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排序方式: 共有193条查询结果,搜索用时 15 毫秒
1.
Surprisingly, both of the synthetic 1-(hydroxymethyl)-25-hydroxyvitamin D3 diastereomers (-)-2 and (+)-3 retained the antiproliferative activity of natural calcitriol in murine keratinocytes. Preliminary studies indicated, however, that both of these synthetic diastereomers were less than 0.1% as effective as calcitriol for binding to the 1,25-(OH)2-D3 receptor and that they were less than 0.1% as potent as calcitriol for calbindin-D28K induction in organ-cultured embryonic chick duodenum. 1-(Hydroxymethyl)-25-hydroxyvitamin D3 homologs (-)-2 and (+)-3 were synthesized in a convergent manner by combining enantiomerically pure C,D-ring ketone 12 with highly enantiomerically enriched A-ring phosphine oxides (-)-11a and (+)-11b. These A-ring chirons were prepared starting from thermal [2 + 4] cycloaddition of 3-bromo-2-pyrone and acrolein. 相似文献
2.
Akman Steven A.; Kensler Thomas W.; Doroshow James H.; Dizdaroglu Miral 《Carcinogenesis》1993,14(9):1971-1974
The mouse skin tumor promoter benzoyl peroxide (BzPO), in conjunctionwith Cu(I), causes promutagenic damage in DNA. Because freeradical intermediates are produced by the reaction of BzPO withCu(I), we sought to determine whether BzPO plus Cu(I) causedDNA base damage typical of that caused by the hydroxyl radical.A broad range of modified DNA bases were measured by GC-MS withselected-ion monitoring after exposure of purified plasmid pCMVßgalDNA to BzPO ± Cu(I). Exposure to BzPO/Cu(I) caused upto 20-fold increases in the levels of adenine-derived modifiedbases, and only a <2-fold increase in thymine-derived modifiedbases. The guanine-derived modified base 8-hydroxyguanine waselevated to the highest net amount, 160 molecules/105 DNA bases.Exposure to BzPO alone or Cu(I) alone induced only minor (<<2-fold) DNA base modification. Also, benzoic acid, the majornon-radical metabolite of BzPO, or BzPO plus Fe(II) were ineffectiveat inducing DNA base modification. The hydroxyl radical scavengerdimethyl sulfoxide inhibited BzPO/Cu(I)-induced base modificationby 1050%. These data suggest that the reaction of BzPOwith Cu(I) generates hydroxyl radical or a similarly reactiveintermediate which causes DNA base damage. This damage may beresponsible for BzPO/Cu(I) mediated mutagenesis. 相似文献
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BenzoyI peroxide (BzPO) is a free radical generating compoundthat acts as a tumor promoter and progressor in mouse skin.BzPO is cleaved in the presence of copper to produce benzoyloxyIand phenyI radicals. Treatment of mutation reporter plasmidswith BzPO and copper yields predominantly single-strand breaksand GT transversion mutations. To explore the role of base modificationsin the possible mammalian mutagenicity of BzPO the formationof 8-hydroxy-2'-deoxyguanosine (8-OHdG) within the DNA of culturedmurine keratinocytes was investigated. Treatment with 10 µMBzPO produced a maximum 3-fold increase in levels of 8-OHdGversus vehicle controls within1-2 h, with significant levelsof 8-OHdG persisting 6 h after initial exposure to BzPO. Pretreatmentwith the copper chelator bathocuproine disulfonic acid reducedthe levelsof 8-OHdG generated by BzOP ot near background. However,treatment with the iron chelator desferal did not. The stablemetabolic product of BzPO benzoic acid was ineffective in producing8-OHdG. Depletion of cellular glutathione with L-buthionine-(S,R)-sulfoximineincreased the amount of BzPO-generated 8-OHdG, while supplementationwith glutathione monoethyI ester reduced the number of 8-OHdGmolecules formed. Collectively, these results suggest that BzPOat non-cytotoxic concentrations undergoes copper-dependent activationto a reactive product to generate 8-OHdG within cultured murinekeratinocytes. 相似文献
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Y Zhang T W Kensler C G Cho G H Posner P Talalay 《Proceedings of the National Academy of Sciences of the United States of America》1994,91(8):3147-3150
Sulforaphane [1-isothiocyanato-4-(methyl-sulfinyl)butane] was recently isolated from one variety of broccoli as the major and very potent inducer of phase 2 detoxication enzymes in murine hepatoma cells in culture. Since phase 2 enzyme induction is often associated with reduced susceptibility of animals and their cells to the toxic and neoplastic effects of carcinogens and other electrophiles, it was important to establish whether sulforaphane could block chemical carcinogenesis. In this paper we report that sulforaphane and three synthetic analogues, designed as potent phase 2 enzyme inducers, block the formation of mammary tumors in Sprague-Dawley rats treated with single doses of 9,10-dimethyl-1,2-benzanthracene. The analogues are exo-2-acetyl-exo-6-isothiocyanatonorbornane, endo-2-acetyl-exo-6-isothiocyanatonorbornane, and exo-2-acetyl-exo-5-isothiocyanatonorbornane. When sulforaphane and exo-2-acetyl-exo-6-isothiocyanatonorbornane were administered by gavage (75 or 150 mumol per day for 5 days) around the time of exposure to the carcinogen, the incidence, multiplicity, and weight of mammary tumors were significantly reduced, and their development was delayed. The analogues endo-2-acetyl-exo-6-isothiocyanatonorbornane and exo-2-acetyl-exo-5-isothiocyanatonorbornane were less potent protectors. Thus, a class of functionalized isothiocyanates with anticarcinogenic properties has been identified. These results validate the thesis that inducers of phase 2 enzymes in cultured cells are likely to protect against carcinogenesis. 相似文献
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Fahey JW Haristoy X Dolan PM Kensler TW Scholtus I Stephenson KK Talalay P Lozniewski A 《Proceedings of the National Academy of Sciences of the United States of America》2002,99(11):7610-7615
Gastric infection with Helicobacter pylori is a cosmopolitan problem, and is especially common in developing regions where there is also a high prevalence of gastric cancer. These infections are known to cause gastritis and peptic ulcers, and dramatically enhance the risk of gastric cancer. Eradication of this organism is an important medical goal that is complicated by the development of resistance to conventional antimicrobial agents and by the persistence of a low level reservoir of H. pylori within gastric epithelial cells. Moreover, economic and practical problems preclude widespread and intensive use of antibiotics in most developing regions. We have found that sulforaphane [(-)-1-isothiocyanato-(4R)-(methylsulfinyl)butane], an isothiocyanate abundant as its glucosinolate precursor in certain varieties of broccoli and broccoli sprouts, is a potent bacteriostatic agent against 3 reference strains and 45 clinical isolates of H. pylori [minimal inhibitory concentration (MIC) for 90% of the strains is 相似文献
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10.
Many quantitative assay measurements of metabolites of environmental toxicants in clinical investigations are subject to left censoring due to values falling below assay detection limits. Moreover, when observations occur in both unexposed individuals and exposed individuals who reflect a mixture of two distributions due to differences in exposure, metabolism, response to intervention and other factors, the measurements of these biomarkers can be bimodally distributed with an extra spike below the limit of detection. Therefore, estimating the effect of interventions on these biomarkers becomes an important and challenging problem. In this article, we present maximum likelihood methods to estimate the effect of intervention in the context of mixture distributions when a large proportion of observations are below the limit of detection. The selection of the number of components of mixture distributions was carried out using both bootstrap-based and cross-validation-based information criterion. We illustrate our methods using data from a randomized clinical trial conducted in Qidong, People's Republic of China. 相似文献