RESUMO
Nitrogen mustards (NMs) are an important class of chemotherapeutic drugs and have been widely employed for the treatment of various cancers. However, due to the high reactivity of nitrogen mustard, most NMs react with proteins and phospholipids within the cell membrane. Therefore, only a very small fraction of NMs can reach the reach nucleus, alkylating and cross-linking DNA. To efficiently penetrate the cell membrane barrier, the hybridization of NMs with a membranolytic agent may be an effective strategy. Herein, the chlorambucil (CLB, a kind of NM) hybrids were first designed by conjugation with membranolytic peptide LTX-315. However, although LTX-315 could help large amounts of CLB penetrate the cytomembrane and enter the cytoplasm, CLB still did not readily reach the nucleus. Our previous work demonstrated that the hybrid peptide NTP-385 obtained by covalent conjugation of rhodamine B with LTX-315 could accumulate in the nucleus. Hence, the NTP-385-CLB conjugate, named FXY-3, was then designed and systematically evaluated both in vitro and in vivo. FXY-3 displayed prominent localization in the cancer cell nucleus and induced severe DNA double-strand breaks (DSBs) to trigger cell apoptosis. Especially, compared with CLB and LTX-315, FXY-3 exhibited significantly increased in vitro cytotoxicity against a panel of cancer cell lines. Moreover, FXY-3 showed superior in vivo anticancer efficiency in the mouse cancer model. Collectively, this study established an effective strategy to increase the anticancer activity and the nuclear accumulation of NMs, which will provide a valuable reference for future nucleus-targeting modification of nitrogen mustards.
Assuntos
Neoplasias , Compostos de Mostarda Nitrogenada , Animais , Camundongos , Clorambucila/farmacologia , DNA/metabolismo , Nitrogênio , Compostos de Mostarda Nitrogenada/farmacologia , Peptídeos/farmacologiaRESUMO
In order to study the variation of water-soluble inorganic ions in the four suburbs of Beijing using the atmospheric fine particulate matter rapid trapping system and chemical composition analysis system (RCFP-IC), we carried out measurements for nine water-soluble inorganic ions (Cl-, NO2-, NO3-, SO42-, Na+, NH4+, K+, Mg2+, Ca2+) in PM2.5 with continuous on-line observations for one year in Beijing's southern suburbs in 2016. The transport process of pollutants and the potential sources of pollutants were evaluated by combining a trajectory clustering method and potential source contribution factor analysis method (PSCF). During the observation period, the total concentration of the nine water-soluble inorganic ions was 38.6 µg ·m-3, and results showed that the concentration in winter and spring was high and in summer and autumn was low. The order of the concentration from high to low was SO42- > NO3- > NH4+ > Ca2+ > NO2- > Cl- > Na+ > K+ > Mg2+. In winter, the SO42-, NO3- and NH4+ accounted for 75.7% of the total measured water-soluble ions, followed by 72.8% in spring and 60.2% in summer. With an increase in air pollution, the concentrations of SO42-, NO3-, and NH4+ increased significantly, indicating that SO42-, NO3-, and NH4+ were closely related to the deterioration of air quality. SO42- was dominant in the formation of secondary ions compared to NO3- and NH4+; and SO42-, NO3-, and NH4+ had significant diurnal variations. The diurnal variation of the SO42- statistic (hours) was bimodal, and the peak values were at about 10:00 and 18:00. The diurnal variation of NO3- and NH4+ had single peaks, with the peak appearing at 10:00. The trend of the diurnal variation for these two ions was similar. Finally, the sources of pollution in the southern suburbs of Beijing mainly included secondary sources, coal-fired sources, and mixed sources of dust and dust. The main potential source of pollution in the southern suburbs was in the southeastern part of the observation site, while the northeastern airflow was favorable for the diffusion and dilution of pollutants.
RESUMO
This study investigated the impacts of four cultivation patterns including farmer practice, high yield and high efficiency practice, super high yield practice, and super high yield and high efficiency practice on yields, soil nitrate and nitrogen (N) balances in 3 winter wheat-summer maize rotations with straw returning in Hebei Province. Results showed that the super high yield practice was identified with greatest winter wheat and summer maize yields, followed by high yield and high efficiency practice, and super high yield and high efficiency practice, which were all greater than that of farmer practice. The N use efficiency of high yield and high efficiency practice was significantly greater than the other cultivation patterns. The total nitrate accumulation in 0-400 cm soil of these cultivation patterns reached 768.4-1133.3 kg·hm-2, where 80%-85% of the accumulated nitrate were in 90-400 cm soil. Meanwhile, the nitrate leaching was observed in all cultivation patterns and nitrate accumulation peaks at 120-150 cm and 270-330 cm were found. Soil nitrate content of high yield and high efficiency practice was less than 30 mg·kg-1 and generally lower than other cultivation patterns, which to some extent reduced the environmental risk. In addition, nitrate surplus in 0-90 cm soil during winter wheat season was lower than that during summer maize season, and the high yield and high efficiency practice had the lowest apparent nitrogen loss. Overall, the high yield and high efficiency practice was evaluated to be the best cultivation pattern in consi-deration of yield, nitrogen use efficiency and nitrate accumulation in soil, but there was still certain achievable improvement potential.
