We have recently reported that Ginsenoside Rh2 （G- Rh2） induces the activation of two initiator caspases, caspase-8 and caspase-9 in human cancer cells. How- ever, the molecular mechanism of its death-inducing funct...We have recently reported that Ginsenoside Rh2 （G- Rh2） induces the activation of two initiator caspases, caspase-8 and caspase-9 in human cancer cells. How- ever, the molecular mechanism of its death-inducing function remains unclear. Here we show that G-Rh2 stimulated the activation of both caspase-8 and cas- pase-9 simultaneously in HeLa cells. Under G-Rh2 treatment, membrane death receptors Fas and TNFR1 are remarkably upregulated. However, the induced expression of Fas but not TNFR1 was contributed to the apoptosis process, Moreover, significant increases in Fas expression and caspase-8 activity temporally coin- cided with an increase in p53 expression in p53-non- mutated HeLa and SK-HEP-1 cells upon G-Rh2 treat- ment. In contrast, Fas expression and caspase-8 activity remained constant with G-Rh2 treatment in p53-mutated SW480 and PC-3 cells. In addition, siRNA-mediated knockdown of p53 diminished G-Rh2-induced Fas expression and caspase-8 activation, These results indicated that G-Rh2-triggered extrinsic apoptosis relies on p53-mediated Fas over-expression. In the intrinsic apoptotic pathway, G-Rh2 induced strong and immedi- ate translocation of cytosolic BAK and BAX to the mitochondria, mitochondrial cytochrome c release, and subsequent caspase-9 activation both in HeLa and in SW480 ceils, p53-mediated Fas expression and sub- sequent downstream caspase-8 activation as well as p53-independent caspase-9 activation all contribute to the activation of the downstream effector caspase-3/-7, leading to tumor cell death. Taken together, we suggest that G-Rh2 induces cancer cell apoptosis in a multi-path manner and is therefore a promising candidate for anti- tumor drug development.展开更多
Annexin A2, a multifunctional tumor associated protein, promotes nuclear factor-kappa B （NF-κB） activation by interacting with NF-κB p50 subunit and facilitating its nuclear translocation. Here we demonstrated tha...Annexin A2, a multifunctional tumor associated protein, promotes nuclear factor-kappa B （NF-κB） activation by interacting with NF-κB p50 subunit and facilitating its nuclear translocation. Here we demonstrated that two ginsenosides Rg5 （G-Rg5） and Rkl （G-Rkl）, with similar structure, directly bound to Annexin A2 by molecular docking and cellular thermal shift assay. Both Rg5 and Rkl inhibited the interaction between Annexin A2 and NF-κB p50 subunit, their translocation to nuclear and NF-κB activation. Inhibition of NF-κB by these two gin- senosides decreased the expression of inhibitor of apoptosis proteins （lAPs）, leading to caspase activation and apoptosis. Over expression of K302A Annexin A2, a mutant version of Annexin A2, which fails to interact with G-Rg5 and G-Rkl, effectively reduced the NF-κB inhibitory effect and apoptosis induced by G-Rg5 and G-Rkl. In addition, the knockdown of Annexin A2 largely enhanced NF-κB activation and apoptosis induced by the two molecules, indicating that the effects of G-Rg5 and G-Rkl on NF-κB were mainly mediated by Annexin A2. Taken together, this study for the first time demon- strated that G-Rg5 and G-Rkl inhibit tumor cell growth by targeting Annexin A2 and NF-κB pathway, and G-Rg5 and G-Rkl might be promising natural compounds for targeted cancer therapy.展开更多
Sequential activation of cyclin-dependent kinases(Cdks)controls mammalian cell cycle.Here we demonstrate that the upregulation of cyclin-dependent kinase 2(Cdk2)activity coincides with the loss of mitochondrial membra...Sequential activation of cyclin-dependent kinases(Cdks)controls mammalian cell cycle.Here we demonstrate that the upregulation of cyclin-dependent kinase 2(Cdk2)activity coincides with the loss of mitochondrial membrane potential(MMP)in paclitaxel-induced apoptosis.Ectopic expression of the dominant negative Cdk2(Cdk2-dn)and a specific Cdk2 inhibitor,p21WAF1/CIP1,effectively suppresses the loss of MMP,the release of cytochrome c,and subsequent activation of caspase-3 in paclitaxel-treated cells.Whereas forced activation of Cdk2 by overexpression of cyclin A dramatically promotes these events.We further show that Cdk2 activation status does not interfere with a procedure that lies downstream of cytochrome c release induced by Bax protein.These findings suggest that Cdk2 kinase can regulate apoptosis at earlier stages than mitochondrial permeability transition and cytochrome c release.展开更多
