/-) mice with the PXR activators 5-pregnen-3beta-ol-20-one-16alpha-carbonitrile (PCN) or 17beta-hydroxy-11beta-[4-dimethylamino phenyl]-17alpha-[1-propynyl] estra-4,9-dien-3-one (RU486) resulted in increased mRNA levels of bsep, mdr1a, mrp2, mrp3, oatp2, and cyp3a11, indicating involvement of PXR in their regulation. Significantly lower mRNA levels of bsep, mdr2, mrp2, mrp3, ntcp, oatp2, and cyp3a11 were found in endotoxin-treated PXR(+/+) mice. In endotoxin-treated PXR(-/-) mice, the extent of mrp2 suppression was significantly diminished. Changes in MRP2 expression were supported by Western blot analysis. Although interleukin (IL)-6 imposed significant decreases in the expression of bsep, mrp2, and cyp3a11 in PXR(+/+) mice, this was not observed in PXR(-/-) mice. Of note, significantly lower levels of PXR mRNA and protein were detected in endotoxin- and IL-6-treated PXR(+/+) mice. In addition, endotoxin and IL-6 were also able to suppress PCN-mediated induction of bsep, mrp2, cyp3a11, and PXR. Taken together, our results suggest that PXR plays a role in the down-regulation of several hepatic proteins during inflammation. 相似文献
9.
Panigrahi S Yacovlev E Gelfand Y Schuger L Slavin S Morecki S 《Cytokines, cellular & molecular therapy》2002,7(3):99-106
Allogeneic immunocompetent splenocytes were tested for their ability to exert a GVT effect in a murine model of liver metastasis. Mammary carcinoma cells originating from an H-2(d) mouse were inoculated through the PV of F(1) (H-2(d/b)) mice, to mimic clinical hepatic involvement in malignant disease. Cell therapy was given either locally (PV) or systemically by IV inoculation to test differential efficacy of the GVT effect, and the differential expression of GVHD symptoms induced by diverse routes of administration. Livers of mice treated with H-2(b) derived splenocytes given PV or IV remained tumor-free for at least 4 weeks following tumor inoculation. Furthermore, all secondary recipients of adoptively transferred (AT) liver cells were tumor-free for >300 days. In contrast, all livers of untreated control mice or mice treated with syngeneic splenocytes displayed tumor metastases as early as 2 weeks following tumor inoculation, and large local tumors developed in AT secondary recipients. Our data demonstrate the efficacy of allogeneic cell therapy, given either locally or systemically, in the eradication of liver metastases. However, diverse routes of cell therapy administration did not show any difference in the expression and outcome of GVHD. 相似文献
10.
M. R. Nijziel † R. Van Oerle† D. Hellenbrand† E. C. M. Van Pampus† H. F. P. Hillen† K. Hamulyák† 《Journal of thrombosis and haemostasis》2003,1(5):982-986
Summary. Elevated levels of soluble uPAR (s‐uPAR) and other fibrinolytic parameters functionally related to the urokinase‐type plasminogen activator system might indicate the presence of cancer cells. In 25 breast cancer patients with metastases s‐uPAR was significantly increased compared with 25 patients without metastases and with 25 healthy controls: 420 pg mL?1 vs. 145 pg mL?1 (P = 0.005) and 190 pg mL?1 (P = 0.003). Plasmin–α2‐antiplasmin (PAP) complexes and d ‐dimers were significantly increased in breast cancer patients with metastases compared with patients without metastases and with healthy controls. The levels of plasminogen activator inhibitor (PAI)‐1 activity, uPA antigen and factor (F)XIIa did not significantly differ between the patient groups and healthy controls. PAP complexes (529 µg L?1 vs. 420 µg L?1; P = 0.03), d ‐dimers (278.5 ng mL?1 vs. 79.0 ng mL?1; P = 0.005) and FXIIa (1.64 ng mL?1 vs. 1.19 ng mL?1; P = 0.01) were significantly higher in patients with metastases not surviving compared with patients with metastases surviving the 3‐year follow‐up period. Plasma s‐uPAR levels in the patients with metastases did not discriminate between patients surviving and patients not surviving after 3‐year follow‐up. No significant differences in s‐uPAR or any of the other parameters were found in the five patients developing metastases during follow‐up. A single value of s‐uPAR is of limited value in the follow‐up of breast cancer patients with and without metastatic disease and does not predict survival or future metastases. 相似文献
11.
