Biomedical subjects

Yumei Ye

Publications and source records attributed to Yumei Ye.

10 recordsLinked to original sources

PubMed2006

Augmentation of myocardial production of 15-epi-lipoxin-a4 by pioglitazone and atorvastatin in the rat.

BACKGROUND: Both statins and thiazolidinediones have antiinflammatory properties. However, the exact mechanisms underlying these effects are unknown. We investigated whether atorvastatin (ATV) and pioglitazone (PIO) increase the myocardial content of lipoxin-A4 and 15(R)-epi-lipoxin-A4 (15-epi-LXA4), both arachidonic acid products with strong antiinflammatory properties. METHODS AND RESULTS: In experiment 1, rats received 3-day pretreatment with water; PIO 2, 5, or 10 mg x kg(-1) x d(-1); ATV 2, 5, or 10 mg x kg(-1) x d(-1); or PIO 10 mg x kg(-1) x d(-1)+ATV 10 mg x kg(-1) x d(-1). In experiment 2, rats received water; PIO 10 mg x kg(-1) x d(-1)+ATV 10 mg x kg(-1) x d(-1); PIO+ATV and valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor; PIO+ATV and zileuton, a selective 5-lipoxygenase inhibitor; or zileuton alone. There were 4 rats in each group. Hearts were harvested and analyzed for myocardial lipoxin-A4 and 15-epi-LXA4 levels and for COX-2 and 5-lipoxygenase protein expression. ATV and PIO at 5 and 10 mg x kg(-1) . d(-1) significantly increased myocardial 15-epi-LXA4 levels compared with the sham-treated group (0.51 +/- 0.02 ng/mg). Myocardial 15-epi-LXA4 were significantly higher in the PIO+ATV group (1.29 +/- 0.02 ng/mg; P < 0.001 versus each other group). Both valdecoxib and zileuton abrogated the PIO+ATV increase in 15-epi-LXA4, whereas zileuton alone had no effect. PIO, ATV, and their combination resulted in a small increase in myocardial lipoxin-A4 levels, which was not statistically significant. ATV alone or in combination with PIO markedly augmented COX-2 expression. PIO had a much smaller effect on COX-2 expression. Myocardial expression of 5-lipoxygenase was not altered by PIO, ATV, or their combination. CONCLUSIONS: Both PIO and ATV increase myocardial levels of 15-epi-LXA4, a mediator with antiinflammatory properties. This finding may explain the antiinflammatory properties of both PIO and ATV.

Animals↗

PubMed2006

Myocardial protection by pioglitazone, atorvastatin, and their combination: mechanisms and possible interactions.

We assessed 1) whether pretreatment before ischemia with pioglitazone (Pio) limits infarct size (IS) and whether this protective effect is due to nitric oxide synthase (NOS) and/or prostaglandin production, as has been shown for atorvastatin (ATV); and 2) whether Pio and ATV have synergistic effects on myocardial protection. Sprague-Dawley rats received oral ATV (10 mg.kg-1.day-1), Pio (10 mg.kg-1.day-1), their combination (Pio+ATV), or water alone for 3 days. Additional rats received Pio (10 mg.kg-1.day-1) for 3 days and intravenous SC-58125 [a cyclooxygenase-2 (COX-2) inhibitor] or SC-560 (a COX-1 inhibitor) 15 min before ischemia. Rats underwent 30 min of myocardial ischemia and 4 h of reperfusion, or hearts were harvested for analysis. IS in the Pio and in the ATV groups was significantly smaller than in the sham-treated group. IS in the Pio+ATV group was smaller than in all other groups (P<0.001 vs. each group). The protective effect of Pio was abrogated by SC-58125 but not by SC-560. Pio, ATV, and Pio + ATV increased the expression and activity of cytosolic phospholipase A2 (cPLA2) and COX-2. ATV increased phosphorylated-Akt, phosphorylated-endothelial NOS (P-eNOS), inducible NOS, and COX-2 levels. In contrast, Pio caused an insignificant increase in myocardial levels of phosphorylated-Akt but did not change P-eNOS and iNOS expression. In conclusion, the IS-limiting effects of Pio and ATV involve COX-2. However, the upstream steps differ. ATV induced eNOS phosphorylation and iNOS, cPLA2, and COX-2 expression, whereas Pio induced mainly the expression and activity of cPLA2. The effects of Pio and ATV were additive.

