Sorafenib is the first-line chemotherapeutic therapy for advanced hepatocellular carcinoma(HCC).However,sorafenib resistance significantly limits its therapeutic efficacy,and the mechanisms underlying resistance have ...Sorafenib is the first-line chemotherapeutic therapy for advanced hepatocellular carcinoma(HCC).However,sorafenib resistance significantly limits its therapeutic efficacy,and the mechanisms underlying resistance have not been fully clarified.Here we report that a circular RNA,circRNA-SORE(a circular RNA upregulated in sorafenib-resistant HCC cells),plays a significant role in sorafenib resistance in HCC.We found that circRNA-SORE is upregulated in sorafenib-resistant HCC cells and depletion of circRNA-SORE substantially increases the cell-killing ability of sorafenib.Further studies revealed that circRNA-SORE binds the master oncogenic protein YBX1 in the cytoplasm,which prevents YBX1 nuclear interaction with the E3 ubiquitin ligase PRP19 and thus blocks PRP19-mediated YBX1 degradation.Moreover,our in vitro and in vivo results suggest that circRNA-SORE is transported by exosomes to spread sorafenib resistance among HCC cells.Using different HCC mouse models,we demonstrated that silencing circRNA-SORE by injection of siRNA could substantially overcome sorafenib resistance.Our study provides a proof-of-concept demonstration for a potential strategy to overcome sorafenib resistance in HCC patients by targeting circRNA-SORE or YBX1.展开更多
Exosomes are a heterogeneous group of cell-derived membranous structures, which mediate crosstalk interaction between cells.Recent studies have revealed a close relationship between exosomes and bone homeostasis. It i...Exosomes are a heterogeneous group of cell-derived membranous structures, which mediate crosstalk interaction between cells.Recent studies have revealed a close relationship between exosomes and bone homeostasis. It is suggested that bone cells can spontaneously secret exosomes containing proteins, lipids and nucleic acids, which then to regulate osteoclastogenesis and osteogenesis. However, the network of regulatory activities of exosomes in bone homeostasis as well as their therapeutic potential in bone injury remain largely unknown. This review will detail and discuss the characteristics of exosomes, the regulatory activities of exosomes in bone homeostasis as well as the clinical potential of exosomes in bone injury.展开更多
Modulating basal ganglia circuitry is of great signifcance in the improvement of motor function in Parkinson’s disease(PD).Here,for the frst time,we demonstrate that noninvasive ultrasound deep brain stimulation(UDBS...Modulating basal ganglia circuitry is of great signifcance in the improvement of motor function in Parkinson’s disease(PD).Here,for the frst time,we demonstrate that noninvasive ultrasound deep brain stimulation(UDBS)of the subthalamic nucleus(STN)or the globus pallidus(GP)improves motor behavior in a subacute mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP).Immunohistochemical c-Fos protein expression confrms that there is a relatively high level of c-Fos expression in the STN-UDBS and GP-UDBS group compared with sham group(both p<0.05).Furthermore,STN-UDBS or GPUDBS signifcantly increases the latency to fall in the rotarod test on day 9(p<0.05)and decreases the time spent climbing down a vertical rod in the pole test on day 12(p<0.05).Moreover,our results reveal that STN-UDBS or GP-UDBS protects the dopamine(DA)neurons from MPTP neurotoxicity by downregulating Bax(p<0.001),upregulating Bcl-2(p<0.01),blocking cytochrome c(Cyt C)release from mitochondria(p<0.05),and reducing cleaved-caspase 3 activity(p<0.01)in the ipsilateral substantia nigra(SN).Additionally,the safety of ultrasound stimulation is characterized by hematoxylin and eosin(HE)and Nissl staining;no hemorrhage or tissue damage is detected.Tese data demonstrate that UDBS enables modulation of STN or GP neural activity and leads to neuroprotection in PD mice,potentially serving as a noninvasive strategy for the clinical treatment of PD.展开更多
基金supported by the National Natural Science Foundation of China under Grant No.81772546(to X.C.),No.81827804(to X.C.)and No.81902367(to J.X.)Zhejiang Provincial Natural Science Foundation of China under Grant No.LQ19H160026(to J.X.)and LGF18H160011(to Y.L.)+6 种基金China Postdoctoral Science Foundation under Grant No.2020M671755(to J.X.)Key Research and Development Project of Zhejiang Province under Grant No.2018C03083(to X.C.)Zhejiang Clinical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases under Grant No.2018E50003(to X.C.)Special fund for basic scientific research operating expenses of Zhejiang University under Grant No.2019XZZX005-4-05(to Y.L.)Hepatobiliary and Pancreatic Cancer Research of Hubei Chen Xiaoping Science and Technology Development Foundation under Grant No.CXPJJH11900001-2019308(to J.X.)CXPJJH11900001-2019209(to X.L.)CXPJJH11900009-03(to X.L.).