Chen M Shabashvili D Nawab A Yang SX Dyer LM Brown KD Hollingshead M Hunter KW Kaye FJ Hochwald SN Marquez VE Steeg P Zajac-Kaye M 《Molecular cancer therapeutics》2012,11(2):370-382
Zebularine is a novel potent inhibitor of both cytidine deaminase and DNA methylation. We examined the effect of zebularine on mammary tumor growth in genetically engineered MMTV-PyMT transgenic mice that develop mammary tumors at 60 days of age with 100% penetrance. The MMTV-PyMT transgenic mice were randomized at 46 days of age into control (n = 25) and zebularine (n = 25) treatment groups and monitored for parameters of tumor growth. Zebularine was administered at 5 mg/mL in drinking water. We observed a significant delay in the growth of mammary tumors in zebularine-treated mice with a statistically significant reduction (P = 0.0135) in total tumor burden at 94 days of age when the mice were sacrificed. After 48 days of zebularine treatment, the tumors were predominantly necrotic compared with untreated animals. In addition, a high apoptotic index by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was observed as early as 13 days following treatment. Immunoblot analysis showed depletion of DNMT1 and partial depletion of DNMT3b after zebularine treatment. Microarray analyses of global gene expression identified upregulation of twelve methylation-regulated genes as well as a set of candidate cancer genes that participate in cell growth and apoptosis. In summary, zebularine inhibits the growth of spontaneous mammary tumors and causes early onset of tumor cell necrosis and apoptosis in a genetically engineered mouse model of breast cancer. Defining the parameters of zebularine-mediated tumor inhibition may advance the future development of DNA methyltransferase inhibitors as an effective cancer treatment. 相似文献
12.
Mu Y Zhang J Zhang S Zhou HH Toma D Ren S Huang L Yaramus M Baum A Venkataramanan R Xie W 《The Journal of pharmacology and experimental therapeutics》2006,316(3):1369-1377
The traditional Chinese medicines (TCMs) are essential components of alternative medicines. Many TCMs are known to alter the expression of hepatic drug-metabolizing enzymes and transporters. The molecular mechanism by which TCMs and/or their constituents regulate enzyme and transporter expression, however, has remained largely unknown. In this report, we show that two TCMs, Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch), and their selected constituents activate the xenobiotic orphan nuclear receptor pregnane X receptor (PXR). Treatment with TCM extracts and the Schisandrol and Schisandrin constituents of Wu Wei Zi induced the expression of drug-metabolizing enzymes and transporters in reporter gene assays and in primary hepatocyte cultures. The affected enzymes and transporters include CYP3A and 2C isozymes and the multidrug resistance-associated protein 2. In transient transfection and reporter gene assays, the Schisandrin constituents of Wu Wei Zi had an estimated EC50 of 2 and 1.25 microM on hPXR and mPXR, respectively. Interestingly, mutations that were intended to alter the pore of the ligand-binding cavity of PXR had species-specific effects on the activities of the individual Schisandrols and Schisandrins. In rats, the administration of Wu Wei Zi and Gan Cao increased the metabolism of the coadministered warfarin, reinforcing concerns involving the safe use of herbal medicines and other nutraceuticals to avoid PXR-mediated drug-drug interactions. Meanwhile, the activation of PXR and induction of detoxifying enzymes provide a molecular mechanism for the hepatoprotective effects of certain TCMs. 相似文献
13.