Based on the empirical likelihood method, the subset selection and hypothesis test for parameters in a partially linear autoregressive model are investigated. We show that the empirical log-likelihood ratio at the tru...Based on the empirical likelihood method, the subset selection and hypothesis test for parameters in a partially linear autoregressive model are investigated. We show that the empirical log-likelihood ratio at the true parameters converges to the standard chi-square distribution. We then present the definitions of the empirical likelihood-based Bayes information criteria （EBIC） and Akaike information criteria （EAIC）. The results show that EBIC is consistent at selecting subset variables while EAIC is not. Simulation studies demonstrate that the proposed empirical likelihood confidence regions have better coverage probabilities than the least square method, while EBIC has a higher chance to select the true model than EAIC.展开更多
The loglinear model under product-multinomial sampling with constraints is considered. The asymptotic expansion and normality of the restricted minimum C-divergence estimator （RMDE） which is a generalization of the ...The loglinear model under product-multinomial sampling with constraints is considered. The asymptotic expansion and normality of the restricted minimum C-divergence estimator （RMDE） which is a generalization of the maximum likelihood estimator is presented. Then various statistics based on C-divergence and RMCDE are used to test various hypothesis test problems under the model considered. These statistics contain the classical loglikelihood ratio test statistics and Pearson chi-squared test statistics. Ia the last section, a simulation study is implemented.展开更多
Polyimine represents a rapidly emerging class of readily accessible and affordable covalent adaptable networks(CANs)that have been extensively studied in the past few years.While being highly malleable and recyclable,...Polyimine represents a rapidly emerging class of readily accessible and affordable covalent adaptable networks(CANs)that have been extensively studied in the past few years.While being highly malleable and recyclable,the pioneering polyimine materials are relatively soft and not suitable for certain applications that require high mechanical performance.Recent studies have demonstrated the possibility of significantly improving polyimine properties by varying its monomer building blocks,but such component variations are usually not straightforward and can be potentially challenging and costly.Herein,we report an in situ oxidation polymerization strategy for preparation of mechanically strong poly(imine-amide)(PIA)hybrid CANs from simple amine and aldehyde monomers.By converting a portion of reversible imine bonds into high-strength amide linkages in situ,the obtained hybrid materials exhibit gradually improved Young’s modulus and ultimate tensile strength as the oxidation level increased.Meanwhile,the PIAs remain reprocessable and can be depolymerized into small molecules and oligomers similar as polyimine.This work demonstrates the great potential of the in situ transformation strategy as a new approach for development of various mechanically tunable CANs from the same starting building blocks.展开更多
文摘We have recently reported that Ginsenoside Rh2 （G- Rh2） induces the activation of two initiator caspases, caspase-8 and caspase-9 in human cancer cells. How- ever, the molecular mechanism of its death-inducing function remains unclear. Here we show that G-Rh2 stimulated the activation of both caspase-8 and cas- pase-9 simultaneously in HeLa cells. Under G-Rh2 treatment, membrane death receptors Fas and TNFR1 are remarkably upregulated. However, the induced expression of Fas but not TNFR1 was contributed to the apoptosis process, Moreover, significant increases in Fas expression and caspase-8 activity temporally coin- cided with an increase in p53 expression in p53-non- mutated HeLa and SK-HEP-1 cells upon G-Rh2 treat- ment. In contrast, Fas expression and caspase-8 activity remained constant with G-Rh2 treatment in p53-mutated SW480 and PC-3 cells. In addition, siRNA-mediated knockdown of p53 diminished G-Rh2-induced Fas expression and caspase-8 activation, These results indicated that G-Rh2-triggered extrinsic apoptosis relies on p53-mediated Fas over-expression. In the intrinsic apoptotic pathway, G-Rh2 induced strong and immedi- ate translocation of cytosolic BAK and BAX to the mitochondria, mitochondrial cytochrome c release, and subsequent caspase-9 activation both in HeLa and in SW480 ceils, p53-mediated Fas expression and sub- sequent downstream caspase-8 activation as well as p53-independent caspase-9 activation all contribute to the activation of the downstream effector caspase-3/-7, leading to tumor cell death. Taken together, we suggest that G-Rh2 induces cancer cell apoptosis in a multi-path manner and is therefore a promising candidate for anti- tumor drug development.
