ABSTRACT
Tumor resistance seriously hinders the clinical application of chloroethylnitrosoureas (CENUs), such as O6-methylguanine-DNA methylguanine (MGMT), which can repair O6-alkyl lesions, thereby inhibiting the formation of cytotoxic DNA interstrand cross-links (ICLs). Metabolic differences between tumor and normal cells provide a biochemical basis for novel therapeutic strategies aimed at selectively inhibiting tumor energy metabolism. In this study, the energy blocker lonidamine (LND) was selected as a chemo-sensitizer of nimustine (ACNU) to explore its potential effects and underlying mechanisms in human glioblastoma in vitro and in vivo. A series of cell-level studies showed that LND significantly increased the cytotoxic effects of ACNU on glioblastoma cells. Furthermore, LND plus ACNU enhanced the energy deficiency by inhibiting glycolysis and mitochondrial function. Notably, LND almost completely downregulated MGMT expression by inducing intracellular acidification. The number of lethal DNA ICLs produced by ACNU increased after the LND pretreatment. The combination of LND and ACNU aggravated cellular oxidative stress. In resistant SF763 mouse tumor xenografts, LND plus ACNU significantly inhibited tumor growth with fewer side effects than ACNU alone. Finally, we proposed a new "HMAGOMR" chemo-sensitizing mechanism through which LND may act as a potential chemo-sensitizer to reverse ACNU resistance in glioblastoma: moderate inhibition of hexokinase (HK) activity (H); mitochondrial dysfunction (M); suppressing adenosine triphosphate (ATP)-dependent drug efflux (A); changing redox homeostasis to inhibit GSH-mediated drug inactivation (G) and increasing intracellular oxidative stress (O); downregulating MGMT expression through intracellular acidification (M); and partial inhibition of energy-dependent DNA repair (R).
ABSTRACT
The current regulations of heavy-duty vehicles in China do not include the emissions in the cold start stage into the overall emission evaluation. However, the speed of heavy-duty diesel vehicles in the cold start stage is often low and the proportion of idle-conditions is large, resulting in the difference between the actual test results and evaluation results of emissions. Therefore, in order to accurately evaluate the impact of emission during cold start on the overall emission, in this study, the OBS-ONE portable vehicle emission test equipment was used to test the emission of three representative heavy-duty diesel vehicles with different types under actual road driving conditions, and the cumulative averaging (CA) method was adopted to calculate and analyze the test emission data. Firstly, the cold start emission of different types of heavy-duty vehicles was evaluated. The results show that the contribution rate of pollutant emission in the cold start stage is high, in which NOx emission accounts for 40-90% of the whole trip. It was unreasonable for regulations to exclude data in the cold start stage. The cold start duration of vehicle A is nearly 300 s longer than that of vehicle C, however, the NOx and PN emission factors of vehicle A are nearly 10 times and 100 times smaller than that of vehicle C at the cold start stage respectively. The cold start duration, fuel consumption and the emission factors in cold start stage of different types of heavy-duty diesel vehicles do not have a unified law. Secondly, the emission characteristics and differences of different types of heavy-duty vehicles are studied at the instantaneous level, and the internal mechanism causing the emission differences is explored and revealed. In the cold stage, CO2 emission shows a good correlation with the fuel consumption. CO, NOx emissions show a good correlation with the fuel consumption when the engine and post-treatment temperature are low, and CO and NOx emissions decrease with the increase of engine and post-treatment temperature. PN emissions are mainly related to the engine working state. Finally, the influence of dynamic parameters v·a and RPA on pollutant emission was analyzed. The results show that driving force is an important factor affecting CO2 emission, and RPA has no obvious correlation with emission at cold start stage.
