Terazosin, a selective alpha 1-adrenergic antagonist, was administered intravenously to 10 patients undergoing cardiac catheterization to determine its short-term hemodynamic effects. Hemodynamic ...measurements were performed before and 30 minutes after three doses of the drug: 1, 1, and 3 mg. One milligram of terazosin reduced the blood pressure (systolic/diastolic, mean) from a mean of 152.0/86.3, 110.7 mm Hg by -24.3/-9.4, -15.3 mm Hg (p less than 0.05). In the five patients who received 5 mg of the drug, blood pressure declined in a dose-dependent manner by -21.8/-3.8, -11.6 mm Hg after 1 mg, and by -35.8/-14.8, -22.8 mm Hg (p less than 0.05) after all 5 mg of the drug. The changes in blood pressure paralleled the terazosin-induced decrease in systemic resistance. Similar changes were recorded for pulmonary artery and capillary wedge pressures and pulmonary vascular resistance. The greatest hemodynamic response was noted with the first drug dose; succeeding doses had a progressively diminished incremental effect. Cardiac output, heart rate, and maximum left ventricular dp/dt demonstrated little change, whereas left ventricular end-diastolic pressure decreased after all three doses, reaching significance after 2 mg (-3.4 +/- 0.9 mm Hg, p less than 0.05), and left ventricular ejection fraction tended to increase (+5.6% +/- 2.4%, p less than 0.05 after 1 mg) and showed a dose dependence analogous to that of systemic resistance. Although not generally reaching statistical significance, indexes of aortic stiffness and compliance displayed a favorable effect. These data are consistent with terazosin's specific alpha 1-antagonism. Left ventricular performance is improved by afterload reduction, since terazosin demonstrated no direct effect on cardiac contractility.
In this article, we have applied the ChIP-on-chip approach to pursue a large scale identification of ERalpha- and ERbeta-binding DNA regions in intact chromatin. We show that there is a high degree ...of overlap between the regions identified as bound by ERalpha and ERbeta, respectively, but there are also regions that are bound by ERalpha only in the presence of ERbeta, as well as regions that are selectively bound by either receptor. Analysis of bound regions shows that regions bound by ERalpha have distinct properties in terms of genome landscape, sequence features, and conservation compared with regions that are bound by ERbeta. ERbeta-bound regions are, as a group, located more closely to transcription start sites. ERalpha- and ERbeta-bound regions differ in sequence properties, with ERalpha-bound regions having an overrepresentation of TA-rich motifs including forkhead binding sites and ERbeta-bound regions having a predominance of classical estrogen response elements (EREs) and GC-rich motifs. Differences in the properties of ER bound regions might explain some of the differences in gene expression programs and physiological effects shown by the respective estrogen receptors.
The onset of the sexually dimorphic pattern of GH secretion and increased hepatic GH-binding capacity in rats at puberty is temporally correlated with the developmental induction of three hepatic ...cytochrome P-450s with steroid hydroxylase activity, P-450 IIC11, P-450 IIC12, and P-450 IIC13, and one cytochrome P-450 with vitamin A hydroxylase activity, P-450 IIC7. In this study we demonstrate that expression of the 2C11, 2C12, and 2C13 genes is modulated by GH at the level of transcriptional initiation both in vivo and in primary cultures of adult hepatocytes. In an effort to define the minimum sequence responsible for the inductive effects of GH, we have analyzed the ability of a 0.7-kilobase fragment isolated from the 5'-flank of the 2C12 gene, including the natural promoter, to drive transcription of a 320-basepair G-less cassette in vitro. We were unable to detect any substantial difference in RNA polymerase-II-dependent transcriptional efficiency toward the 2C12 promoter between liver nuclear extracts from normal and hypophysectomized rats of both sexes. This observation supports the assumption that the sequence information contained between bases -700 and 1 is sufficient to support basal transcription of the 2C12 gene. Sequence information residing 5' or 3' of the 0.7-kilobase 5'-flank or a higher ordered chromatin structure may be necessary for the sex-specific transcriptional activation of the 2C12 gene.
Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease primarily affecting the brainstem, retina and Purkinje cells of the cerebellum. The disease is caused by a polyglutamine expansion ...in ataxin-7, a protein found in two complexes TFTC and STAGA, involved in transcriptional regulation. Transcriptional dysregulation has been implicated in the pathology of several polyglutamine diseases. In this paper, we analyzed the effect of both wild-type and expanded ataxin-7 on transcription driven by the co-activator CBP and the Purkinje cell expressed nuclear receptor RORα1. We could show that transcription mediated by both CBP and RORα1 was repressed by expanded ataxin-7. Interestingly, repression of transcription could also be observed with wild-type full-length ataxin-7, not only on CBP- and RORα1-mediated transcription, but also on basal transcription. The repression could be counteracted by inhibition of deacetylation, suggesting that ataxin-7 may act as a repressor of transcription by inhibiting the acetylation activity of TFTC and STAGA.
Osteopontin (OPN) is a cell-binding phosphoprotein with proposed functions in atherosclerosis. The aim of this study was to examine how OPN deficiency affects the atherosclerotic process.