Animals↗

PubMed2006

Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen.

Conjugates of the anti-CanAg humanized monoclonal antibody huC242 with the microtubule-formation inhibitor DM1 (a maytansinoid), or with the DNA alkylator DC1 (a CC1065 analogue), have been evaluated for their ability to eradicate mixed cell populations formed from CanAg-positive and CanAg-negative cells in culture and in xenograft tumors in mice. We found that in culture, conjugates of either drug killed not only the target antigen-positive cells but also the neighboring antigen-negative cells. Furthermore, we showed that, in vivo, these conjugates were effective in eradicating tumors containing both antigen-positive and antigen-negative cells. The presence of antigen-positive cells was required for this killing of bystander cells. This target cell-activated killing of bystander cells was dependent on the nature of the linker between the antibody and the drug. Conjugates linked via a reducible disulfide bond were capable of exerting the bystander effect whereas equally potent conjugates linked via a nonreducible thioether bond were not. Our data offer a rationale for developing optimally constructed antibody-drug conjugates for treating tumors that express the target antigen either in a homogeneous or heterogeneous manner.

Animals↗

PubMed2006

Enhanced cardioprotection against ischemia-reperfusion injury with combining sildenafil with low-dose atorvastatin.

PURPOSE: Both ATV and SL reduce myocardial infarct size (IS) by enhancing expression and activity of NOS isoforms. We investigated whether atorvastatin (ATV) and sildenafil (SL) have synergistic effects on myocardial infarct size (IS) reduction and enhancing nitric oxide synthase (NOS) expression. METHOD: Rats were randomized to nine groups: ATV-1 (1 mg/kg/d); ATV-10 (10 mg/kg/d); SL-0.7 (0.7 mg/kg); SL-1 (1 mg/kg); ATV-1 + SL-0.7; water alone (controls); 1400W (iNOS inhibitor; 1 mg/kg); ATV-10 + 1400W; and ATV-1 + SL-0.7 + 1400W. ATV was administered orally for 3 days. SL was administered intraperitoneally 18 h before surgery and 1400W intravenously 15 min before surgery. Rats either underwent 30 min ischemia-4 h reperfusion or the hearts were explanted for immunoblotting and enzyme activity tests without being exposed to ischemia. RESULTS: IS (% risk area, mean +/- SEM) was smaller in the ATV-10 (13 +/- 1%), SL-1 (11 +/- 2%), SL-0.7 (18 +/- 2%) and ATV-1 + SL-0.7 (9 +/- 1%) groups as compared with controls (34 +/- 3%; P < 0.001), whereas ATV-1 had no effect (29 +/- 2%). ATV-1 + SL-0.7 (9 +/- 1%) reduced IS more than SL-0.7 alone (p = 0.012). 1400W abrogated the protective effect of ATV-10 (35 +/- 3%) and ATV-1 + SL-0.7 (34 +/- 1%). SL-0.7 and ATV-10 increased phosphorylated endothelial (P-eNOS; 210 +/- 2.5% and 220 +/- 8%) and inducible (iNOS; 151 +/- 1% and 154 +/- 1%) NOS expression, whereas ATV-1 did not. These changes were significantly enhanced by ATV-1 + SL-0.7 (P-eNOS, 256 +/- 2%, iNOS 195 +/- 1%). SL-1 increased P-eNOS (311 +/- 22%) and iNOS (185 +/- 1%) concentrations. CONCLUSIONS: Combining low-dose ATV with SL augments the IS limiting effects through enhanced P-eNOS and iNOS expression.

Amidines↗

PubMed2005

Atorvastatin-induced cardioprotection is mediated by increasing inducible nitric oxide synthase and consequent S-nitrosylation of cyclooxygenase-2.

