Objective:To study the effect of atorvastatin on atherosclerotic rabbits.Methods:A total of 60 Now Zealand male rabbits were randomly divided into the normal group,model group and atorvastatin group.The replication ra...Objective:To study the effect of atorvastatin on atherosclerotic rabbits.Methods:A total of 60 Now Zealand male rabbits were randomly divided into the normal group,model group and atorvastatin group.The replication rabbit atherosclerotic model with immune injury combined with a high fat diet feeding was used.All rabbits were sacrificed after 3 months.TLR4 and NF-κB p65 were observed by HE staining,immunohistochemistry and western blotting.Results: The expression of TLR4,NF- k B p65 were significantly increased in the model group compared widi the normal group.The expression of TI.R4 and NK- k B p65 decreased significantly in the atorvastatin group,and there was no difference compared with the normal group.Conclusions: The effect of atorvastatin on adierosclerosis may be achieved by the inhibition of the expression of TLK4 and NF-κB p65.展开更多
Subretinal fibrosis is a major cause of the poor visual prognosis for patients with neovascular age-related macular degeneration(nAMD).Myofibroblasts originated from retinal pigment epithelial(RPE)cells through epithe...Subretinal fibrosis is a major cause of the poor visual prognosis for patients with neovascular age-related macular degeneration(nAMD).Myofibroblasts originated from retinal pigment epithelial(RPE)cells through epithelial-mesenchymal transition(EMT)contribute to the fibrosis formation.N^(6)-Methyladenosine(m^(6)A)modification has been implicated in the EMT process and multiple fibrotic diseases.The role of m^(6)A modification in EMT-related subretinal fibrosis has not yet been elucidated.In this study,we found that during subretinal fibrosis in the mouse model of laser-induced choroidal neovascularization,METTL3 was upregulated in RPE cells.Through m^(6)A epitranscriptomic microarray and further verification,high-mobility group AT-hook 2(HMGA2)was identified as thekey downstream target of METTL3,subsequently activating potent EMT-inducing transcription factor SNAIL.Finally,by subretinal injections of adeno-associated virus vectors,we confirmed that METTL3 deficiency in RPE cells could efficiently attenuate subretinal fibrosis in vivo.In conclusion,our present research identified an epigenetic mechanism of METTL3-m^(6)A-HMGA2 in subretinal fibrosis and EMT of RPE cells,providing a novel therapeutic target for subretinal fibrosis secondary to nAMD.展开更多
Acetylcholinesterase(AChE)is emerging as an important contributor to apoptosis in various cell types.However,overexpression of AChE does not initiate apoptosis,and cells which express AChE at basal levels grow normall...Acetylcholinesterase(AChE)is emerging as an important contributor to apoptosis in various cell types.However,overexpression of AChE does not initiate apoptosis,and cells which express AChE at basal levels grow normally,suggesting that AChE may function differently between normal and apoptotic conditions.In this study,we determined that an AChE-derived protein(∼55 kDa)positively correlated with cellular apoptotic levels.The 55 kDa AChE protein was not a result of a novel splice variant of the AChE primary transcript.Instead,it was determined to be a cleaved fragment of the full-length 68 kDa AChE protein that could not be inhibited by cycloheximide(CHX)but could be suppressed by caspase inhibitors in apoptotic PC-12 cells.Furthermore,activation of the Akt cascade abolished the 55 kDa protein,and both AChE protein forms(68 and 55 kDa)accumulated in the nucleus during apoptosis.In a mouse model for ischemia/reperfusion(I/R)-induced acute renal failure,the 55 kDa AChE protein was detected in the impaired organs but not in the normal ones,and its levels correlated with the genotype of the mice.In summary,a 55 kDa AChE protein resulting from the cleavage of 68 kDa AChE is induced during apoptosis,and it is negatively regulated by the Akt pathway.This study suggests that an alternative form of AChE may play a role in apoptosis.展开更多
基金supportcd by the National Natural Science Fnundation of China(No:81202731)Shanghai Monicipal Health Bureau Fund(No.20114047)
文摘Objective:To study the effect of atorvastatin on atherosclerotic rabbits.Methods:A total of 60 Now Zealand male rabbits were randomly divided into the normal group,model group and atorvastatin group.The replication rabbit atherosclerotic model with immune injury combined with a high fat diet feeding was used.All rabbits were sacrificed after 3 months.TLR4 and NF-κB p65 were observed by HE staining,immunohistochemistry and western blotting.Results: The expression of TLR4,NF- k B p65 were significantly increased in the model group compared widi the normal group.The expression of TI.R4 and NK- k B p65 decreased significantly in the atorvastatin group,and there was no difference compared with the normal group.Conclusions: The effect of atorvastatin on adierosclerosis may be achieved by the inhibition of the expression of TLK4 and NF-κB p65.
