BACKGROUND The therapeutic potential of induced pluripotent stem cells(iPSCs)for Parkinson’s disease(PD)has been demonstrated.Exercise can also modulate metabolism to improve motor dysfunction in PD patients.AIM To i...BACKGROUND The therapeutic potential of induced pluripotent stem cells(iPSCs)for Parkinson’s disease(PD)has been demonstrated.Exercise can also modulate metabolism to improve motor dysfunction in PD patients.AIM To investigate the therapeutic effect of exercise combined with iPSCs in a PD mouse model and explore the underlying mechanisms.METHODS In this study,we included 10 normal mice and 40 PD model mice,which were divided into five groups:The control group(n=10),the sedentary PD group(St group,n=10),the exercise PD group(E group,n=10),the iPSC-treated PD group(T group,n=10),and the combined exercise and iPSC-treated PD group(ET group,n=10).The T and ET groups received cell injection therapy,while the E and ET groups underwent an 8-week exercise intervention.After the intervention,behavioral tests were performed on mice from all groups.Serum levels of epinephrine(EPI)and nerve growth factor were measured,and the expression of Wnt1,Lmx1a,and other factors related to the Wnt signaling pathway in the midbrain of mice were assessed.RESULTS The motor ability of the T group was higher than that of the St group,but the difference was not significant.However,the protein and gene expression levels of Wnt1,Lmx1a,Neurog2,and TH in the T group were significantly higher than those in the St group(P<0.01).Compared with the T group,the motor ability of the E group was significantly enhanced(P<0.01),and the gene expression level of Wnt1 in the midbrain of the E group was significantly higher than that of the T group(P<0.05).The levels of EPI and nerve growth factor were increased in both the E and ET groups.Exercise can improve motor dysfunction in PD,increase EPI levels,and elevate Wnt1 levels.However,western blot results revealed no significant change in the TH level of the E group,which may be because exercise does not cause a noticeable change in the number of neurons.Compared with the St group,both the E and ET groups showed improved motor function(P<0.01).The results showed that compared with the St group,the protein and gene expression levels of Wnt1,Lmx1a,and Neurog2 were significantly increased in the E,T,and ET groups(P<0.05).Compared with the T and E groups,the protein and gene expression levels of Wnt1,Lmx1a,and Neurog2 were significantly increased in the ET group(P<0.05).CONCLUSION Exercise increases EPI levels,activates the Wnt signaling pathway throughβ2 receptors,enhances the Wnt1-Lmx1a regulatory loop,and promotes the differentiation of iPSCs into dopaminergic neurons,thereby increasing the number of neurons.展开更多
Isolation rearing(IR) enhances aggressive behavior, and the central serotonin(5-hydroxytryptamine,5-HT) system has been linked to IR-induced aggression.However, whether the alteration of central serotonin is the cause...Isolation rearing(IR) enhances aggressive behavior, and the central serotonin(5-hydroxytryptamine,5-HT) system has been linked to IR-induced aggression.However, whether the alteration of central serotonin is the cause or consequence of enhanced aggression is still unknown. In the present study, using mice deficient in central serotonin Tph2-/-and Lmx1 b-/-, we examined the association between central serotonin and aggression with or without social isolation. We demonstrated that central serotonergic neurons are critical for the enhanced aggression after IR. 5-HT depletion in wild-type mice increased aggression. On the other hand, application of 5-HT in Lmx1 b-/-mice inhibited the enhancement of aggression under social isolation conditions. Dopamine was downregulated in Lmx1 b-/-mice. Similar to 5-HT, L-DOPA decreased aggression in Lmx1 b-/-mice. Our results linkthe serotoninergic system directly to aggression and this may have clinical implications for aggression-related human conditions.展开更多
Nail- patella syndrome (NPS) is an autosomal dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and nephro pathy. Recently, it was shown that NPS is the result of hete...Nail- patella syndrome (NPS) is an autosomal dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and nephro pathy. Recently, it was shown that NPS is the result of heterozygous mutations i n the LIM- homeodomain gene, LMX1B. Subsequently, many mutations of the LMX1B g ene have been reported in NPS patients. However, functional analyses of the muta nt proteins have been performed in only a few mutations. Furthermore, the mechan isms of dominant inheritance in humans have not been established. In the present study, we analyzed the LMX1B gene in three Japanese patients with NPS and ident ified two novel mutations, 6 nucleotide deletion (Δ 246N 247Q) and V242L. These two mutations are located in the homeodomain of LMX1B. Functional analyses of t he LMX1B mutants revealed that these mutants had diminished transcriptional activity and had lost DNA binding ability. Furthermore, we demonstrated that each mutant did not manifest a dominant- negative effect on the transcriptional activity of wild- type LMX1B. These results suggested that NPS is caused by lo ss- of- function mutations of LMX1B, and haploin sufficiency of LMX1B should b e the predominant pathogenesis of NPS in humans.展开更多
基金Supported by the Central Government Guides Local Science and Technology Development Funds,No.YDZX2022091General Program of Natural Sciences of Qilu Medical University,No.X24ZKQN03.
