The incidence and mortality rate of lung cancer rank among the highest worldwide,severely endangering human health and life.Metformin,an anti-diabetes drug,has been shown to elicit anticancer activities in various tum...The incidence and mortality rate of lung cancer rank among the highest worldwide,severely endangering human health and life.Metformin,an anti-diabetes drug,has been shown to elicit anticancer activities in various tumors.However,its underlying mechanisms remain elusive.In this work,we explore the role of receptor-interacting protein 1(RIP1)which plays a crucial role in the process of cell death,in metformin-induced anticancer activities in lung cancer.Metformin inhibits lung cancer cell proliferation in a dose-dependent manner and promotes apoptotic cell death,as evidenced by metformin-induced PARP and caspase cleavage.Furthermore,the pan-caspase inhibitor z-VAD-fmk reverses metformin-induced cell death.Western blot and qPCR results suggest that metformin markedly downregulates RIP1 expression without affecting its mRNA and ubiquitination levels(0 vs 80 mmol/L,100%vs 20%,100%vs 15%).Additionally,co-immunoprecipitation and immunofluorescence results reveal that metformin may suppress RIP1 expression in an Hsp70-dependent manner,as metformin promotes Hsp70 degradation,and Hsp70 endogenously interacts with RIP1.Subsequent CCK-8,flow cytometry,and Western blot analyses suggest that metformin decreases Hsp70/RIP1 expression through AMPK/PKA/GSK-3βaxis.Consistently,results from a subcutaneous transplant tumor model indicate that metformin retards tumor growth without affecting mouse body weight.Collectively,these data highlight the part of RIP1 in metformin-induced anticancer activities in lung cancer in vitro and in vivo,providing novel strategy for lung cancer administration.展开更多
Installing the splitter plates is a passive aerodynamic solution for eliminating vortex-induced vibration (VIV). However, the influences of splitter plates on the VIV and aerostatic performances are more complicated d...Installing the splitter plates is a passive aerodynamic solution for eliminating vortex-induced vibration (VIV). However, the influences of splitter plates on the VIV and aerostatic performances are more complicated due to aerodynamic interference between highway and railway decks. To study the effects of splitter plates, wind tunnel experiments for measuring VIV and aerostatic forces of twin decks under two opposite flow directions were conducted, while the surrounding flow and wind pressure of static twin decks with and without splitter plates are numerically simulated. The results showed that the incoming flow direction affects the VIV response and aerostatic coefficients. The highway deck has poor vertical and torsional VIV, and the VIV region and amplitude are different under different directions. While the railway deck only has vertical VIV when located upstream. The splitter plates can impede the process of vortex generation, shedding and impinging at the gap between twin deck, and significantly reducing the surface fluctuating pressure coefficient, thus effectively suppressing the VIV of twin decks. While, the splitter plates hurt the upstream deck regarding static wind stability and have little effect on the downstream deck. The splitter plates of appropriate width are recommended to improve VIV performances in twin parallel bridges.展开更多
文摘The incidence and mortality rate of lung cancer rank among the highest worldwide,severely endangering human health and life.Metformin,an anti-diabetes drug,has been shown to elicit anticancer activities in various tumors.However,its underlying mechanisms remain elusive.In this work,we explore the role of receptor-interacting protein 1(RIP1)which plays a crucial role in the process of cell death,in metformin-induced anticancer activities in lung cancer.Metformin inhibits lung cancer cell proliferation in a dose-dependent manner and promotes apoptotic cell death,as evidenced by metformin-induced PARP and caspase cleavage.Furthermore,the pan-caspase inhibitor z-VAD-fmk reverses metformin-induced cell death.Western blot and qPCR results suggest that metformin markedly downregulates RIP1 expression without affecting its mRNA and ubiquitination levels(0 vs 80 mmol/L,100%vs 20%,100%vs 15%).Additionally,co-immunoprecipitation and immunofluorescence results reveal that metformin may suppress RIP1 expression in an Hsp70-dependent manner,as metformin promotes Hsp70 degradation,and Hsp70 endogenously interacts with RIP1.Subsequent CCK-8,flow cytometry,and Western blot analyses suggest that metformin decreases Hsp70/RIP1 expression through AMPK/PKA/GSK-3βaxis.Consistently,results from a subcutaneous transplant tumor model indicate that metformin retards tumor growth without affecting mouse body weight.Collectively,these data highlight the part of RIP1 in metformin-induced anticancer activities in lung cancer in vitro and in vivo,providing novel strategy for lung cancer administration.
基金Projects(51925808,52078504,51822803) supported by the National Natural Science Foundation of ChinaProject(2022JJ10082) supported by the Natural Science Foundation of Hunan Province,China+1 种基金Project(N2022Z004) supported by the Research on Technology Development Trend and Key Common Problems in Railway,ChinaProject(Xplorer Prize 2021) supported by the Tencent Foundation,China。
文摘Installing the splitter plates is a passive aerodynamic solution for eliminating vortex-induced vibration (VIV). However, the influences of splitter plates on the VIV and aerostatic performances are more complicated due to aerodynamic interference between highway and railway decks. To study the effects of splitter plates, wind tunnel experiments for measuring VIV and aerostatic forces of twin decks under two opposite flow directions were conducted, while the surrounding flow and wind pressure of static twin decks with and without splitter plates are numerically simulated. The results showed that the incoming flow direction affects the VIV response and aerostatic coefficients. The highway deck has poor vertical and torsional VIV, and the VIV region and amplitude are different under different directions. While the railway deck only has vertical VIV when located upstream. The splitter plates can impede the process of vortex generation, shedding and impinging at the gap between twin deck, and significantly reducing the surface fluctuating pressure coefficient, thus effectively suppressing the VIV of twin decks. While, the splitter plates hurt the upstream deck regarding static wind stability and have little effect on the downstream deck. The splitter plates of appropriate width are recommended to improve VIV performances in twin parallel bridges.