We determined the effects of cyclooxygenase-1 (COX-1; SC-560), COX-2 (SC-58125), and inducible nitric oxide synthase (iNOS; 1400W) inhibitors on atorvastatin (ATV)-induced myocardial protection and whether iNOS mediates the ATV-induced increases in COX-2. Sprague-Dawley rats received 10 mg ATV.kg(-1).day(-1) added to drinking water or water alone for 3 days and received intravenous SC-58125, SC-560, 1400W, or vehicle alone. Anesthesia was induced with ketamine and xylazine and maintained with isoflurane. Fifteen minutes after intravenous injection rats underwent 30-min myocardial ischemia followed by 4-h reperfusion [infarct size (IS) protocol], or the hearts were explanted for biochemical analysis and immunoblotting. Left ventricular weight and area at risk (AR) were comparable among groups. ATV reduced IS to 12.7% (SD 3.1) of AR, a reduction of 64% vs. 35.1% (SD 7.6) in the sham-treated group (P < 0.001). SC-58125 and 1400W attenuated the protective effect without affecting IS in the non-ATV-treated rats. ATV increased calcium-independent NOS (iNOS) [11.9 (SD 0.8) vs. 3.9 (SD 0.1) x 1,000 counts/min; P < 0.001] and COX-2 [46.7 (SD 1.1) vs. 6.5 (SD 1.4) pg/ml of 6-keto-PGF(1alpha); P < 0.001] activity. Both SC-58125 and 1400W attenuated this increase. SC-58125 did not affect iNOS activity, whereas 1400W blocked iNOS activity. COX-2 was S-nitrosylated in ATV-treated but not sham-treated rats or rats pretreated with 1400W. COX-2 immunoprecipitated with iNOS but not with endothelial nitric oxide synthase. We conclude that ATV reduced IS by increasing the activity of iNOS and COX-2, iNOS is upstream to COX-2, and iNOS activates COX-2 by S-nitrosylation. These results are consistent with the hypothesis that preconditioning effects are mediated via PG.

Animals↗

PubMed2005

Prostaglandins mediate the cardioprotective effects of atorvastatin against ischemia-reperfusion injury.

OBJECTIVES: Statins attenuate myocardial ischemic injury by activating nitric oxide synthase (NOS). It is unknown whether cyclooxygenase-2 (COX2), which mediates late ischemic preconditioning, also mediates statins-induced cardioprotection. We investigated the involvement of the prostaglandins and NOS in the cardioprotective effect of atorvastatin (ATV) in the rat. METHODS: Sprague-Dawley rats were randomized to a 3-day oral treatment with ATV 10 mg/kg, valdecoxib, a selective COX2 inhibitor (VAL) 3 mg/kg, ATV+VAL or water alone. Rats underwent 30-min myocardial ischemia followed by 4-h reperfusion. RESULTS: Infarct size was smaller in the ATV group (31.3+/-1.9%) than controls (44.5+/-3.1%; p=0.011) and VAL (44.5+/-3.1%; p=0.008). VAL attenuated the protective effect of ATV when administered together (40.2+/-2.5%). ATV pretreatment increased myocardial content of 6-keto-PGF(1alpha) (69.5+/-1.5 pg/mg) and PGE2 (57.9+/-0.6 pg/mg) compared with controls (16.2+/-0.2 and 42.1+/-2.0 pg/mg, respectively) and ATV+VAL (15.8+/-0.3 and 39.9+/-1.9 pg/mg, respectively). ATV increased myocardial content of cytosolic phospholipase A2 (cPLA2) (174.8+/-0.5%), COX2 (446.2+/-0.9%), PGI2 synthase (201.8+/-1.1%) and PGE2 synthase (122+/-0.7%), whereas ATV+VAL did not (123.0+/-7.9%, 93.8+/-8.5%, 103.0+/-1.6% and 99.0+/-0%, respectively). ATV did not change the myocardial content of eNOS and nNOS, but increased the concentration of phosphorylated eNOS (231.8+/-2.4%) and iNOS (154.5+/-1.2%). This effect was not blocked by coadministration of VAL (231.5+/-3.0% and 154.5+/-1.8%, respectively). CONCLUSIONS: Our results suggest that the prostaglandins are essential for mediating the myocardial protective effects of ATV and their production is downstream to eNOS phosphorylation and iNOS.

Animals↗

PubMed2004

Effects of pooling mRNA in microarray class comparisons.

