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941.
Identification of metabolic pattern and bioactive form of resveratrol in human medulloblastoma cells
Xiao-Hong Shu 《Biochemical pharmacology》2010,79(10):1516-1525
Cancer preventive reagent trans-resveratrol is intracellularly biotransformed to different metabolites. However, it is still unclear whether trans-resveratrol exerts its biological effects directly or through its metabolite(s). This issue was addressed here by identifying the metabolic pattern and the bioactive form of resveratrol in a resveratrol-sensitive human medulloblastoma cell line, UW228-3. The cell lysates and condition media of UW228-3 cells with or without 100 μM resveratrol treatment were analyzed by HPLC and LC/MS which revealed (1) that resveratrol was chemically unstable and the spontaneous generation of cis-resveratrol reduced resveratrol's anti-medulloblastoma efficacy and (2) that resveratrol monosulfate was the major metabolite of the cells. To identify the bioactive form of resveratrol, a mixture-containing approximately half fraction of resveratrol monosulfate was prepared by incubating trans-resveratrol with freshly prepared rat brain lysates. Medulloblastoma cells treated by 100 μM of this mixture showed attenuated cell crisis. The overall levels of the three brain-associated sulfotransferases (SULT1A1, 1C2 and 4A1) were low in medulloblastoma cells in vivo and in vitro in comparison with that in human noncancerous and rat normal cerebella; resveratrol could more or less up-regulate the production of these enzymes in UW228-3 cells but their overall level was still lower than that in normal cerebellum tissue. Our study thus demonstrated for the first time that trans-resveratrol is the bioactive form in medulloblastoma cells in which the expression of brain-associated SULTs was down-regulated, resulting in the increased intracellular bioavailability and anti-medulloblastoma efficacy of trans-resveratrol. 相似文献
942.
Robert Ramer 《Biochemical pharmacology》2010,80(6):846-857
Cannabinoids have received considerable attention as potential antiglaucomatous drugs. Recently, prostaglandins (PG) have been suggested to contribute to this effect. Within the factors conferring the development of glaucoma, depletion of the aqueous humor outflow-regulating trabecular meshwork (TM) cells elicited by migration from the outflow system is considered to play a pivotal role. This study therefore investigates the impact of two cannabinoids, Δ9-tetrahydrocannabinol (THC) and R(+)-methanandamide (MA), on the migration of human TM cells and the involvement of the PG-synthesizing enzyme cyclooxygenase-2 (COX-2) and one of its potential downstream targets, the tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), to this response. Using Boyden chamber assays cannabinoids were shown to elicit an antimigratory effect that was reversed by antagonists for CB1 as well as CB2 receptors and accompanied by upregulation of COX-2 and TIMP-1 expression and PGE2 synthesis. Knockdown of cannabinoid-induced COX-2 or TIMP-1 expression by siRNA or inhibition of COX-2 activity by NS-398 led to a significant suppression of this antimigratory action. Migration was also diminished by the major COX-2 product PGE2 and by recombinant TIMP-1. Experiments using selective E prostanoid (EP) receptor agonists and antagonists revealed that decreased migration by PGE2, THC and MA was mediated via EP2 and EP4 receptors. Finally, the cannabinoid-mediated increases of TIMP-1 levels were abolished by NS-398, and PGE2 was shown to elicit a concentration-dependent increase of TIMP-1. Collectively, this data demonstrate a COX-2-dependent upregulation of TIMP-1 conferring the antimigratory action of cannabinoids. A decreased migration reducing TM cell loss in glaucoma might be involved in the antiglaucomatous action of cannabinoids. 相似文献
943.
Activated hepatic stellate cells (HSCs) play a crucial role in the development of liver fibrosis. Noninvasive monitoring of the activation of HSCs has been challenging due to the lack of specific receptors or motifs on the cells. The present study provides the evidence that integrin αvβ3 expressed on HSCs is a biomarker reflecting the activation of HSCs. Solid-phase synthesis of cRGDyK (Arg-Gly-Asp-DTyr-Lys) peptide and FAM-conjugated peptide were employed for binding to integrin αvβ3. The increased expression of integrin αv and β3 at mRNA and protein levels was detected during HSC activation. The affinity of cRGDyK to integrin αvβ3 was examined by both radioligand binding assay and FAM-conjugated peptide binding measurements. Quantitative RT-PCR and Western blotting showed a less dramatic, but significant increase in αv and β3 integrin mRNA and protein expression following activation of rat HSCs. Radioiodinated cRGDyK binds to both purified and membrane-bound integrin αvβ3 with high affinity in a dissociable manner. FAM-conjugated cRGDyK was coupled to activated HSCs in a time- and dose-dependent, receptor-mediated manner. Activated HSCs express sufficient number of integrin αvβ3 receptor. cRGDyK peptide binds to both purified and membrane-bound integrin αvβ3 with high affinity in a reversible fashion. Thus, the cRGDyK peptide represented a new agent potentially useful for the diagnosis of liver fibrosis. 相似文献
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947.
