Olfactory dysfunction is accompanied with anxiety-and depressive-like behaviors.Impaired neurogenesis in hippocampus and subventricular zone(SVZ)-olfactory bulb(OB)contribute to anxiety-and depressive behaviors and ol...Olfactory dysfunction is accompanied with anxiety-and depressive-like behaviors.Impaired neurogenesis in hippocampus and subventricular zone(SVZ)-olfactory bulb(OB)contribute to anxiety-and depressive behaviors and olfactory dysfunctions.However,the underlying mechanisms remain unclear.Adaptor proteins containing the pleckstrin homology domain,phosphotyrosine binding domain,and leucine zipper motif(APPLs)are involved in regulating many biological activities.APPL2 showed the potentials to modulate cell growth,but whether APPL2 could affect adult neurogenesis and animal mood behaviors remains unknown.Herein,we tested the hypothesis that APPL2 could affect glucocorticoid receptor(GR)signaling and modulate hippocampal neurogenesis,contributing to depressive and anxiety behaviors.APPL2 Tg mice had enhanced GR phosphorylation under basic condition but had no different plasma corticosterone(CORT)level and GR phosphorylation under stress stimulation.APPL2 Tg mice had decreased hippocampal neurogenesis that was reversed by GR antagonist RU486.APPL2 Tg mice had impaired hippocampal neurogenesis and depressive and anxiety behaviors.We further identified the roles of APPL2 in olfactory functions.APPL2 Tg mice displayed higher GR activity and less neurogenesis at olfactory system with less olfactory sensitivity than WT mice,indicating that APPL2 could be a potential therapeutic target for depression and olfactory deficits.We then studied the effects of baicalin,a natural antioxidant,on modulating APPL2/GR signaling pathway and promoting neurogenesis for antidepressant and improving olfactory functions.Baicalin inhibited APPL2/GR signaling pathway and improved neurogenesis at SVZ,OB,and hippocampus in APPL2 Tg mice and chronic corticosterone-induced depression mouse model.Baicalin attenuated depressive-and anxietylike behaviors and improved olfactory functions in chronic depression mouse model and APPL2 Tg mice.In conclusion,APPL2 could be a novel therapeutic target for improving depressant related olfactory dysfunctions.Antioxidant therapy with baicalin could inhibit APPL2-mediated GR hyperactivity and promote neurogenesis,releasing depressive and anxiety symptoms and improving olfactory functions.展开更多
Adult olfactory neurogenesis plays critical roles in maintaining olfactory functions.Newly-generated neurons in the subventricular zone migrate to the olfactory bulb(OB) and determine olfactory discrimination,but the ...Adult olfactory neurogenesis plays critical roles in maintaining olfactory functions.Newly-generated neurons in the subventricular zone migrate to the olfactory bulb(OB) and determine olfactory discrimination,but the mechanisms underlying the regulation of olfactory neurogenesis remain unclear.Our previous study indicated the potential of APPL2(adaptor protein,phosphotyrosine interacting with PH domain and leucine zipper 2) as a modulating factor for neurogenesis in the adult olfactory system.In the present study,we report how APPL2 affects neurogenesis in the OB and thereby mediates olfactory discrimination by using both in vitro neural stem cells(NSCs) and an in vivo animal model-APPL2 transgenic(Tg) mice.In the in vitro study,we found that APPL2 overexpression resulted in NSCs switching from neuronal differentiation to gliogenesis while APPL2 knockdown promoted neurogenesis.In the in vivo study,APPL2 Tg mice had a higher population of glial cells and dampened neuronal production in the olfactory system,including the corpus callosum,OB,and rostral migratory stream.Adult APPL2 Tg mice displayed impaired performance in olfactory discrimination tests compared with wild-type mice.Furthermore,we found that an interaction of APPL2 with Notch1 contributed to the roles of APPL2 in modulating the neurogenic lineage-switching and olfactory behaviors.In conclusion,APPL2 controls olfactory discrimination by switching the fate choice of NSCs via interaction with Notch1 signaling.展开更多