Velliquette RA Friedman JE Shao J Zhang BB Ernsberger P 《The Journal of pharmacology and experimental therapeutics》2005,314(1):422-430
Insulin resistance clusters with hyperlipidemia, impaired glucose tolerance, and hypertension as metabolic syndrome X. We tested a low molecular weight insulin receptor activator, demethylasterriquinone B-1 (DMAQ-B1), and a novel indole peroxisome proliferator-activated receptor gamma agonist, 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (PPEIA), in spontaneously hypertensive obese rats (SHROB), a genetic model of syndrome X. Agents were given orally for 19 days. SHROB showed fasting normoglycemia but impaired glucose tolerance after an oral load, as shown by increased glucose area under the curve (AUC) [20,700 mg x min/ml versus 8100 in lean spontaneously hypertensive rats (SHR)]. Insulin resistance was indicated by 20-fold excess fasting insulin and increased insulin AUC (6300 ng x min/ml versus 990 in SHR). DMAQ-B1 did not affect glucose tolerance (glucose AUC = 21,300) but reduced fasting insulin 2-fold and insulin AUC (insulin AUC = 4300). PPEIA normalized glucose tolerance (glucose AUC = 9100) and reduced insulin AUC (to 3180) without affecting fasting insulin. PPEIA also increased food intake, fat mass, and body weight gain (81 +/- 12 versus 45 +/- 8 g in untreated controls), whereas DMAQ-B1 had no effect on body weight but reduced subscapular fat mass. PPEIA but not DMAQ-B1 reduced blood pressure. In skeletal muscle, insulin-stimulated phosphorylation of the insulin receptor and insulin receptor substrate protein 1-associated phosphatidylinositol 3-kinase activity were decreased by 40 to 55% in SHROB relative to lean SHR. PPEIA, but not DMAQ-B1, enhanced both insulin actions. SHROB also showed severe hypertriglyceridemia (355 +/- 42 mg/dl versus 65 +/- 3 in SHR) attenuated by both agents (DMAQ-B1, 228 +/- 18; PPEIA, 79 +/- 3). Both these novel antidiabetic agents attenuate insulin resistance and hypertriglyceridemia associated with metabolic syndrome but via distinct mechanisms. 相似文献
14.
Induction of human CYP2C9 by rifampicin, hyperforin, and phenobarbital is mediated by the pregnane X receptor 总被引:7,自引:0,他引:7
Chen Y Ferguson SS Negishi M Goldstein JA 《The Journal of pharmacology and experimental therapeutics》2004,308(2):495-501
Human CYP2C9 is important in the metabolism of numerous clinically used drugs such as the anticoagulant warfarin, the anticonvulsant phenytoin, antidiabetic drugs such as tolbutamide and glipizide, the hypertensive agent losartan, and numerous nonsteroidal anti-inflammatory drugs. Several studies have reported that certain drugs such as rifampicin and phenobarbital induce CYP2C9, but the molecular basis for this induction remains unknown. In the present study, we demonstrate that the human pregnane X receptor (hPXR) mediates induction of CYP2C9 by the prototype drugs rifampicin, hyperforin (found in St. John's Wart), and phenobarbital. Deletion and mutagenesis studies with luciferase reporter constructs showed that a functional PXR-responsive element located -1839/-1824 base pairs upstream from the translation start site was the primary binding site mediating the rifampicin induction of CYP2C9. This site was previously described as a constitutive androstane receptor-responsive element (CAR-RE). Mutational analysis of 3- and 12-kilobase CYP2C9 promoter fragments indicated that this proximal binding site was essential for rifampicin inducibility, although a cooperative effect could be attributed to a second CAR-RE located at -2899/-2883. In summary, we have demonstrated rifampicin induction of CYP2C9 promoter constructs that is consistent with the magnitude of induction of CYP2C9 protein and mRNA reported in vivo and in primary human hepatocytes, and we have identified the cis-element essential for this response. This is the first report to demonstrate that the nuclear receptor PXR mediates induction of CYP2C9 with rifampicin, phenobarbital, and hyperforin. 相似文献
15.
