The purpose of this study was to elucidate the mechanisms of blood-to-retina creatine transport across the blood-retinal barrier (BRB) in vivo and in vitro, and to identify the responsible transporter(s). The creatine transport across the BRB in vivo and creatine uptake in an in vitro model of the inner BRB (TR-iBRB2 cells) were examined using [14 C]creatine.Identification and localization of the creatine transporter (CRT) were carried out by RT-PCR, western blot, and immunoperoxidase electron microscopic analyses. An in vivo intravenous administration study suggested that [ 14 C]creatine is transported from the blood to the retina against the creatine concentration gradient that exists between the retina and blood. Creatine plays an essential role in the storage and transmission of phosphate-bound energy due to the conversion of creatine to phosphocreatine catalyzed by creatine kinase. Creatine would therefore be present at a high concentration in cellular ATP homeostasis, particularly in tissues subject to high metabolic demands, such as the retina, brain, heart, and muscle (Wyss and Kaddurah-Daouk 2000). Although there is no published study of the creatine concentration in the mammalian retina, it has been reported to be 10-15 mM in chicken photoreceptors (Wallimann et al. 1986). Therefore, it is hypothesized that the creatine concentration in the mammalian retina is at least a 2-log scale order of magnitude greater than that in plasma, since the plasma creatine concentration is 50-100 lM in humans (Marescau et al. 1986;Harris et al. 1992) and 140-600 lM in rats (Fitch and Shields 1966;Horn et al. 1998). To maintain a high concentration of creatine in the retina, the blood-retinal barrier (BRB) may regulate creatine movement between the circulating blood and the neural retina.Creatine is biosynthesized mainly in the kidney and liver in two steps by L-arginine:glycine amidinotransferase Received October 6, 2003; revised manuscript received January 14, 2004; accepted February 9, 2004. Address correspondence and reprint requests to Ken-ichi Hosoya, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630, Sugitani, Toyama, 930-0194, Japan. E-mail: hosoyak@ms.toyama-mpu.ac.jpAbbreviations used: AGAT, L-arginine:glycine amidinotransferase; BBB, blood-brain barrier; BRB, blood-retinal barrier; CL retina , the apparent influx permeability clearance of retina; CRT, creatine transporter; GA, gyrate atrophy; GAMT, S-adenosylmethionine:guanidinoacetate N-methyltransferase; inner BRB, inner blood-retinal barrier; K p,app (t), the apparent tissue-to-plasma concentration ratio; RPE, (outer BRB), retinal pigmented epithelial cells; TR-iBRB2, conditionally immortalized rat retinal capillary endothelial cell line.
BackgroundBortezomib offers a novel approach to the treatment of multiple myeloma producing rapid control. The aim of this study was to investigate the outcomes of bortezomib and dexamethasone-treated patients with multiple myeloma.MethodsWe conducted a retrospective study of 44 consecutively-treated multiple myeloma patients with bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle or 1.3 mg/m2 intravenously 1, 8, 15, and 22 of every 35-day cycle) and dexamethasone.ResultsThe median time to progression, progression free survival time, and overall survival time in the treatment groups was 14.9, 14.9, and 38.3 months, respectively. The present study also suggests the possibility that the prognosis of patients with high levels of AST and LDH might be worse.ConclusionsOur results indicate that the treatment of multiple myeloma with bortezomib and dexamethasone is feasible.
In high-energy metabolic tissues like the retina, creatine may play an important role in energy storage and in transmission of phosphate-bound energy substrates. To prove this, we investigated creatine synthesis in Müller glia. We also characterized the localization of the creatine synthetic enzyme, S-adenosyl-L-methionine:N-guanidinoacetate methyltransferase (GAMT) in the retina. Reverse transcription-polymerase chain reaction analysis revealed that L-arginine:glycine amidinotransferase and GAMT mRNAs were expressed in the retina and the Müller cell line, TR-MUL5. [(14)C]Creatine was detected after incubation of isolated rat retina or TR-MUL5 cells with [(14)C]glycine, L-arginine and L-methionine, suggesting creatine synthesis in Müller glia. Western blot analysis also revealed expression of GAMT protein in the rat retina and TR-MUL5 cells. Furthermore, confocal immunofluorescent microscopy of dual-labeled rat retinal sections demonstrated co-localization of GAMT with glutamine synthetase. Taken together, the results of the present study indicate creatine synthesis in Müller glia, implying an important role of creatine in energy metabolism in the retina.
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