Obesity-linked type 2 diabetes is one of the paramount causes of morbidity and mortality worldwide,posing a major threat on human health,productivity,and quality of life.Despite great progressmadetowards a better unde...Obesity-linked type 2 diabetes is one of the paramount causes of morbidity and mortality worldwide,posing a major threat on human health,productivity,and quality of life.Despite great progressmadetowards a better understanding of the molecular basis of diabetes,the available clinical counter-measures against insulin resistance,a defect that is central to obesity-linked type 2 diabetes,remain inadequate.Adiponectin,an abundant adipocyte-secreted factor with a wide-range of biological activities,improves insulin sensitivity in major insulin target tissues,modulates inflammatory responses,and plays a crucial role in the regulation of energy metabolism.However,adiponectin as a promising therapeutic approach has not been thoroughly explored in the context of pharmacological intervention,and extensive efforts are being devoted to gain mechanistic understanding of adiponectin signaling and its regulation,and reveal therapeutic targets.Here,we discuss tissue-and cell-specific functions of adiponectin,with an emphasis on the regulation of adiponectin signaling pathways,and the potential crosstalk between the adiponectin and other signaling pathways involved in metabolic regulation.Understanding better just why and how adiponectin and its downstream effector molecules work will be essential,together with empirical trials,to guide us to therapies that target the root cause(s)of type 2 diabetes and insulin resistance.展开更多
Background Adaptor proteins containing PH domain, PTB domain, and leucine zipper motif 1 and 2 （APPL1/2） play a key role in cell proliferation in many tissues. APPL1 or APPL2 as an adaptor for adiponectin receptors ...Background Adaptor proteins containing PH domain, PTB domain, and leucine zipper motif 1 and 2 （APPL1/2） play a key role in cell proliferation in many tissues. APPL1 or APPL2 as an adaptor for adiponectin receptors mediates the signaling pathway of adiponectin which acts as an anti-atherosclerotic adipokine. This study aimed to investigate whether genetic variations in the APPL 1/2 genes affect the risk of coronary artery disease （CAD） in Chinese patients with type 2 diabetes mellitus （T2DM）. Methods Seven haplotype-tagging single nucleotide polymorphisms （tag-SNPs） were selected from CHB HapMap database （Phase II） and total 203 CAD-positive cases and 106 CAD-negative controls with T2DM were genotyped for the 7 tag-SNPs by polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） assay. Results The minor allele G of rs4640525 at APPL1 locus was protective from CAD in patients with T2DM, with the carriers of genotype CC at higher risk of CAD compared with non-carriers （OR=2.830, 95% Cl 1.285-6.230, P=0.010; OR＇=4.992, 95% C1=1.758-14.173, P＇0.003, after adjustment for the other known CAD risk factors）; the homozygotes of AA at rs11112412 in APPL2 gene had higher risk of CAD compared with those of GG （adjusted OFt=5.697, 95% Cl 1.006-32.257, P=0.049）. Conclusion Genetic variation（s） in APPL 1/2 may be associated with CAD risk in T2DM in Chinese population.展开更多
文摘Olfactory dysfunction is accompanied with anxiety-and depressive-like behaviors.Impaired neurogenesis in hippocampus and subventricular zone(SVZ)-olfactory bulb(OB)contribute to anxiety-and depressive behaviors and olfactory dysfunctions.However,the underlying mechanisms remain unclear.Adaptor proteins containing the pleckstrin homology domain,phosphotyrosine binding domain,and leucine zipper motif(APPLs)are involved in regulating many biological activities.APPL2 showed the potentials to modulate cell growth,but whether APPL2 could affect adult neurogenesis and animal mood behaviors remains unknown.Herein,we tested the hypothesis that APPL2 could affect glucocorticoid receptor(GR)signaling and modulate hippocampal neurogenesis,contributing to depressive and anxiety behaviors.APPL2 Tg mice had enhanced GR phosphorylation under basic condition but had no different plasma corticosterone(CORT)level and GR phosphorylation under stress stimulation.APPL2 Tg mice had decreased hippocampal neurogenesis that was reversed by GR antagonist RU486.APPL2 Tg mice had impaired hippocampal neurogenesis and depressive and anxiety behaviors.We further identified the roles of APPL2 in olfactory functions.APPL2 Tg mice displayed higher GR activity and less neurogenesis at olfactory system with less olfactory sensitivity than WT mice,indicating that APPL2 could be a potential therapeutic target for depression and olfactory deficits.We then studied the effects of baicalin,a natural antioxidant,on modulating APPL2/GR signaling pathway and promoting neurogenesis for antidepressant and improving olfactory functions.Baicalin inhibited APPL2/GR signaling pathway and improved neurogenesis at SVZ,OB,and hippocampus in APPL2 Tg mice and chronic corticosterone-induced depression mouse model.Baicalin attenuated depressive-and anxietylike behaviors and improved olfactory functions in chronic depression mouse model and APPL2 Tg mice.In conclusion,APPL2 could be a novel therapeutic target for improving depressant related olfactory dysfunctions.Antioxidant therapy with baicalin could inhibit APPL2-mediated GR hyperactivity and promote neurogenesis,releasing depressive and anxiety symptoms and improving olfactory functions.
