Breast cancer is the most frequently diagnosed cancer in women under 60, and the second most diagnosed cancer in women over 60. While significant </span><span style="font-family:Verdana;">progres...Breast cancer is the most frequently diagnosed cancer in women under 60, and the second most diagnosed cancer in women over 60. While significant </span><span style="font-family:Verdana;">progress has been made in developing targeted therapies for breast cancer,</span> <span style="font-family:Verdana;">advanced breast cancer continues to have high mortality, with poor 5-year</span> <span style="font-family:Verdana;">survival rates. Thus, current therapies are insufficient in treating advanced</span><span style="font-family:Verdana;"> stages of breast cancer;new treatments are sorely needed to address the complexity of advanced-stage breast cancer. Oncolytic virotherapy has been explored as a therapeutic approach capable of systemic administration, targeting cancer cells, and sparing normal tissue. In particular, oncolytic adenoviruses have been exploited as viral vectors due to their ease of manipulation, production, and demonstrated clinical safety profile. In this study, we engineered an oncolytic adenovirus to target the chemokine receptors CXCR4 and CXCR7. The overexpression of CXCR4 and CXCR7 is implicated in the initiation, survival, progress, and metastasis of breast cancer. Both receptors bind to the ligand, CXCL12 (SDF-1), which has been identified to play a crucial role in the metastasis of breast cancer cells. This study incorporated a T4 fibritin protein fused to CXCL12 into the tail domain of an adenovirus fiber </span><span style="font-family:Verdana;">to retarget the vector to the CXCR4 and CXCR7 chemokine receptors. We</span> <span style="font-family:Verdana;">showed that the modified virus targets and infects CXCR4- and CXCR7-</span><span style="font-family:Verdana;">overexpressing breast cancer cells more efficiently than a wild-type control</span><span style="font-family:Verdana;"> vector. In addition, the substitution of the wild-type fiber and knob with the modified chimeric fiber did not interfere with oncolytic capability. Overall, the results of this study demonstrate the feasibility of retargeting adenovirus vectors to chemokine receptor-positive tumors.展开更多
Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair.We previously reported that induced neural stem cells ...Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair.We previously reported that induced neural stem cells can modulate the behavior of activated microglia via CXCL12/CXCR4 signaling,influencing their activation such that they can promote neurological recovery.However,the mechanism of CXCR4 upregulation in induced neural stem cells remains unclear.In this study,we found that nuclear factor-κB activation induced by closed head injury mouse serum in microglia promoted CXCL12 and tumor necrosis factor-αexpression but suppressed insulin-like growth factor-1 expression.However,recombinant complement receptor 2-conjugated Crry(CR2-Crry)reduced the effects of closed head injury mouse serum-induced nuclear factor-κB activation in microglia and the levels of activated microglia,CXCL12,and tumor necrosis factor-α.Additionally,we observed that,in response to stimulation(including stimulation by CXCL12 secreted by activated microglia),CXCR4 and Crry levels can be upregulated in induced neural stem cells via the interplay among CXCL12/CXCR4,Crry,and Akt signaling to modulate microglial activation.In agreement with these in vitro experimental results,we found that Akt activation enhanced the immunoregulatory effects of induced neural stem cell grafts on microglial activation,leading to the promotion of neurological recovery via insulin-like growth factor-1 secretion and the neuroprotective effects of induced neural stem cell grafts through CXCR4 and Crry upregulation in the injured cortices of closed head injury mice.Notably,these beneficial effects of Akt activation in induced neural stem cells were positively correlated with the therapeutic effects of induced neural stem cells on neuronal injury,cerebral edema,and neurological disorders post–closed head injury.In conclusion,our findings reveal that Akt activation may enhance the immunoregulatory effects of induced neural stem cells on microglial activation via upregulation of CXCR4 and Crry,thereby promoting induced neural stem cell–mediated improvement of neuronal injury,cerebral edema,and neurological disorders following closed head injury.展开更多
Background:Recurrent miscarriage(RM)affects an estimated 1-3%of couples attempting to conceive,and its molecular components stay ineffectively caught on.This study aims to explore potential therapeutic targets for RM ...Background:Recurrent miscarriage(RM)affects an estimated 1-3%of couples attempting to conceive,and its molecular components stay ineffectively caught on.This study aims to explore potential therapeutic targets for RM by examining gene expression patterns and biological pathways in both mouse and human RM models.Meanwhile,explore relevant traditional Chinese medicine(TCM)components targeting potential therapeutic targets.Methods:We utilized the GSE211251 mouse and the GSE26787 human datasets,employing gene set enrichment analysis and gene metaphysics analysis to examine differentially expressed genes and enriched pathways.Single-cell RNA analysis uncovered cellular heterogeneity and arranged pharmacology-mapped potential drug-target intelligence.We employed molecular docking strategies to assess the affinity of TCM components for key proteins.Results:In the mouse model,genes such as Ly6f1 and Gpr26 were upregulated,while Stc5a and Galca exhibited downregulation.Gene set enrichment analysis identified key pathways,including the tumor necrosis factor-mediated signaling pathway.In human samples,Gene Ontology analysis highlighted processes such as apoptosis and cell adhesion.Single-cell RNA analysis revealed distinct cellular populations between normal and RM samples.Systems pharmacology identified C-X-C motif chemokine receptor 4(CXCR4)and endothelin 1(EDN1)as potential key targets,and molecular docking confirmed that stearic acid from TCM appears to regulate these proteins.Conclusion:This study presents a comprehensive analysis of the genetic and cellular underpinnings of RM,identifying CXCR4 and EDN1 as promising therapeutic targets.Stearic acid from TCM could provide targeted treatment by modulating these key proteins,paving the way for new RM treatment strategies.展开更多