文摘Sorafenib is the first-line chemotherapeutic therapy for advanced hepatocellular carcinoma(HCC).However,sorafenib resistance significantly limits its therapeutic efficacy,and the mechanisms underlying resistance have not been fully clarified.Here we report that a circular RNA,circRNA-SORE(a circular RNA upregulated in sorafenib-resistant HCC cells),plays a significant role in sorafenib resistance in HCC.We found that circRNA-SORE is upregulated in sorafenib-resistant HCC cells and depletion of circRNA-SORE substantially increases the cell-killing ability of sorafenib.Further studies revealed that circRNA-SORE binds the master oncogenic protein YBX1 in the cytoplasm,which prevents YBX1 nuclear interaction with the E3 ubiquitin ligase PRP19 and thus blocks PRP19-mediated YBX1 degradation.Moreover,our in vitro and in vivo results suggest that circRNA-SORE is transported by exosomes to spread sorafenib resistance among HCC cells.Using different HCC mouse models,we demonstrated that silencing circRNA-SORE by injection of siRNA could substantially overcome sorafenib resistance.Our study provides a proof-of-concept demonstration for a potential strategy to overcome sorafenib resistance in HCC patients by targeting circRNA-SORE or YBX1.
基金the support from Perron Institute for Neurological and Translational Science, Department of Orthopaedics, The Second Affiliated HospitalYuying Children's Hospital of Wenzhou Medical UniversityDepartment of Orthopaedics, Shanghai Sixth People’s Hospital of Shanghai Jiaotong University
文摘Exosomes are a heterogeneous group of cell-derived membranous structures, which mediate crosstalk interaction between cells.Recent studies have revealed a close relationship between exosomes and bone homeostasis. It is suggested that bone cells can spontaneously secret exosomes containing proteins, lipids and nucleic acids, which then to regulate osteoclastogenesis and osteogenesis. However, the network of regulatory activities of exosomes in bone homeostasis as well as their therapeutic potential in bone injury remain largely unknown. This review will detail and discuss the characteristics of exosomes, the regulatory activities of exosomes in bone homeostasis as well as the clinical potential of exosomes in bone injury.
基金We wish to thank Dr.Jun Jia(Capital Medical University)for assisting us with experimental design and Dr.Yunhui Liu(Shenzhen Institutes of Advanced Technology)for technical guidance.This work was supported by the National Natural Science Foundation of China(Grants nos.81527901,11534013,11774371,11574341,11674347,and 11874381)Natural Science Foundation of Guangdong Province(2017B030306011)Youth Innovation Promotion Association CAS(2018393).
文摘Modulating basal ganglia circuitry is of great signifcance in the improvement of motor function in Parkinson’s disease(PD).Here,for the frst time,we demonstrate that noninvasive ultrasound deep brain stimulation(UDBS)of the subthalamic nucleus(STN)or the globus pallidus(GP)improves motor behavior in a subacute mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP).Immunohistochemical c-Fos protein expression confrms that there is a relatively high level of c-Fos expression in the STN-UDBS and GP-UDBS group compared with sham group(both p<0.05).Furthermore,STN-UDBS or GPUDBS signifcantly increases the latency to fall in the rotarod test on day 9(p<0.05)and decreases the time spent climbing down a vertical rod in the pole test on day 12(p<0.05).Moreover,our results reveal that STN-UDBS or GP-UDBS protects the dopamine(DA)neurons from MPTP neurotoxicity by downregulating Bax(p<0.001),upregulating Bcl-2(p<0.01),blocking cytochrome c(Cyt C)release from mitochondria(p<0.05),and reducing cleaved-caspase 3 activity(p<0.01)in the ipsilateral substantia nigra(SN).Additionally,the safety of ultrasound stimulation is characterized by hematoxylin and eosin(HE)and Nissl staining;no hemorrhage or tissue damage is detected.Tese data demonstrate that UDBS enables modulation of STN or GP neural activity and leads to neuroprotection in PD mice,potentially serving as a noninvasive strategy for the clinical treatment of PD.