基金supported by grants from the National Natural Science Foundation of China(81730026)National Key Technologies R&D Program(2017YFA0105301)Shanghai Hospital Development Center(SHDC2020CR2040B and SHDC2020CR5014).
文摘Subretinal fibrosis is a major cause of the poor visual prognosis for patients with neovascular age-related macular degeneration(nAMD).Myofibroblasts originated from retinal pigment epithelial(RPE)cells through epithelial-mesenchymal transition(EMT)contribute to the fibrosis formation.N^(6)-Methyladenosine(m^(6)A)modification has been implicated in the EMT process and multiple fibrotic diseases.The role of m^(6)A modification in EMT-related subretinal fibrosis has not yet been elucidated.In this study,we found that during subretinal fibrosis in the mouse model of laser-induced choroidal neovascularization,METTL3 was upregulated in RPE cells.Through m^(6)A epitranscriptomic microarray and further verification,high-mobility group AT-hook 2(HMGA2)was identified as thekey downstream target of METTL3,subsequently activating potent EMT-inducing transcription factor SNAIL.Finally,by subretinal injections of adeno-associated virus vectors,we confirmed that METTL3 deficiency in RPE cells could efficiently attenuate subretinal fibrosis in vivo.In conclusion,our present research identified an epigenetic mechanism of METTL3-m^(6)A-HMGA2 in subretinal fibrosis and EMT of RPE cells,providing a novel therapeutic target for subretinal fibrosis secondary to nAMD.
基金supported in part by the grants from the National Natural Science Foundation of China(Nos.30971481 and 31071213)the Major State Basic Research Development Program of China(973 Program)(No.2007CB947901)the Third Phase Creative Program of Chinese Academy of Sciences(No.KSCX2-YW-R-13).
文摘Acetylcholinesterase(AChE)is emerging as an important contributor to apoptosis in various cell types.However,overexpression of AChE does not initiate apoptosis,and cells which express AChE at basal levels grow normally,suggesting that AChE may function differently between normal and apoptotic conditions.In this study,we determined that an AChE-derived protein(∼55 kDa)positively correlated with cellular apoptotic levels.The 55 kDa AChE protein was not a result of a novel splice variant of the AChE primary transcript.Instead,it was determined to be a cleaved fragment of the full-length 68 kDa AChE protein that could not be inhibited by cycloheximide(CHX)but could be suppressed by caspase inhibitors in apoptotic PC-12 cells.Furthermore,activation of the Akt cascade abolished the 55 kDa protein,and both AChE protein forms(68 and 55 kDa)accumulated in the nucleus during apoptosis.In a mouse model for ischemia/reperfusion(I/R)-induced acute renal failure,the 55 kDa AChE protein was detected in the impaired organs but not in the normal ones,and its levels correlated with the genotype of the mice.In summary,a 55 kDa AChE protein resulting from the cleavage of 68 kDa AChE is induced during apoptosis,and it is negatively regulated by the Akt pathway.This study suggests that an alternative form of AChE may play a role in apoptosis.