基金supported by Areas of Excellence (AoE/P-705/16)the General Research Fund,Hong Kong SAR (GRF No.777313 M)。
文摘Adult olfactory neurogenesis plays critical roles in maintaining olfactory functions.Newly-generated neurons in the subventricular zone migrate to the olfactory bulb(OB) and determine olfactory discrimination,but the mechanisms underlying the regulation of olfactory neurogenesis remain unclear.Our previous study indicated the potential of APPL2(adaptor protein,phosphotyrosine interacting with PH domain and leucine zipper 2) as a modulating factor for neurogenesis in the adult olfactory system.In the present study,we report how APPL2 affects neurogenesis in the OB and thereby mediates olfactory discrimination by using both in vitro neural stem cells(NSCs) and an in vivo animal model-APPL2 transgenic(Tg) mice.In the in vitro study,we found that APPL2 overexpression resulted in NSCs switching from neuronal differentiation to gliogenesis while APPL2 knockdown promoted neurogenesis.In the in vivo study,APPL2 Tg mice had a higher population of glial cells and dampened neuronal production in the olfactory system,including the corpus callosum,OB,and rostral migratory stream.Adult APPL2 Tg mice displayed impaired performance in olfactory discrimination tests compared with wild-type mice.Furthermore,we found that an interaction of APPL2 with Notch1 contributed to the roles of APPL2 in modulating the neurogenic lineage-switching and olfactory behaviors.In conclusion,APPL2 controls olfactory discrimination by switching the fate choice of NSCs via interaction with Notch1 signaling.
基金supported by grants from the National Institutes of Health (R01 DK102965)the American Diabetes Association (#7-13-BS-043)to L.Q.D.
文摘Obesity-linked type 2 diabetes is one of the paramount causes of morbidity and mortality worldwide,posing a major threat on human health,productivity,and quality of life.Despite great progressmadetowards a better understanding of the molecular basis of diabetes,the available clinical counter-measures against insulin resistance,a defect that is central to obesity-linked type 2 diabetes,remain inadequate.Adiponectin,an abundant adipocyte-secreted factor with a wide-range of biological activities,improves insulin sensitivity in major insulin target tissues,modulates inflammatory responses,and plays a crucial role in the regulation of energy metabolism.However,adiponectin as a promising therapeutic approach has not been thoroughly explored in the context of pharmacological intervention,and extensive efforts are being devoted to gain mechanistic understanding of adiponectin signaling and its regulation,and reveal therapeutic targets.Here,we discuss tissue-and cell-specific functions of adiponectin,with an emphasis on the regulation of adiponectin signaling pathways,and the potential crosstalk between the adiponectin and other signaling pathways involved in metabolic regulation.Understanding better just why and how adiponectin and its downstream effector molecules work will be essential,together with empirical trials,to guide us to therapies that target the root cause(s)of type 2 diabetes and insulin resistance.
文摘Background Adaptor proteins containing PH domain, PTB domain, and leucine zipper motif 1 and 2 （APPL1/2） play a key role in cell proliferation in many tissues. APPL1 or APPL2 as an adaptor for adiponectin receptors mediates the signaling pathway of adiponectin which acts as an anti-atherosclerotic adipokine. This study aimed to investigate whether genetic variations in the APPL 1/2 genes affect the risk of coronary artery disease （CAD） in Chinese patients with type 2 diabetes mellitus （T2DM）. Methods Seven haplotype-tagging single nucleotide polymorphisms （tag-SNPs） were selected from CHB HapMap database （Phase II） and total 203 CAD-positive cases and 106 CAD-negative controls with T2DM were genotyped for the 7 tag-SNPs by polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） assay. Results The minor allele G of rs4640525 at APPL1 locus was protective from CAD in patients with T2DM, with the carriers of genotype CC at higher risk of CAD compared with non-carriers （OR=2.830, 95% Cl 1.285-6.230, P=0.010; OR＇=4.992, 95% C1=1.758-14.173, P＇0.003, after adjustment for the other known CAD risk factors）; the homozygotes of AA at rs11112412 in APPL2 gene had higher risk of CAD compared with those of GG （adjusted OFt=5.697, 95% Cl 1.006-32.257, P=0.049）. Conclusion Genetic variation（s） in APPL 1/2 may be associated with CAD risk in T2DM in Chinese population.