ApoE/LDL ...receptor/OPN triple knockout (ALO) mice were generated by crossing OPN null mice with ApoE/LDL receptor-deficient (AL) mice. Analysis were made on tissue sections from the aortic arch of 8-, 20- and 34-week female AL and ALO mice and included morphometric measurements, collagen staining, TUNEL staining and immunohistochemistry with antibodies to OPN, macrophages and proliferating cellular nuclear antigen (PCNA).
Lesion and media areas were significantly smaller and collagen accumulation in lesions was significantly reduced in 34-week-old ALO mice compared with AL mice. The numbers of proliferating and apoptotic cells were increased in lesions of 34 weeks old ALO mice. Furthermore, the plasma levels of SAA and total cholesterol were significantly decreased in 34 weeks old ALO mice.
The present study shows that OPN deficiency reduces atherogenesis in atherosclerotic mice. The results corroborate and extend recently published findings and also include novel data on the role of OPN in the process of remodeling, inflammation and lipid metabolism.
Carbon black aerosols were used as a probe of the pulmonary retention and clearance of submicron particles. Male Fischer rats (COBS CD) were exposed for 20 h/d, 7 d/wk for 1, 3, or 6 wk to either 7 ...+/- 2 mg/m3 carbon black or filtered air. The submicron aerosol (mass median aerodynamic diameter, MMAD, 0.24 microns) was generated with a Wright dust feed-cyclone system. Lung and hilar lymph node particle burdens were determined immediately following the exposure and at preselected intervals up to 1 yr postexposure. After 1-, 3-, and 6-wk exposures, the lung burdens were 1.1 +/- 0.1, 3.5 +/- 0.2, and 5.9 +/- 0.1 mg, respectively. One year after a 1-, 3-, or 6-wk exposure, 8%, 46%, and 61% of the initial lung burden remained in the lungs. Initially, the hilar lymph nodes contained 0.2%, 0.9%, and 2.0% of the lung burdens in the 3 exposure groups, respectively. At 1 yr postexposure, particle translocation from the lungs led to a rise in lymph node burdens to 1%, 21%, and 27% of the initial lung burden. The retention of carbon black in both the lungs and lymph nodes combined was 9%, 67%, and 89% for the 1-, 3-, and 6-wk exposed animals. Lung clearance was modeled as a compartmental system consisting of four lung compartments and a regional lymph node compartment. The results from the model are similar for carbon black and diesel engine exhaust particles. However, the compartmental kinetics of carbon black differed in two ways: the deposition efficiency in the alveolar region was lower than that for diesel exhaust particles, and there was earlier transport of particles to the regional lymph nodes. These results showed that when lung burdens reached 0.8 mg, lung clearance was decreased by 50% and lymphatic transport of insoluble particles was increased.
Effects of dietary conjugated linoleic acids (CLAs) and docosahexaenoic acid (DHA) on the fatty acid composition of different egg compartments after storage were studied. Four dietary treatments ...supplemented with safflower oil (SAFF, control group), DHA, CLAs plus DHA (CAD), and CLAs alone were administered to Single Comb White Leghorn (SCWL) laying hens. Eggs from the different treatment groups were collected and stored for 10 weeks at 4 °C before analysis. Fatty acids from the yolk (yolk granules and plasma), egg albumen, and vitelline membrane were analyzed by gas chromatography. The yolk of eggs from hens given CLAs had significantly higher amounts of saturated fatty acids, typically 16:0 and 18:0, but lower amounts of polyunsaturated fatty acids (PUFAs) compared to eggs from the control group (SAFF). CLA content was highest in the yolk and present in both neutral and polar lipids, with the greatest concentrations in neutral lipids. DHA was incorporated mainly into yolk polar lipids. Lipids in yolk plasma and granules contained similar amounts of CLAs. The fatty acid compositions of vitelline membrane and egg albumen mirrored that of the egg yolk. CLA supplementation resulted in hard and rubbery yolks when compared to hard-cooked eggs from the control group. This study showed that feeding CLAs to hens led to accumulation of the isomers in polar and neutral lipids of the egg yolk and that these isomers migrated into egg albumen. Because the sensory properties of hard-cooked eggs were negatively affected by the enrichment of a mixture of CLA isomers in this study, further research should be conducted to evaluate how the different isomers alter the properties of egg yolk and albumen so that the quality of designed eggs containing CLAs and DHA can be improved. Keywords: Conjugated linoleic acids; docosahexaenoic acid; yolk; granule; plasma; designer eggs
We have studied the effect of the aryl hydrocarbon receptor ligand 2,3,7,8-tetrachlorodibenzo-
p-dioxin (TCDD) on estrogen receptor (ER) β gene expression in the human breast cancer cell line, T47D. ...TCDD inhibited 17β-estradiol (E
2)-induced up-regulation of both ER β wild type and ER β cx mRNA. Cycloheximide pre-treatment had no inhibitory effect, and the estimated half-life of ER β mRNA of about 33
min was not changed by any hormone administration. Chromatin immunoprecipitation experiments showed recruitment of ER α to the ER β promoter. Gel mobility shift experiments revealed an E
2-induced protein binding to a half site estrogen response element in the ER β promoter, and TCDD reduced that binding. These results show that ER α regulates the expression of its own heterodimerization partner, ER β, in T47D cells. TCDD, an anti-estrogenic compound, inhibits ER α-mediated induction of ER β mRNA. These findings add to our understanding of cross talk between dioxin and estrogen signaling in human cells.
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