The unique phenotype of each differentiated cell in an animal (or plant) arises from selective expression of genes in a cell- or tissue-specific fashion, which is controlled primarily at the level of ...transcription. This review will focus on transcription factors that regulate cell-specific transcription in one intensely studied cell type, the hepatocyte or parenchymal liver cell. All of the recently isolated transcription factors that are important in hepatocyte-specific gene expression were identified in adult liver and there are strong hints that some of these may play an important role in embryogenesis.
Laropiprant is a selective antagonist of the prostaglandin D2 receptor subtype 1, and is primarily eliminated via glucuronidation with a minor contribution from oxidative metabolism via CYP3A. The ...effects of multiple oral doses of clarithromycin on the pharmacokinetics of laropiprant were investigated in an open‐labeled, randomized, 2‐period cross‐over study. A single oral dose of 40 mg laropiprant was administered alone or coadministered with 500 mg clarithromycin b.i.d. on Day 5 of a 7‐day clarithromycin regimen. Geometric mean ratios (90% confidence intervals) for AUC0‐∞ and Cmax of laropiprant in the presence versus absence of clarithromycin were 1.39 (1.19, 1.62) and 1.46 (1.17, 1.80), respectively. No statistically significant differences were observed in Tmax (P= 0.543) or apparent terminal half‐life (P= 0.502) of laropiprant, which implies that the effect of clarithromycin on laropiprant is largely a first‐pass rather than a systemic effect. The results of this study suggest that laropiprant is not a sensitive CYP3A substrate, and strong CYP3A inhibitors like clarithromycin are not expected to have a clinically meaningful impact on the pharmacokinetics of laropiprant.
One of the earliest events in the development of the central nervous system is the establishment of positional identity along the anteroposterior (A-P) axis of the neuroepithelium. In recent years, ...regulatory genes with regionally restricted expression in the neuroepithelium have been identified which are believed to specify its developmental fate. We have previously described Brain Factor-1 (BF-1), a winged helix (WH) transcription factor expressed in the telencephalic neuroepithelium (Tao and Lai, 1992) Neuron 8:957-966. Here we report the cloning of the mouse cDNA for a novel WH protein, BF-2. We show that BF-2 is a sequence-specific DNA binding protein with a binding specificity distinct from BF-1. Its expression in the CNS during embryogenesis is restricted to the rostral diencephalic neuroepithelium. The caudal boundary of BF-2 expression is at the zona limitans intrathalamica. Rostrally, the BF-2 expression domain is adjacent to that of BF-1. The expression domains of these two factors define a boundary within the developing forebrain neuroepithelium. The BF-1/BF-2 boundary also extends laterally to divide the optic stalk and the retina into nasal (anterior) and temporal (posterior) domains. These observations suggest that in addition to playing a role in the subdivision of the forebrain, these two WH factors may also function to establish positional information in the retinal neuroepithelium.
Grafting experiments have demonstrated that determination of anteroposterior (AP) identity is an early step in neural patterning that precedes dorsoventral (DV) specification 1,2. These studies used ...pieces of tissue, however, rather than individual cells to address this question. It thus remains unclear whether the maintenance of AP identity is a cell-autonomous property or a result of signaling between cells within the grafted tissue. Previously, we and others 3–5 have used transplants of dissociated brain cells to show that individual telencephalic precursor cells can adopt host-specific DV identities when they integrate within novel regions of the telencephalon. We have now undertaken a set of transplantations during the same mid-neurogenic period used in the previous studies to assess the ability of telencephalic progenitors to integrate and differentiate into more posterior regions of the neuraxis. We observed that telencephalic progenitors were capable of integrating and migrating within different AP levels of the central nervous system (CNS). Despite this, we found that telencephalic progenitors that integrated within the diencephalon and the mesencephalon continued to express a telencephalic marker until adulthood. We speculate that during neurogenesis individual progenitors are determined in terms of their AP but not their DV identity. Hence, AP identity is maintained cell autonomously within individual progenitors.
Tissue-specific expression in the hepatocyte appears to require the actions of multiple factors in specific combinations for each gene. The interactions between two or more positive-acting factors ...that raise transcription to optimal levels and those between positive and negative factors that enforce strict cell-specific transcription remain to be elucidated. However, recent progress in the identification and cloning of the genes for many of these factors will make it possible to begin to answer these important questions.
Laropiprant (LRPT), a prostaglandin D(2) receptor-1 antagonist shown to reduce niacin-induced flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This open-label, ...randomized, 2-period crossover study assessed the pharmacokinetics of single-dose rosiglitazone in the presence and absence of multiple-dose LRPT. Twelve healthy male and female subjects, 34-64 years of age, received two, once-daily oral treatments in random sequence separated by >/=3-day washout: (1) multiple-dose LRPT 40 mg/day for 7 days (Days 1 to 7) coadministered with single-dose rosiglitazone 4 mg on Day 6; (2) single-dose rosiglitazone 4 mg on Day 1. Comparability was declared because the 90% confidence interval (CI) for the AUC(0-infinity) geometric mean ratio (GMR; rosiglitazone + LRPT/rosiglitazone alone) 0.92 (0.86, 0.99), was contained within prespecified bounds (0.70, 1.43). The C(max) GMR (90% CI) for rosiglitazone was 0.98 (0.95, 1.02). There was no evidence of clinically meaningful alterations in the pharmacokinetics of rosiglitazone, a probe CYP2C8 substrate, following coadministration of multiple-dose LRPT in healthy subjects. Therefore, findings suggest that LRPT does not inhibit CYP2C8-mediated metabolism.
Image registration of 131I SPECT with CT scans was performed in a patient with metastatic thyroid carcinoma using an external fiduciary band and a three-dimensional surface-fitting algorithim. Areas ...of metastatic disease taking up 131I were accurately localized to the liver, lungs and vertebral bodies; providing information that could not be obtained by planar or SPECT images alone. Based on these findings, further invasive diagnostic procedures were not performed, therefore considerably altering management in this patient. This approach to image registration has immediate clinical utility in the registration and interpretation of SPECT studies with corresponding CT or MRI scans.
Cell cycle withdrawal in postmitotic cells involves cyclin-dependent kinase (Cdk) inhibitors that repress cell cycle Cdk activity. During mouse neurogenesis, cortical postmitotic neurons are shown ...here to accumulate high levels of the p27 Cdk inhibitor compared with their progenitor neuroblasts. Elevated p27 levels in staged embryo brain extracts correlate with p27 binding to Cdk2, and Cdk2 inactivation. Yet, Cdk5, which is associated with the noncyclin activator p35 in neurons, remains active in the presence of high p27 levels. Both in vitro and in vivo, p27 and related inhibitors can recognize a cyclin D-Cdk5 complex but not a p35-Cdk5 complex. The results indicate that the choice of activator determines the susceptibility of Cdk5 to p27 and related Cdk inhibitors, and thus its ability to act in postmitotic cells.
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