VEGF-C反义多肽对乳腺癌裸鼠移植瘤影响的实验研究 总被引:1,自引:0,他引:1
目的观察血管内皮生长因子C(VEGF—C)反义多肽对乳腺癌裸鼠皮下移植瘤的影响,探讨以VEGF—C反义多肽用于乳腺癌基因治疗的应用前景。方法制备靶向VEGF—C的反义多肽,构建乳腺癌细胞MCF-7裸鼠皮下移植瘤模型,瘤体内注射VEGF—C反义多肽,观察其对乳腺癌细胞的抑制作用;免疫印迹(Western Blot)检测VEGF—C在瘤组织的表达情况。结果VEGF—C反义多肽具有较强的生物学活性,瘤组织内给予VEGF-C反义多肽后,Western blot分析VEGF—C在瘤组织中的表达降低,肿瘤生长受制,抑瘤率为52%(P〈0.05)。结论 制备出的VEGF—C具有良好的生物学活性,有抗乳腺癌作用。 相似文献
16.
目的:探讨尿激酶型纤溶酶原激活物(uPA)及其受体(uPAR)和抑制剂(PAI-1)血浆含量与卵巢恶性肿瘤之间的关系。方法:收集52例卵巢恶性肿瘤患者血液标本,以30例健康人作对照,用ELISA法分别检测uPA、uPAR和PAI-1的含量。结果:uPA、uPAR在卵巢恶性肿瘤各期之间均有极显著性差异(P〈0.01),PAI-1在卵巢恶性肿瘤FIGO Ⅰ~Ⅲ期的含量逐渐升高,但在FIG0Ⅳ期时显著下降(P〈0.05)。患者组uPA、uPAR、PAI-1均较对照组升高,差异极显著(P〈0.01)。结论uPA、uPAR在卵巢恶性肿瘤患者可作为预后的判断指标,PAI-1与卵巢恶性肿瘤的分期有一定的相关性。 相似文献
17.
Stutchbury TK Al-Ejeh F Stillfried GE Croucher DR Andrews J Irving D Links M Ranson M 《Molecular cancer therapeutics》2007,6(1):203-212
Tumor-associated urokinase plasminogen activator (uPA) is a critical marker of invasion and metastasis, has strong prognostic relevance, and is thus a potential therapeutic target. Experimental data published to date has established the proof-of-principle of uPA targeting by (213)Bi-labeled plasminogen activator inhibitor type 2 (alpha-PAI-2) in multiple carcinoma models. Here, we present preclinical toxicologic and efficacy assessment of alpha-PAI-2 in mice, using both single and multiple-dose schedules, administered by an i.p. route. We also present novel data showing that human PAI-2 inhibited murine uPA and was specifically endocytosed by murine fibroblast cells. This diminishes potential problems associated with species specificity of the targeting reagent in toxicologic assessments as human alpha-PAI-2 should interact with any uPA-expressing host cells. In this model, single bolus doses up to 36 mCi/kg alpha-PAI-2 did not reach the maximum tolerated dose (MTD). The MTD for a multiple fractionated (once daily for 5 days) administration schedule was determined to lie between 4.8 and 6.0 mCi/kg/d x 5. Comparison of the tumor growth rates and survival using sub-MTD single and multiple-dose schedules in an orthotopic human breast carcinoma xenograft murine model indicated that 4.8 mCi/kg/d x 5 was the most efficacious schedule. In conclusion, we have determined a safe dose and schedule of alpha-PAI-2 administration in mice, thus confirming that it is an efficacious therapeutic modality against tumor growth. This will allow detailed safety evaluation in a second species and for the initiation of human studies. 相似文献
18.
