Programmed cell death 4 （PDCD4） is a RNA-binding protein that acts as a tumor suppressor in many cancer types, including colorectal cancer （CRC）. During CRC carcinogenesis, PDCD4 protein levels remarkably decrease...Programmed cell death 4 （PDCD4） is a RNA-binding protein that acts as a tumor suppressor in many cancer types, including colorectal cancer （CRC）. During CRC carcinogenesis, PDCD4 protein levels remarkably decrease, but the underlying molecular mechanism for decreased PDCD4 expression is not fully understood. In this study, we performed bioinformatics analysis to identify miRNAs that potentially target PDCD4. We demonstrated miR-181b as a direct regulator of PDCD4. We further showed that activation of IL6/STAT3 signaling pathway increased miR-181b expression and conse- quently resulted in downregulation of PDCD4 in CRC cells. In addition, we investigated the biological effects of PDCD4 inhibition by miR-181b both in vitro and in vivo and found that miR-181b could promote cell proliferation and migration and suppress apoptosis in CRC cells and accelerate tumor growth in xenograft mice, potentially through targeting PDCD4. Taken toge- ther, this study highlights an oncomiR role for miR-181b in regulating PDCD4 in CRC and suggests that miR-181b may be a novel molecular therapeutic target for CRC.展开更多
The mechanism underlying T cell-mediated fulminant hepatitis is not fully understood. In this study, we investigated whether myeloid derived suppressor cells （MDSCs） could prevent the concanavalin A （ConA）- induce...The mechanism underlying T cell-mediated fulminant hepatitis is not fully understood. In this study, we investigated whether myeloid derived suppressor cells （MDSCs） could prevent the concanavalin A （ConA）- induced hepatitis through suppressing T cell proliferation. We observed an increase in the frequencies of MDSCs in mouse spleen and liver at early stage of ConA treatment, implicating that the MDSCs might be involved in the initial resistance of mice against ConA- mediated inflammation. Subpopulation analysis showed that the MDSCs in liver of ConA-induced mice were mainly granulocytic MDSCs. Adoptive transfer of the bone marrow-derived MDSCs into ConA-treated mice showed that the MDSCs migrated into the liver and spleen where they suppressed T cell proliferation through ROS pathway. In addition, the frequencies of MDSCs in mice were also significantly increased by the treatment with immune suppressor glucocorticoids. Transfer of MDSCs into the regulatory T cell （Treg）- depleted mice showed that the protective effect of MDSCs on ConA-induced hepatitis is Treg-independent. In conclusion, our results demonstrate that MDSCs possess a direct protective role in T cell-mediated hepatitis, and increasing the frequency of MDSCs by either adoptive transfer or glucocorticoid treatment represents a potential cell-based therapeutic strategy for the acute inflammatory disease.展开更多
Herein,the nanoscaled ATP-responsive upconversion metal-organic frameworks(UCMOFs)are aqueousphase synthesized for co-delivery of therapeutic protein cytochrome c(Cyt c)and chemodrugs doxorubicin(DOX),achieving target...Herein,the nanoscaled ATP-responsive upconversion metal-organic frameworks(UCMOFs)are aqueousphase synthesized for co-delivery of therapeutic protein cytochrome c(Cyt c)and chemodrugs doxorubicin(DOX),achieving targeted combinational therapy of human cervical cancer.The UCMOFs are rationally fabricated by growing ZIF-90 on mesoporous silica-coated upconversion nanoparticles(UCNPs),in which the ZIF-90 layer attenuates the upconversion luminescence(UCL)and the rigid frameworks increase the stability of encapsulated proteins.Once the UCMOF@DOX/Cyt c are internalized into HeLa cells via specific recognition of sgc8 aptamers,the intracellular ATP triggers the dissolution of ZIF-90 into Zn^(2+),which facilitates not only the release of Cyt c and DOX but also the restoration of UCL for real-time monitoring of drug release.It has been demonstrated that the therapeutic efficacy is greatly improved by the combination of caspase-mediated apoptosis activated by Cyt c(protein therapeutics),DNA fragmentation induced by DOX(chemotherapy),and Zn;-promoted generation of reactive oxygen species(ROS)(oxidative stress).Overall,our proposed multifunctional UCMOFs provide an effective platform for targeted combinational cancer therapy and in situ imaging,which hold great promise in biomedical and clinical applications.展开更多
基金Acknowledgments We thank Drs Fengyong Liu and Sheng Luan at UC Berkeley, USA, for their discussion and help with the writing of the manuscript. This work was supported by grants from the National Natural Science Foundation of China （no. 30225037, 30471991, 30570731）, National Basic Research Program of China （973 Program） （no. 2006CB503909, 2004CB518603）, the ＂111＂ Project, and the Natural Science Foundation of Jiangsu Province （no. BK2004082, BK2006714）.
