Mitochondrion is a semi-autonomous organelle,important for cell energy metabolism,apoptosis,the production of reactive oxygen species(ROS),and Ca2+homeostasis.Mitochondrial DNA(mtDNA)mutation is one of the primary fac...Mitochondrion is a semi-autonomous organelle,important for cell energy metabolism,apoptosis,the production of reactive oxygen species(ROS),and Ca2+homeostasis.Mitochondrial DNA(mtDNA)mutation is one of the primary factors in mitochondrial disorders.Though much progress has been made,there remain many difficulties in constructing cell models for mitochondrial diseases.This seriously restricts studies related to targeted drug discovery and the mechanism and therapy for such diseases.Here we summarize the characteristics of patient-specific immortalized lymphoblastoid cells,fibroblastoid cells,cytoplasmic hybrid(cybrid)cell lines,and induced pluripotent stem cells(iPSCs)-derived differentiation cells in the study of mitochondrial disorders,as well as offering discussion of roles and advances of these cell models,particularly in the screening of drugs.展开更多
Activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes(cGAS/STING)signaling has emerged as a promising anti-tumor strategy due to the important role of the pathwa...Activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes(cGAS/STING)signaling has emerged as a promising anti-tumor strategy due to the important role of the pathway in innate and adaptive immunity,yet the selective delivery of STING agonists to tumors following systemic administration remains challenging.Herein,we develop a nano-STING agonist-decorated microrobot platform to achieve the enhanced anti-tumor effect.Fe ions and the STING agonist 2’3’-cyclic guanosine monophosphate-adenosine monophosphate(cGAMP)are co-encapsulated in the mitochondria-targeting nanoparticles(mTNPs),which can trigger the release of mitochondrial DNA(mtDNA)by Fenton reactioninduced mitochondria oxidative damage.The exogenous cGAMP and the endogenous mtDNA can work synergistically to induce potent cGAS/STING signaling activation.Furthermore,we decorate mTNPs onto Salmonella typhimurium VNP20009(VNP)bacteria to facilitate tumor accumulation and deep penetration.We demonstrate that the systemic administration of this microrobot activates both innate and adaptive immunity,improving the immunotherapeutic efficacy of the STING agonists.展开更多
基金Project supported by the National Basic Research Program of China(No.2014CB943001)the National Natural Science Foundation of China(Nos.31771398 and 31571299)+1 种基金the Fundamental Research Funds for the Central Universities(No.2019QNA6001)the Zhejiang Provincial Natural Science Foundation of China(Nos.LZ19C060001 and LY14C060004)
文摘Mitochondrion is a semi-autonomous organelle,important for cell energy metabolism,apoptosis,the production of reactive oxygen species(ROS),and Ca2+homeostasis.Mitochondrial DNA(mtDNA)mutation is one of the primary factors in mitochondrial disorders.Though much progress has been made,there remain many difficulties in constructing cell models for mitochondrial diseases.This seriously restricts studies related to targeted drug discovery and the mechanism and therapy for such diseases.Here we summarize the characteristics of patient-specific immortalized lymphoblastoid cells,fibroblastoid cells,cytoplasmic hybrid(cybrid)cell lines,and induced pluripotent stem cells(iPSCs)-derived differentiation cells in the study of mitochondrial disorders,as well as offering discussion of roles and advances of these cell models,particularly in the screening of drugs.
基金This work was supported by the start-up package from the University of Wisconsin-Madison(to Q.Y.H.).
文摘Activating the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes(cGAS/STING)signaling has emerged as a promising anti-tumor strategy due to the important role of the pathway in innate and adaptive immunity,yet the selective delivery of STING agonists to tumors following systemic administration remains challenging.Herein,we develop a nano-STING agonist-decorated microrobot platform to achieve the enhanced anti-tumor effect.Fe ions and the STING agonist 2’3’-cyclic guanosine monophosphate-adenosine monophosphate(cGAMP)are co-encapsulated in the mitochondria-targeting nanoparticles(mTNPs),which can trigger the release of mitochondrial DNA(mtDNA)by Fenton reactioninduced mitochondria oxidative damage.The exogenous cGAMP and the endogenous mtDNA can work synergistically to induce potent cGAS/STING signaling activation.Furthermore,we decorate mTNPs onto Salmonella typhimurium VNP20009(VNP)bacteria to facilitate tumor accumulation and deep penetration.We demonstrate that the systemic administration of this microrobot activates both innate and adaptive immunity,improving the immunotherapeutic efficacy of the STING agonists.
