A novel series of antagonists of the human P2X7 receptor is described. Modification of substituents enabled identification of compounds selective for the rat P2X7 receptor and provides useful pharmacological tools for evaluation of the role of P2X7 in disease.
Efficient tissue-specific delivery is a crucial factor in the successful development of therapeutic oligonucleotides. Screening for novel delivery methods with unique tissue-homing properties requires a rapid, sensitive, flexible and unbiased technique able to visualize the in vivo biodistribution of these oligonucleotides. Here, we present whole body scanning PCR, a platform that relies on the local extraction of tissues from a mouse whole body section followed by the conversion of target-specific qPCR signals into an image. This platform was designed to be compatible with a novel RT-qPCR assay for the detection of siRNAs and with an assay suitable for the detection of heavily chemically modified oligonucleotides, which we termed Chemical-Ligation qPCR (CL-qPCR). In addition to this, the platform can also be used to investigate the global expression of endogenous mRNAs and non-coding RNAs. Incorporation of other detection systems, such as aptamers, could even further expand the use of this technology.
Atylamines and nitroarenes are very important environmental and occupational pollutants. Genotoxic effects of arylamines are believed to be initiated by the formation of DNA adducts. DNA adducts of arylamines have been found in experimental animals and in exposed humans, and are predominantly formed with the carbon 8 of 2'-deoxyguanosine. Reference standards are necessary to develop methods for the quantification of DNA-adducts. Therefore, we have synthesized the 2'-deoxyguanosin-8-yI adducts of 2-methylaniline, 2-chloroaniline, 4-chloroaniline, 2,4dimethylaniline, and 2,6-dimethylaniline. The products were characterized by (1)H-NMR, (13)C-NMR, MS and UV. The corresponding 2'-deoxyguanosine-3' -monophosphate adducts were synthesized for the quantification of DNA adducts by the (32)P-postlabelling technique. A GC-MS method was developed for the analysis of the new adducts as an alternative to the (32)P-postlabelling. DNA was spiked with the synthesized adducts and treated with 0.3 m NaOH overnight at 110 °C in the presence of a deuterated internal standard. We observed up to 80% recovery from about 1 adduct in 10(8) to 1 in 10(5) nucleotides.
Benzidine (Bz) is a known human carcinogen. Several azo dyes have been synthesized with Bz. Bz can be metabolically released from azo dyes. In a group of Indian workers producing Bz and azo dyes the presence of hemoglobin (Hb) adducts was investigated. The following Hb adducts were identified and quantified by GC-MS: Bz, N-acetylbenzidine (AcBz), 4-aminobiphenyl (4ABP), aniline. 4ABP and aniline were quantitatively the major adducts. In the exposed workers (n = 33) all correlations between 4ABP, Bz and AcBz were r = 0.89 (P < 0.01) or greater. The group of workers exposed to Bz (Bz workers, n = 15) had 10-17-fold higher adduct levels than the workers exposed to dyes (dye workers, n = 18). 4ABP can be metabolically released from Bz and azo dyes. Aniline can be metabolically released from azo dyes. Therefore, the presence of 4ABP and aniline as Hb adducts is a consequence of exposure to the parent compounds or to the exposure of Bz and azo dyes and a consequent metabolical release of the arylamine moiety. The mean adduct ratios of 4ABP/(AcBz + Bz) varied up to 4-fold across all seven factories. Therefore, it is possible that 4ABP may have derived from general contamination in the work environment or endogenous metabolism, or a combination of the two. Since 4ABP is also a known human carcinogen, tumors observed in workers exposed to Bz or Bz dyes might be caused by both compounds. Further, these results suggest that understanding the role that genetic variants in NAT1 and NAT2 play in modifying the impact of Bz on bladder cancer risk may be complicated, as N-acetylation detoxifies 4ABP and activates Bz.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.