文摘Programmed cell death 4 （PDCD4） is a RNA-binding protein that acts as a tumor suppressor in many cancer types, including colorectal cancer （CRC）. During CRC carcinogenesis, PDCD4 protein levels remarkably decrease, but the underlying molecular mechanism for decreased PDCD4 expression is not fully understood. In this study, we performed bioinformatics analysis to identify miRNAs that potentially target PDCD4. We demonstrated miR-181b as a direct regulator of PDCD4. We further showed that activation of IL6/STAT3 signaling pathway increased miR-181b expression and conse- quently resulted in downregulation of PDCD4 in CRC cells. In addition, we investigated the biological effects of PDCD4 inhibition by miR-181b both in vitro and in vivo and found that miR-181b could promote cell proliferation and migration and suppress apoptosis in CRC cells and accelerate tumor growth in xenograft mice, potentially through targeting PDCD4. Taken toge- ther, this study highlights an oncomiR role for miR-181b in regulating PDCD4 in CRC and suggests that miR-181b may be a novel molecular therapeutic target for CRC.
基金ACKNOWLEDGEMENTS This work was supported by grants from the National Basic Research Program （973 Program） （Nos. 2012CB517603 and 2011CB504803）, the National Natural Science Foundation of China （Grant No. 31301061）, the Natural Science Foundation of Jiangsu Province （No. BK2011013 and BK20130564）, and the Specialized Research Fund for the Doctoral Program of Higher Education （20130091120037）.
文摘The mechanism underlying T cell-mediated fulminant hepatitis is not fully understood. In this study, we investigated whether myeloid derived suppressor cells （MDSCs） could prevent the concanavalin A （ConA）- induced hepatitis through suppressing T cell proliferation. We observed an increase in the frequencies of MDSCs in mouse spleen and liver at early stage of ConA treatment, implicating that the MDSCs might be involved in the initial resistance of mice against ConA- mediated inflammation. Subpopulation analysis showed that the MDSCs in liver of ConA-induced mice were mainly granulocytic MDSCs. Adoptive transfer of the bone marrow-derived MDSCs into ConA-treated mice showed that the MDSCs migrated into the liver and spleen where they suppressed T cell proliferation through ROS pathway. In addition, the frequencies of MDSCs in mice were also significantly increased by the treatment with immune suppressor glucocorticoids. Transfer of MDSCs into the regulatory T cell （Treg）- depleted mice showed that the protective effect of MDSCs on ConA-induced hepatitis is Treg-independent. In conclusion, our results demonstrate that MDSCs possess a direct protective role in T cell-mediated hepatitis, and increasing the frequency of MDSCs by either adoptive transfer or glucocorticoid treatment represents a potential cell-based therapeutic strategy for the acute inflammatory disease.
基金the support from the National Natural Science Foundation of China(Nos.21834004 and 22076087)the Special Funds of the Taishan Scholar Program of Shandong Province(No.tsqn20161028)+2 种基金the Natural Science Outstanding Youth Fund of Shandong Province(No.ZR2020JQ08)the Youth Innovation Technology Program of Shandong Province(No.2019KJC029)the Program B for Outstanding PhD Candidate of Nanjing University(No.201902B069)。
文摘Herein,the nanoscaled ATP-responsive upconversion metal-organic frameworks(UCMOFs)are aqueousphase synthesized for co-delivery of therapeutic protein cytochrome c(Cyt c)and chemodrugs doxorubicin(DOX),achieving targeted combinational therapy of human cervical cancer.The UCMOFs are rationally fabricated by growing ZIF-90 on mesoporous silica-coated upconversion nanoparticles(UCNPs),in which the ZIF-90 layer attenuates the upconversion luminescence(UCL)and the rigid frameworks increase the stability of encapsulated proteins.Once the UCMOF@DOX/Cyt c are internalized into HeLa cells via specific recognition of sgc8 aptamers,the intracellular ATP triggers the dissolution of ZIF-90 into Zn^(2+),which facilitates not only the release of Cyt c and DOX but also the restoration of UCL for real-time monitoring of drug release.It has been demonstrated that the therapeutic efficacy is greatly improved by the combination of caspase-mediated apoptosis activated by Cyt c(protein therapeutics),DNA fragmentation induced by DOX(chemotherapy),and Zn;-promoted generation of reactive oxygen species(ROS)(oxidative stress).Overall,our proposed multifunctional UCMOFs provide an effective platform for targeted combinational cancer therapy and in situ imaging,which hold great promise in biomedical and clinical applications.