目的 建立一个小鼠转移性乳腺癌净化后骨髓移植模型,并探讨益康唑(Econazole,Ec)药物净化效果。方法 将小鼠自发性乳腺癌细胞系TSA转染新霉素抗性基因(Neo^R基因)后与小鼠骨髓细胞混合,体外短期培养净化;通过移植后造血恢复,肺转移性结节和小鼠的存活进行评估。结果 接受放射治疗后经尾静脉注射TSA细胞的小鼠均可产生乳腺癌肺转移;Ec体外净化后骨髓移植小鼠造血恢复没有明显延迟,移植后4周内未见肺转移性结节;小鼠的总生存状况明显改善。结论 成功建立了TSA小鼠乳腺癌净化后骨髓移植模型,方法简单、易行、重复性好;Ec可用于转移性乳腺癌净化后骨髓移植。 相似文献
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A novel panel of mouse models to evaluate the role of human pregnane X receptor and constitutive androstane receptor in drug response 总被引:1,自引:0,他引:1
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Scheer N Ross J Rode A Zevnik B Niehaves S Faust N Wolf CR 《The Journal of clinical investigation》2008,118(9):3228-3239
The pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are closely related orphan nuclear hormone receptors that play a critical role as xenobiotic sensors in mammals. Both receptors regulate the expression of genes involved in the biotransformation of chemicals in a ligand-dependent manner. As the ligand specificity of PXR and CAR have diverged between species, the prediction of in vivo PXR and CAR interactions with a drug are difficult to extrapolate from animals to humans. We report the development of what we believe are novel PXR- and CAR-humanized mice, generated using a knockin strategy, and Pxr- and Car-KO mice as well as a panel of mice including all possible combinations of these genetic alterations. The expression of human CAR and PXR was in the predicted tissues at physiological levels, and splice variants of both human receptors were expressed. The panel of mice will allow the dissection of the crosstalk between PXR and CAR in the response to different drugs. To demonstrate the utility of this panel of mice, we used the mice to show that the in vivo induction of Cyp3a11 and Cyp2b10 by phenobarbital was only mediated by CAR, although this compound is described as a PXR and CAR activator in vitro. This panel of mouse models is a useful tool to evaluate the roles of CAR and PXR in drug bioavailability, toxicity, and efficacy in humans. 相似文献
20.
Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia 总被引:21,自引:0,他引:21
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Eberhardt RT Forgione MA Cap A Leopold JA Rudd MA Trolliet M Heydrick S Stark R Klings ES Moldovan NI Yaghoubi M Goldschmidt-Clermont PJ Farber HW Cohen R Loscalzo J 《The Journal of clinical investigation》2000,106(4):483-491
Homocysteine is a risk factor for the development of atherosclerosis and its thrombotic complications. We have employed an animal model to explore the hypothesis that an increase in reactive oxygen species and a subsequent loss of nitric oxide bioactivity contribute to endothelial dysfunction in mild hyperhomocysteinemia. We examined endothelial function and in vivo oxidant burden in mice heterozygous for a deletion in the cystathionine beta-synthase (CBS) gene, by studying isolated, precontracted aortic rings and mesenteric arterioles in situ. CBS(-/+) mice demonstrated impaired acetylcholine-induced aortic relaxation and a paradoxical vasoconstriction of mesenteric microvessels in response to superfusion of methacholine and bradykinin. Cyclic GMP accumulation following acetylcholine treatment was also impaired in isolated aortic segments from CBS(-/+) mice, but aortic relaxation and mesenteric arteriolar dilation in response to sodium nitroprusside were similar to wild-type. Plasma levels of 8-epi-PGF(2alpha) (8-IP) were somewhat increased in CBS(-/+) mice, but liver levels of 8-IP and phospholipid hydroperoxides, another marker of oxidative stress, were normal. Aortic tissue from CBS(-/+) mice also demonstrated greater superoxide production and greater immunostaining for 3-nitrotyrosine, particularly on the endothelial surface. Importantly, endothelial dysfunction appears early in CBS(-/+) mice in the absence of structural arterial abnormalities. Hence, mild hyperhomocysteinemia due to reduced CBS expression impairs endothelium-dependent vasodilation, likely due to impaired nitric oxide bioactivity, and increased oxidative stress apparently contributes to inactivating nitric oxide in chronic, mild hyperhomocysteinemia. 相似文献