Polyphyllin I(PPI)and polyphyllin II(PII)are the main active substances in the Paris polyphylla.However,liver toxicity of these compounds has impeded their clinical application and the potential hepatotoxicity mechani...Polyphyllin I(PPI)and polyphyllin II(PII)are the main active substances in the Paris polyphylla.However,liver toxicity of these compounds has impeded their clinical application and the potential hepatotoxicity mechanisms remain to be elucidated.In this work,we found that PPI and PII exposure could induce significant hepatotoxicity in human liver cell line L-02 and zebrafish in a dose-dependent manner.The results of the proteomic analysis in L-02 cells and transcriptome in zebrafish indicated that the hepatotoxicity of PPI and PII was associated with the cholesterol biosynthetic pathway disorders,which were alleviated by the cholesterol biosynthesis inhibitor lovastatin.Additionally,3-hydroxy-3-methy-lglutaryl CoA reductase(HMGCR)and squalene epoxidase(SQLE),the two rate-limiting enzymes in the cholesterol synthesis,selected as the potential targets,were confirmed by the molecular docking,the overexpression,and knockdown of HMGCR or SQLE with siRNA.Finally,the pull-down and surface plasmon resonance technology revealed that PPI could directly bind with SQLE but not with HMGCR.Collectively,these data demonstrated that PPI-induced hepatotoxicity resulted from the direct binding with SQLE protein and impaired the sterol-regulatory element binding protein 2/HMGCR/SQLE/lanosterol synthase pathways,thus disturbing the cholesterol biosynthesis pathway.The findings of this research can contribute to a better understanding of the key role of SQLE as a potential target in drug-induced hepatotoxicity and provide a therapeutic strategy for the prevention of drug toxic effects with similar structures in the future.展开更多
This paper investigates the influence of the deviation in freeze pipe installation on the development of the frozen wall in long cross passages by numerical simulation with ANSYS software.The study case is from the ar...This paper investigates the influence of the deviation in freeze pipe installation on the development of the frozen wall in long cross passages by numerical simulation with ANSYS software.The study case is from the artificial ground freezing project along the Fuzhou Metro Line 2 between Ziyang Station and Wuliting Station.Two freezepipe configurations,i.e.,one with perfectly aligned pipes without any deviation from design and another with randomly distributed deviation,are included for comparison.The effect of the random deviation in the freeze pipes on frozen wall interconnection time,the thickness of the frozen wall and the development of the temperature field is explored.For the characteristic section of the numerical model at a depth of 25 m,it is found that the frozen wall interconnection time under the random deviation case and no deviation case is 24 days and 18 days,respectively.The difference in the thickness of the thinnest frozen wall segment between the random deviation and no deviation cases is the largest in the early freezing stage(up to 0.75 m),which decreases with time to 0.31 m in the late freezing stage.The effects of random deviation are more significant in the early freezing stage and diminish as the freezing time increases.展开更多
Activating transcription factors, ATFs, are a group of bZIP transcription factors that act as homodimers or heterodimers with a range of other bZIP factors. In general, ATFs respond to extracellular signals, indicatin...Activating transcription factors, ATFs, are a group of bZIP transcription factors that act as homodimers or heterodimers with a range of other bZIP factors. In general, ATFs respond to extracellular signals, indicating their important roles in maintaining homeostasis. The ATF family includes ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, and ATF7. Consistent with the diversity of cellular processes reported to be regulated by ATFs, the functions of ATFs are also diverse. ATFs play an important role in cell proliferation, apoptosis, differentiation and inflammation-related pathological processes. The expression and phosphorylation status of ATFs are also related to neurodegenerative diseases and polycystic kidney disease. Various miRNAs target ATFs to regulate cancer proliferation, apoptosis, autophagy, sensitivity and resistance to radiotherapy and chemotherapy. Moreover, ATFs are necessary to maintain cell redox homeostasis. Therefore, deepening our understanding of the regulation and function of ATFs will provide insights into the basic regulatory mechanisms that influence how cells integrate extracellular and intracellular signals into genomic responses through transcription factors. Under pathological conditions, especially in cancer biology and response to treatment, the characterization of ATF dysfunction is important for understanding how to therapeutically utilize ATF2 or other pathways controlled by transcription factors. In this review, we will demonstrate how ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, and ATF7 function in promoting or suppressing cancer development and identify their roles in tumour immunotherapy.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.:82204753),the Scientific Research Staring Foundation for the New Teachers of Beijing University of Chinese Medicine(Grant No.:2020-JYB-XJSJJ-009),and Special Scientific Research for Traditional Chinese Medicine of State Administration of Traditional Chinese Medicine of China(Grant No.:201507004).The funders had no role in the study design,data collection,data analysis,interpretation,or writing of the report.