文摘BACKGROUND The therapeutic potential of induced pluripotent stem cells(iPSCs)for Parkinson’s disease(PD)has been demonstrated.Exercise can also modulate metabolism to improve motor dysfunction in PD patients.AIM To investigate the therapeutic effect of exercise combined with iPSCs in a PD mouse model and explore the underlying mechanisms.METHODS In this study,we included 10 normal mice and 40 PD model mice,which were divided into five groups:The control group(n=10),the sedentary PD group(St group,n=10),the exercise PD group(E group,n=10),the iPSC-treated PD group(T group,n=10),and the combined exercise and iPSC-treated PD group(ET group,n=10).The T and ET groups received cell injection therapy,while the E and ET groups underwent an 8-week exercise intervention.After the intervention,behavioral tests were performed on mice from all groups.Serum levels of epinephrine(EPI)and nerve growth factor were measured,and the expression of Wnt1,Lmx1a,and other factors related to the Wnt signaling pathway in the midbrain of mice were assessed.RESULTS The motor ability of the T group was higher than that of the St group,but the difference was not significant.However,the protein and gene expression levels of Wnt1,Lmx1a,Neurog2,and TH in the T group were significantly higher than those in the St group(P<0.01).Compared with the T group,the motor ability of the E group was significantly enhanced(P<0.01),and the gene expression level of Wnt1 in the midbrain of the E group was significantly higher than that of the T group(P<0.05).The levels of EPI and nerve growth factor were increased in both the E and ET groups.Exercise can improve motor dysfunction in PD,increase EPI levels,and elevate Wnt1 levels.However,western blot results revealed no significant change in the TH level of the E group,which may be because exercise does not cause a noticeable change in the number of neurons.Compared with the St group,both the E and ET groups showed improved motor function(P<0.01).The results showed that compared with the St group,the protein and gene expression levels of Wnt1,Lmx1a,and Neurog2 were significantly increased in the E,T,and ET groups(P<0.05).Compared with the T and E groups,the protein and gene expression levels of Wnt1,Lmx1a,and Neurog2 were significantly increased in the ET group(P<0.05).CONCLUSION Exercise increases EPI levels,activates the Wnt signaling pathway throughβ2 receptors,enhances the Wnt1-Lmx1a regulatory loop,and promotes the differentiation of iPSCs into dopaminergic neurons,thereby increasing the number of neurons.
基金supported by the National Natural Science Foundation of China (81425009, 31630028, 91632305, 30950030, 31170988, and 81671044)the National Basic Research Development Program (973 Program) of China (2009CB522002)
文摘Isolation rearing(IR) enhances aggressive behavior, and the central serotonin(5-hydroxytryptamine,5-HT) system has been linked to IR-induced aggression.However, whether the alteration of central serotonin is the cause or consequence of enhanced aggression is still unknown. In the present study, using mice deficient in central serotonin Tph2-/-and Lmx1 b-/-, we examined the association between central serotonin and aggression with or without social isolation. We demonstrated that central serotonergic neurons are critical for the enhanced aggression after IR. 5-HT depletion in wild-type mice increased aggression. On the other hand, application of 5-HT in Lmx1 b-/-mice inhibited the enhancement of aggression under social isolation conditions. Dopamine was downregulated in Lmx1 b-/-mice. Similar to 5-HT, L-DOPA decreased aggression in Lmx1 b-/-mice. Our results linkthe serotoninergic system directly to aggression and this may have clinical implications for aggression-related human conditions.
文摘Nail- patella syndrome (NPS) is an autosomal dominant disease characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and nephro pathy. Recently, it was shown that NPS is the result of heterozygous mutations i n the LIM- homeodomain gene, LMX1B. Subsequently, many mutations of the LMX1B g ene have been reported in NPS patients. However, functional analyses of the muta nt proteins have been performed in only a few mutations. Furthermore, the mechan isms of dominant inheritance in humans have not been established. In the present study, we analyzed the LMX1B gene in three Japanese patients with NPS and ident ified two novel mutations, 6 nucleotide deletion (Δ 246N 247Q) and V242L. These two mutations are located in the homeodomain of LMX1B. Functional analyses of t he LMX1B mutants revealed that these mutants had diminished transcriptional activity and had lost DNA binding ability. Furthermore, we demonstrated that each mutant did not manifest a dominant- negative effect on the transcriptional activity of wild- type LMX1B. These results suggested that NPS is caused by lo ss- of- function mutations of LMX1B, and haploin sufficiency of LMX1B should b e the predominant pathogenesis of NPS in humans.