文摘Breast cancer is the most frequently diagnosed cancer in women under 60, and the second most diagnosed cancer in women over 60. While significant </span><span style="font-family:Verdana;">progress has been made in developing targeted therapies for breast cancer,</span> <span style="font-family:Verdana;">advanced breast cancer continues to have high mortality, with poor 5-year</span> <span style="font-family:Verdana;">survival rates. Thus, current therapies are insufficient in treating advanced</span><span style="font-family:Verdana;"> stages of breast cancer;new treatments are sorely needed to address the complexity of advanced-stage breast cancer. Oncolytic virotherapy has been explored as a therapeutic approach capable of systemic administration, targeting cancer cells, and sparing normal tissue. In particular, oncolytic adenoviruses have been exploited as viral vectors due to their ease of manipulation, production, and demonstrated clinical safety profile. In this study, we engineered an oncolytic adenovirus to target the chemokine receptors CXCR4 and CXCR7. The overexpression of CXCR4 and CXCR7 is implicated in the initiation, survival, progress, and metastasis of breast cancer. Both receptors bind to the ligand, CXCL12 (SDF-1), which has been identified to play a crucial role in the metastasis of breast cancer cells. This study incorporated a T4 fibritin protein fused to CXCL12 into the tail domain of an adenovirus fiber </span><span style="font-family:Verdana;">to retarget the vector to the CXCR4 and CXCR7 chemokine receptors. We</span> <span style="font-family:Verdana;">showed that the modified virus targets and infects CXCR4- and CXCR7-</span><span style="font-family:Verdana;">overexpressing breast cancer cells more efficiently than a wild-type control</span><span style="font-family:Verdana;"> vector. In addition, the substitution of the wild-type fiber and knob with the modified chimeric fiber did not interfere with oncolytic capability. Overall, the results of this study demonstrate the feasibility of retargeting adenovirus vectors to chemokine receptor-positive tumors.
基金supported by the National Natural Science Foundation of China,Nos.82271397(to MG),82001293(to MG),82171355(to RX),81971295(to RX),and 81671189(to RX)。
文摘Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair.We previously reported that induced neural stem cells can modulate the behavior of activated microglia via CXCL12/CXCR4 signaling,influencing their activation such that they can promote neurological recovery.However,the mechanism of CXCR4 upregulation in induced neural stem cells remains unclear.In this study,we found that nuclear factor-κB activation induced by closed head injury mouse serum in microglia promoted CXCL12 and tumor necrosis factor-αexpression but suppressed insulin-like growth factor-1 expression.However,recombinant complement receptor 2-conjugated Crry(CR2-Crry)reduced the effects of closed head injury mouse serum-induced nuclear factor-κB activation in microglia and the levels of activated microglia,CXCL12,and tumor necrosis factor-α.Additionally,we observed that,in response to stimulation(including stimulation by CXCL12 secreted by activated microglia),CXCR4 and Crry levels can be upregulated in induced neural stem cells via the interplay among CXCL12/CXCR4,Crry,and Akt signaling to modulate microglial activation.In agreement with these in vitro experimental results,we found that Akt activation enhanced the immunoregulatory effects of induced neural stem cell grafts on microglial activation,leading to the promotion of neurological recovery via insulin-like growth factor-1 secretion and the neuroprotective effects of induced neural stem cell grafts through CXCR4 and Crry upregulation in the injured cortices of closed head injury mice.Notably,these beneficial effects of Akt activation in induced neural stem cells were positively correlated with the therapeutic effects of induced neural stem cells on neuronal injury,cerebral edema,and neurological disorders post–closed head injury.In conclusion,our findings reveal that Akt activation may enhance the immunoregulatory effects of induced neural stem cells on microglial activation via upregulation of CXCR4 and Crry,thereby promoting induced neural stem cell–mediated improvement of neuronal injury,cerebral edema,and neurological disorders following closed head injury.
基金support from the Ningxia Hui Autonomous Region Key Research and Development Program(Project No.2021BEG03041).
文摘Background:Recurrent miscarriage(RM)affects an estimated 1-3%of couples attempting to conceive,and its molecular components stay ineffectively caught on.This study aims to explore potential therapeutic targets for RM by examining gene expression patterns and biological pathways in both mouse and human RM models.Meanwhile,explore relevant traditional Chinese medicine(TCM)components targeting potential therapeutic targets.Methods:We utilized the GSE211251 mouse and the GSE26787 human datasets,employing gene set enrichment analysis and gene metaphysics analysis to examine differentially expressed genes and enriched pathways.Single-cell RNA analysis uncovered cellular heterogeneity and arranged pharmacology-mapped potential drug-target intelligence.We employed molecular docking strategies to assess the affinity of TCM components for key proteins.Results:In the mouse model,genes such as Ly6f1 and Gpr26 were upregulated,while Stc5a and Galca exhibited downregulation.Gene set enrichment analysis identified key pathways,including the tumor necrosis factor-mediated signaling pathway.In human samples,Gene Ontology analysis highlighted processes such as apoptosis and cell adhesion.Single-cell RNA analysis revealed distinct cellular populations between normal and RM samples.Systems pharmacology identified C-X-C motif chemokine receptor 4(CXCR4)and endothelin 1(EDN1)as potential key targets,and molecular docking confirmed that stearic acid from TCM appears to regulate these proteins.Conclusion:This study presents a comprehensive analysis of the genetic and cellular underpinnings of RM,identifying CXCR4 and EDN1 as promising therapeutic targets.Stearic acid from TCM could provide targeted treatment by modulating these key proteins,paving the way for new RM treatment strategies.
