Gluteal muscle contracture (GMC) is a chronic fibrotic disease of gluteal muscles due to multiple etiologies. The main pathologic process is characterized by proliferation of fibroblasts and excessive accumulation of collagen in the extracellular matrix of the muscle. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid and has been reported to be associated with various fibrotic diseases. However, the role of S1P in GMC remains unknown. Here in this articl e, High-perform ance liquid chromatography and immunohistochemistry were applied to evaluate S1P localization and expression in clinical samples from patients with GMC, Quantitative real time PCR, Western blot, and enzyme-linked immunosorbent assa y were used to explore the link between transforming growth factor-β 1 (TGF-β 1), plasminogen activator inhibitor-1 (PAI-1) and S1P. The results showed that S1P was enhanced in contraction band (CB) tissues. Studies using the cell proliferation and transformation assay indicated that exogenous S1P stimulated CB fibroblast proliferation in a time-depen dent manner and in higher concentration also in a dose-dependent manner. Furthermore, we demonstrated that S1P not only promoted collagen type I production, but also up-regulated mRNA and protein expression of transforming growth factor-β 1 and plasminogen activator inhibitor-1. These findings suggest that S1P may regulate increased synthesis of collagen and other fibrogenic factors, and significantly contributes to the process of gluteal muscle scarring in patients with GMC., A. Babicová ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
The aim of the present study was to describe the currently poorly
understood pharmacokinetics (PK) of boldine in control rats (LW,
Lewis rats), and Mrp2 transporter-deficient rats (TR-). Animals from the LW and TR- groups underwent a bolus dose study with 10 mg/kg of boldine applied either orally or intravenously in order to evaluate the major PK parameters. The TR- rats demonstrated significantly reduced total clearance with prolonged biological half-life (LW 12±4.6 versus TR
- 20±4.4 min), decreased volume of distribution (LW 3.2±0.4 l/kg versus TR- 2.4±0.4 l/kg) and reduced bioavailability (LW 7 % versus TR- 4.5 %). Another set of LW and TR- rats were used for a clearance study with continuous intravenous administration of boldine. The LW rats showed that biliary and renal clearance formed less than 2 % of the total
clearance of boldine. The treatment of samples with β-glucuronidase showed at least a 38 % contribution of conjugation reactions to the overall clearance of boldine. The TR- rats demonstrated reduced biliary
clearance of boldine and its conjugates, which was partly compensated by their increased renal clearance. In conclusion, this study presents the PK parameters of boldine and shows the importance of the Mrp2 transporter and conjugation reactions in the elimination of the compound.