文摘Annexin A2, a multifunctional tumor associated protein, promotes nuclear factor-kappa B （NF-κB） activation by interacting with NF-κB p50 subunit and facilitating its nuclear translocation. Here we demonstrated that two ginsenosides Rg5 （G-Rg5） and Rkl （G-Rkl）, with similar structure, directly bound to Annexin A2 by molecular docking and cellular thermal shift assay. Both Rg5 and Rkl inhibited the interaction between Annexin A2 and NF-κB p50 subunit, their translocation to nuclear and NF-κB activation. Inhibition of NF-κB by these two gin- senosides decreased the expression of inhibitor of apoptosis proteins （lAPs）, leading to caspase activation and apoptosis. Over expression of K302A Annexin A2, a mutant version of Annexin A2, which fails to interact with G-Rg5 and G-Rkl, effectively reduced the NF-κB inhibitory effect and apoptosis induced by G-Rg5 and G-Rkl. In addition, the knockdown of Annexin A2 largely enhanced NF-κB activation and apoptosis induced by the two molecules, indicating that the effects of G-Rg5 and G-Rkl on NF-κB were mainly mediated by Annexin A2. Taken together, this study for the first time demon- strated that G-Rg5 and G-Rkl inhibit tumor cell growth by targeting Annexin A2 and NF-κB pathway, and G-Rg5 and G-Rkl might be promising natural compounds for targeted cancer therapy.
基金supported by the National Natural Science Foundation of China(Grant Nos.90813003 and 31070670)by a grant from the National Research Laboratory Fund(M10104000129-02J0000-05910)from the Ministry of Science and Technology,Korea,to S.K.Lee.
文摘Sequential activation of cyclin-dependent kinases(Cdks)controls mammalian cell cycle.Here we demonstrate that the upregulation of cyclin-dependent kinase 2(Cdk2)activity coincides with the loss of mitochondrial membrane potential(MMP)in paclitaxel-induced apoptosis.Ectopic expression of the dominant negative Cdk2(Cdk2-dn)and a specific Cdk2 inhibitor,p21WAF1/CIP1,effectively suppresses the loss of MMP,the release of cytochrome c,and subsequent activation of caspase-3 in paclitaxel-treated cells.Whereas forced activation of Cdk2 by overexpression of cyclin A dramatically promotes these events.We further show that Cdk2 activation status does not interfere with a procedure that lies downstream of cytochrome c release induced by Bax protein.These findings suggest that Cdk2 kinase can regulate apoptosis at earlier stages than mitochondrial permeability transition and cytochrome c release.
基金Supported by the National Natural Science Foundation of China(No.10871188,10801123)
文摘Based on the empirical likelihood method, the subset selection and hypothesis test for parameters in a partially linear autoregressive model are investigated. We show that the empirical log-likelihood ratio at the true parameters converges to the standard chi-square distribution. We then present the definitions of the empirical likelihood-based Bayes information criteria （EBIC） and Akaike information criteria （EAIC）. The results show that EBIC is consistent at selecting subset variables while EAIC is not. Simulation studies demonstrate that the proposed empirical likelihood confidence regions have better coverage probabilities than the least square method, while EBIC has a higher chance to select the true model than EAIC.
基金Supported by the National Natural Science Foundation of China (No. 10871188, 10801123, 11231010)Guang-dong Province Natural Science Fund (No.S2012040007622)the Knowledge Innovation Program of the Chinese Academy of Sciences (Grant No. KJCX3-SYW-S02)
文摘The loglinear model under product-multinomial sampling with constraints is considered. The asymptotic expansion and normality of the restricted minimum C-divergence estimator （RMDE） which is a generalization of the maximum likelihood estimator is presented. Then various statistics based on C-divergence and RMCDE are used to test various hypothesis test problems under the model considered. These statistics contain the classical loglikelihood ratio test statistics and Pearson chi-squared test statistics. Ia the last section, a simulation study is implemented.
基金the University of Colorado Boulder and the National Science Foundation (No. 49100423C0008, Y.J.) for financial support
文摘Polyimine represents a rapidly emerging class of readily accessible and affordable covalent adaptable networks(CANs)that have been extensively studied in the past few years.While being highly malleable and recyclable,the pioneering polyimine materials are relatively soft and not suitable for certain applications that require high mechanical performance.Recent studies have demonstrated the possibility of significantly improving polyimine properties by varying its monomer building blocks,but such component variations are usually not straightforward and can be potentially challenging and costly.Herein,we report an in situ oxidation polymerization strategy for preparation of mechanically strong poly(imine-amide)(PIA)hybrid CANs from simple amine and aldehyde monomers.By converting a portion of reversible imine bonds into high-strength amide linkages in situ,the obtained hybrid materials exhibit gradually improved Young’s modulus and ultimate tensile strength as the oxidation level increased.Meanwhile,the PIAs remain reprocessable and can be depolymerized into small molecules and oligomers similar as polyimine.This work demonstrates the great potential of the in situ transformation strategy as a new approach for development of various mechanically tunable CANs from the same starting building blocks.