文摘Polyphyllin I(PPI)and polyphyllin II(PII)are the main active substances in the Paris polyphylla.However,liver toxicity of these compounds has impeded their clinical application and the potential hepatotoxicity mechanisms remain to be elucidated.In this work,we found that PPI and PII exposure could induce significant hepatotoxicity in human liver cell line L-02 and zebrafish in a dose-dependent manner.The results of the proteomic analysis in L-02 cells and transcriptome in zebrafish indicated that the hepatotoxicity of PPI and PII was associated with the cholesterol biosynthetic pathway disorders,which were alleviated by the cholesterol biosynthesis inhibitor lovastatin.Additionally,3-hydroxy-3-methy-lglutaryl CoA reductase(HMGCR)and squalene epoxidase(SQLE),the two rate-limiting enzymes in the cholesterol synthesis,selected as the potential targets,were confirmed by the molecular docking,the overexpression,and knockdown of HMGCR or SQLE with siRNA.Finally,the pull-down and surface plasmon resonance technology revealed that PPI could directly bind with SQLE but not with HMGCR.Collectively,these data demonstrated that PPI-induced hepatotoxicity resulted from the direct binding with SQLE protein and impaired the sterol-regulatory element binding protein 2/HMGCR/SQLE/lanosterol synthase pathways,thus disturbing the cholesterol biosynthesis pathway.The findings of this research can contribute to a better understanding of the key role of SQLE as a potential target in drug-induced hepatotoxicity and provide a therapeutic strategy for the prevention of drug toxic effects with similar structures in the future.
基金This research was supported by the project of Natural Science Foundation of Fujian Province(No.2022J01925)supported by the project of the Fuzhou Science and Technology Plan Project(2021-P-047)supported by the Open Project Program Foundation of Engineering Research Center of underground mine construction,Ministry of Education(Anhui University of Science and Technology)(No.JYBGCZX2021104).
文摘This paper investigates the influence of the deviation in freeze pipe installation on the development of the frozen wall in long cross passages by numerical simulation with ANSYS software.The study case is from the artificial ground freezing project along the Fuzhou Metro Line 2 between Ziyang Station and Wuliting Station.Two freezepipe configurations,i.e.,one with perfectly aligned pipes without any deviation from design and another with randomly distributed deviation,are included for comparison.The effect of the random deviation in the freeze pipes on frozen wall interconnection time,the thickness of the frozen wall and the development of the temperature field is explored.For the characteristic section of the numerical model at a depth of 25 m,it is found that the frozen wall interconnection time under the random deviation case and no deviation case is 24 days and 18 days,respectively.The difference in the thickness of the thinnest frozen wall segment between the random deviation and no deviation cases is the largest in the early freezing stage(up to 0.75 m),which decreases with time to 0.31 m in the late freezing stage.The effects of random deviation are more significant in the early freezing stage and diminish as the freezing time increases.
文摘Activating transcription factors, ATFs, are a group of bZIP transcription factors that act as homodimers or heterodimers with a range of other bZIP factors. In general, ATFs respond to extracellular signals, indicating their important roles in maintaining homeostasis. The ATF family includes ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, and ATF7. Consistent with the diversity of cellular processes reported to be regulated by ATFs, the functions of ATFs are also diverse. ATFs play an important role in cell proliferation, apoptosis, differentiation and inflammation-related pathological processes. The expression and phosphorylation status of ATFs are also related to neurodegenerative diseases and polycystic kidney disease. Various miRNAs target ATFs to regulate cancer proliferation, apoptosis, autophagy, sensitivity and resistance to radiotherapy and chemotherapy. Moreover, ATFs are necessary to maintain cell redox homeostasis. Therefore, deepening our understanding of the regulation and function of ATFs will provide insights into the basic regulatory mechanisms that influence how cells integrate extracellular and intracellular signals into genomic responses through transcription factors. Under pathological conditions, especially in cancer biology and response to treatment, the characterization of ATF dysfunction is important for understanding how to therapeutically utilize ATF2 or other pathways controlled by transcription factors. In this review, we will demonstrate how ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, and ATF7 function in promoting or suppressing cancer development and identify their roles in tumour immunotherapy.
