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Cordero, C.

Publications and source records attributed to Cordero, C..

2 recordsLinked to original sources

Amphetamine and Nicotine Reduce Sucrose Self-Administration Independent of Sex

Amphetamine and nicotine are two widely used and abused drugs that are taken for legitimate pharmaceutical purposes but are also highly abused through illicit recreational use. Both of these drugs have been widely shown to decrease food intake in both humans and pre-clinical models, and although amphetamine and nicotine clearly affect food intake under normal baseline ( homeostatic) conditions, there has been limited examination of the ability of these drugs to affect reward-related ( hedonic) aspects of feeding. Furthermore, there are sex differences in the behavioral responses to both drugs, but it is unclear if these sex differences also translate to their effects on feeding. This study examined whether nicotine and amphetamine regulate sucrose intake in a food self-administration paradigm in a sex-dependent manner across both fixed and progressive schedules of reinforcement. Amphetamine reduced operant responding for sucrose pellets and decreased acute intake of sucrose during ad libitum free-feeding access in a dose-dependent manner, whereas nicotine reduced sucrose self-administration and free intake only at higher doses that also impaired locomotor activity in open field tests. The effects of both amphetamine and nicotine did not differ by sex for either drug. Overall, these results suggest that the mechanisms mediating the addictive qualities of these drugs and their appetite suppressing effects may be distinct and therefore could be a potential target for future obesity therapeutics.

neuroscience↗

Hierarchical determinants of the oxidation-induced mutational landscape in human cells.

8-oxoguanine (8-oxoG) is a common oxidative DNA lesion, which causes G>T substitutions that compose COSMIC single base substitution signature 18 (SBS18) in human cancers. Determinants of local and regional differences in 8-oxoG-induced mutability are currently unknown. To uncover factors influencing the topology of 8-oxoG-induced mutations, we assessed spontaneous and KBrO3-induced 8-oxoG mutagenesis in human cell lines. KBrO3 exposure produced a SBS18-like substitution spectrum and a distinct never-before reported INDEL signature that we also observed in human cancers. KBrO3-induced 8-oxoG lesions occurred with similar sequence preference as KBrO3-induced substitutions, indicating that the reactivity of specific reactive oxygen species (ROS) dictates the trinucleotide motif specificity for 8-oxoG-induced mutagenesis. While 8-oxoG lesions occurred relatively uniformly across chromatin states and nucleosomes, 8-oxoG-induced mutations occurred more frequently in more compact regions of the genome, within nucleosomal DNA, and at inward facing guanines within strongly positioned nucleosomes. Cryo-EM structures of OGG1 bound to nucleosomes indicate that these effects originate from OGG1s ability to flip outward positioned 8-oxoG lesions into the catalytic pocket with only minor alterations to nucleosome structure, while inward facing lesions occluded by the histone octamer are unrecognized. Mutation spectra from cells with DNA repair deficiencies revealed a hierarchical DNA repair network limiting 8-oxoG mutagenesis in human cells, where OGG1- and MUTY-mediated BER is supplemented by replication-associated factors participating in tolerance of 8-oxoG or derived repair intermediates (i.e. Pol {eta} and HMCES). Surprisingly, analysis of transcriptional asymmetry of KBrO3-induced mutations demonstrated transcription-coupled repair of 8-oxoG in Pol {eta}-deficient cells. Thus, radical chemistry, chromatin structures, and DNA repair processes combine to dictate the oxidative mutational landscape in human genomes.

cancer biology↗