MOTIVATION: In microarray experiments investigators sometimes wish to pool RNA samples before labeling and hybridization due to insufficient RNA from each individual sample or to reduce the number of arrays for the purpose of saving cost. The basic assumption of pooling is that the expression of an mRNA molecule in the pool is close to the average expression from individual samples. Recently, a method for studying the effect of pooling mRNA on statistical power in detecting differentially expressed genes between classes has been proposed, but the different sources of variation arising in microarray experiments were not distinguished. Another paper recently did take different sources of variation into account, but did not address power and sample size for class comparison. In this paper, we study the implication of pooling in detecting differential gene expression taking into account different sources of variation and check the basic assumption of pooling using data from both the cDNA and Affymetrix GeneChip microarray experiments. RESULTS: We present formulas for the required number of subjects and arrays to achieve a desired power at a specified significance level. We show that due to the loss of degrees of freedom for a pooled design, a large increase in the number of subjects may be required to achieve a power comparable to that of a non-pooled design. The added expense of additional samples for the pooled design may outweigh the benefit of saving on microarray cost. The microarray data from both platforms show that the major assumption of pooling may not hold. SUPPLEMENTARY INFORMATION: Supplementary material referenced in the text is available at http://linus.nci.nih.gov/brb/TechReport.htm.

Algorithms↗

PubMed2004

Genomic approaches to understanding mammary tumor progression in transgenic mice and responses to therapy.

Scores of genetically engineered mice have been generated in the quest to understand mechanisms of breast cancer development and progression. More recently, there has been a growing trend for using such models for testing various therapeutic strategies and agents. The application of these mouse models for these purposes requires that they be characterized in ways that demonstrate they possess important similarities to human breast cancer. In particular, detailed comparisons of the features of the models to human breast cancer must include attention to the histological phenotypes, chromosomal and molecular alterations, and the predictive value of the models for preclinical testing. Whereas these models have become important tools for the study of breast cancer, the great majority of existing mouse mammary cancer models develop tumors that are estrogen receptor negative, with relatively few models demonstrating metastatic spread to the lungs, and none developing metastases to bone. This review focuses on recent studies using genomic approaches to further understand the oncogenic processes occurring in mouse models of mammary cancer and to compare these changes with those identified in human breast cancer. Gene expression profiling is being applied to help define pharmacological responses that occur in vivo. Detailed genomic analyses will provide important information for selecting models for specific experimental purposes, contribute to the understanding of oncogene-specific expression signatures and potential therapeutic targets, and further define mechanisms of chemoprevention and chemotherapy.

Animals↗

PubMed2004

Molecular mechanisms of breast cancer progression: lessons from mouse mammary cancer models and gene expression profiling.

The development of breast cancer is thought to occur through a multi-step process. The majority of breast cancers likely develop over extended periods of time arising from early, pre-invasive lesions such as atypical ductal hyperplasia (ADH) and carcinoma in situ (DCIS), progressing to invasive carcinoma and culminating in metastatic disease. However, the molecular mechanisms underlying this process are still poorly understood. The molecular analysis of this multi-step process in human patients is hampered by the difficulty in obtaining tissue samples at all tumor stages, especially from the same patient. In contrast, mouse models of mammary cancer progression are amenable to pathological, genetic and biochemical analyses at all tumor stages. Global gene expression profiling allows for simultaneous interrogation of the expression of thousands of genes and provides important opportunities to identify molecular signatures of tumor progression. This approach provides a means to define networks of cancer-related genes and their potential role in tumor progression. In this review, we discuss mouse models that have contributed substantially to understanding the molecular mechanisms of breast cancer progression and insights gained from gene expression profiling of mouse mammary cancer models and human breast cancer.

Journal Article↗

PubMedDate not supplied

Application of gene expression profiling for validating models of human breast cancer.

While classical histopathologic approaches are invaluable in classifying tumors and understanding aspects of cellular interactions, genomic approaches provide a means to molecularly dissect tumorigenesis. The relationship of gene expression to the development of neoplasia remains an area of intensive research. With the advent of large-scale genomic platforms, alterations in gene expression can be related to the morphological development of cancer. The feasibility of using large-scale genomic analysis platforms has dramatically changed the landscape of biological sciences, as cellular processes must be considered in the context of complex networks. Alterations in gene expression must now be understood in a systems approach in which the relationships between genes expression changes are studied by considering the interplay of multiple regulatory networks. Ultimately, such changes must be understood at the protein level. We have begun to apply this technology to determine changes in gene expression that differentiate various types of mammary cancers that arise in mouse models that have been initiated by different genetic alterations. Ultimately, a molecular catalogue of similarities and differences between rodent and human tumors can be created which will serve to validate or credential particular models for specific experimental purposes, such as preclinical testing. These approaches have led to new insights into molecular pathways involved in oncogenesis, new classifications of human breast cancer, and the identification of new genes that may be relevant to understanding and treating human cancer.

Animals↗