Opment, or both. We speculate that there may be interspecies differences in the regulation of MEF2c expression by benzene on the basis of the reasons stated above. In conclusion, a human-like hematopoietic lineage established in NOG mice by transplanting human hematopoietic stem/ progenitor cells exhibited human-like susceptibility to at least 1 hematotoxicant, benzene. Hu-NOG and Mo-NOG mice offer a well-defined, reproducible, and easy-to-manipulate in vivo system for performing species-specific biochemical analyses of benzene metabolism. We think it is reasonable to assume that Hu-NOG mice will provide a powerful in vivo tool for assessing the hematotoxicity of chemical and physical agents on human hematopoietic cells. In the future, the similarities of thehematotoxic responses induced in Hu-NOG mice and humans should be evaluated more carefully by analyzing the detailed toxic response mechanism in Hu-NOG mice. Our strategy may be applicable to the study of other organs [47] and other toxicants as well.AcknowledgmentsThe authors would like to thank Takeshi Oda, Mitsuo Takizawa, Naomi Iizawa, and Etsuko Kato for their assistance in the ZK-36374 chemical information maintenance of our mouse populations. We would like to thank Editage for providing editorial assistance.Author ContributionsConceived and designed the experiments: MT TY TM SN. Performed the experiments: MT NT MH SN. Analyzed the data: MT NT. Contributed reagents/materials/analysis tools: MH KO. Wrote the paper: MT SN.
Circadian clocks generate a multitude of circadian PS 1145 rhythms in behavioral, neuronal, physiological, and endocrine functions [1,2]. While these rhythms have endogenous periodicity of circa 24 h, in nature they are entrained by light and temperature cycles associated with solar days. Circadian clocks consist of transcriptional and translational feedback loops working in a cell autonomous manner that are largely conserved between Drosophila and humans [3,4]. At the core of the Drosophila circadian clock there are four clock genes: Clock (Clk), cycle (cyc), timeless (tim), and period (per) [5]. They interact in a negative feedback loop, such that loss of function in any of these genes results in disruption of the clock mechanism [6]. The expression levels of per and tim are regulated by transcriptional activators encoded by Clk and cyc. This leads to periodic increase in the levels of PER and TIM proteins. The latter accumulate in cell nuclei, and repress CLK/CYC activators, leading to suppression of per and tim transcription. In addition to per and tim, CLK/ CYC heterodimers activate genes that participate in additional clock feedback loops and a substantial number of clock output genes [7,8]. Clock-controlled output genesmodulate a myriad of metabolic 23977191 and cellular functions, such as the regulation of energy balance, DNA-damage repair and xenobiotic detoxification in both mammals [9?1] and Drosophila [12?4]. There is emerging evidence that circadian clocks regulate processes that protect an organism from oxidative stress. Previously, we reported that levels of reactive oxygen species (ROS) and protein carbonyls fluctuate in a daily rhythm in heads of young wild type flies, whereas they were non-rhythmic and significantly higher in clock deficient per01 mutants [15]. These mutants also accumulated higher levels of protein carbonyls and peroxidated lipids during aging [16,17], suggesting that antioxidant defenses were compromised by the loss of clock function. In mice, deficiency of the clock pro.Opment, or both. We speculate that there may be interspecies differences in the regulation of MEF2c expression by benzene on the basis of the reasons stated above. In conclusion, a human-like hematopoietic lineage established in NOG mice by transplanting human hematopoietic stem/ progenitor cells exhibited human-like susceptibility to at least 1 hematotoxicant, benzene. Hu-NOG and Mo-NOG mice offer a well-defined, reproducible, and easy-to-manipulate in vivo system for performing species-specific biochemical analyses of benzene metabolism. We think it is reasonable to assume that Hu-NOG mice will provide a powerful in vivo tool for assessing the hematotoxicity of chemical and physical agents on human hematopoietic cells. In the future, the similarities of thehematotoxic responses induced in Hu-NOG mice and humans should be evaluated more carefully by analyzing the detailed toxic response mechanism in Hu-NOG mice. Our strategy may be applicable to the study of other organs [47] and other toxicants as well.AcknowledgmentsThe authors would like to thank Takeshi Oda, Mitsuo Takizawa, Naomi Iizawa, and Etsuko Kato for their assistance in the maintenance of our mouse populations. We would like to thank Editage for providing editorial assistance.Author ContributionsConceived and designed the experiments: MT TY TM SN. Performed the experiments: MT NT MH SN. Analyzed the data: MT NT. Contributed reagents/materials/analysis tools: MH KO. Wrote the paper: MT SN.
Circadian clocks generate a multitude of circadian rhythms in behavioral, neuronal, physiological, and endocrine functions [1,2]. While these rhythms have endogenous periodicity of circa 24 h, in nature they are entrained by light and temperature cycles associated with solar days. Circadian clocks consist of transcriptional and translational feedback loops working in a cell autonomous manner that are largely conserved between Drosophila and humans [3,4]. At the core of the Drosophila circadian clock there are four clock genes: Clock (Clk), cycle (cyc), timeless (tim), and period (per) [5]. They interact in a negative feedback loop, such that loss of function in any of these genes results in disruption of the clock mechanism [6]. The expression levels of per and tim are regulated by transcriptional activators encoded by Clk and cyc. This leads to periodic increase in the levels of PER and TIM proteins. The latter accumulate in cell nuclei, and repress CLK/CYC activators, leading to suppression of per and tim transcription. In addition to per and tim, CLK/ CYC heterodimers activate genes that participate in additional clock feedback loops and a substantial number of clock output genes [7,8]. Clock-controlled output genesmodulate a myriad of metabolic 23977191 and cellular functions, such as the regulation of energy balance, DNA-damage repair and xenobiotic detoxification in both mammals [9?1] and Drosophila [12?4]. There is emerging evidence that circadian clocks regulate processes that protect an organism from oxidative stress. Previously, we reported that levels of reactive oxygen species (ROS) and protein carbonyls fluctuate in a daily rhythm in heads of young wild type flies, whereas they were non-rhythmic and significantly higher in clock deficient per01 mutants [15]. These mutants also accumulated higher levels of protein carbonyls and peroxidated lipids during aging [16,17], suggesting that antioxidant defenses were compromised by the loss of clock function. In mice, deficiency of the clock pro.