Matsumoto T Akutsu S Wakana N Morito M Shimada A Yamane A 《Archives of oral biology》2006,51(7):603-611
OBJECTIVE: The mechanism regulating skeletal muscle mass is unclear. The purpose of the present study was to investigate the extent to which insulin-like growth factors (IGFs), their receptors (IGFRs), and binding proteins (IGFBPs) are involved in the regulation of skeletal muscle mass. DESIGN: We measured the mRNA expression levels for IGFs, IGFRs, and IGFBPs in the rat masseter muscle hypertrophied by oral administration of clenbuterol for 3 weeks and determined the correlations between the weight of masseter muscle and the mRNA expression levels. RESULTS: The mRNA expression levels for IGF-I and II, IGFR1 and 2, and IGFBP4 and 6 showed clenbuterol-induced elevations and positive correlations with the weight of masseter muscle. That for IGFBP3 only exhibited a clenbuterol-induced decrease and a strong negative correlation with the weight of masseter muscle. The mRNA expression levels for IGFBP2 and 5 showed no significant changes between the control and clenbuterol groups, and no significant correlations. IGFBP1 mRNA was not detectable. CONCLUSION: These results suggest that IGF-I, II, IGFR1 and 2, and IGFBP3, 4 and 6 are related to the mechanism regulating masseter muscle mass in the rat. 相似文献
948.
目的研究唾液酸转运蛋白Sialin在正常涎腺组织和颌下腺细胞系HSG的表达.方法应用基因芯片检测正常人腮腺、颌下腺组织Sialin编码基因SLC17A5的表达;提取腮腺、颌下腺组织及颌下腺细胞系(HSG)总RNA,通过RT-PCR在基因水平上验证SLC17A5基因的表达;提取HSG细胞总蛋白,用免疫印迹法检测Sialin在蛋白水平表达.结果基因芯片检测到Sialin编码基因SLC17A5基因在正常人腮腺、颌下腺均有表达,表达比值分别为226、206.9,不存在表达差异;RT-PCR验证芯片结果并在其他涎腺样本及颌下腺细胞系HSG中能扩增出其全部翻译区1485bp的片段,应用商业化的抗体能够在HSG细胞检测到Sialin相应的约54KDa蛋白.结论正常腮腺、颌下腺组织和颌下腺细胞系HSG均表达SLC17A5基因,但是唾液酸转运蛋白Sialin在组织、细胞内定位和功能需要进一步研究. 相似文献
949.
950.
Morsi WG Shaker OG Ismail EF Ahmed HH El-Serafi TI Maklady FA Abdel-Aziz MT El-Asmar MF Atta HM 《Clinical biochemistry》2006,39(11):1057-1062
OBJECTIVES: Both heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) have been shown to be involved in the progression of atherosclerosis. The relationship between HO-1 and VEGF gene expression and their proteins in endothelial cells from human atherosclerotic arterial specimens was investigated. DESIGN AND METHODS: The study included seventeen human arterial specimens with early and six specimens with advanced atherosclerotic lesions. Ten specimens were obtained from healthy young adults undergoing arterial reconstruction for trauma and were considered as non-atherosclerotic control. HO-1 and VEGF expressions as well as HO activity and VEGF protein content were measured in isolated endothelial cells (ECs). RESULTS: HO-1 expression and activity (5.3+/-2.1 nmol bilirubin/mg protein/h) were only present in ECs from advanced atherosclerotic lesions. VEGF expression was more strongly expressed in ECs from advanced lesion compared with early lesions and was absent in healthy arteries. VEGF protein (1.35+/-0.69 ng/mg) was only detected in advanced lesions. A significant positive correlation (r=0.9, p<0.01) exists between HO activity and VEGF protein content in ECs of advanced lesions. CONCLUSIONS: This study demonstrated that HO-1 expression and activity in ECs are present only in advanced atherosclerosis whereas, VEGF expression is present in early as well as in advanced atherosclerosis and the degree of its expression increases with severity of atherosclerosis. This study suggests an association between HO activity and VEGF protein in human ECs from advanced atherosclerotic lesions. 相似文献