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
Liver injury remains a significant global health problem and has a variety of causes,including oxidative stress(OS),inflammation,and apoptosis of liver cells.There is currently no curative therapy for this disorder.Sa...Liver injury remains a significant global health problem and has a variety of causes,including oxidative stress(OS),inflammation,and apoptosis of liver cells.There is currently no curative therapy for this disorder.Sanwei Ganjiang Prescription(SWGJP),derived from traditional Chinese medicine(TCM),has shown its effectiveness in long-term liver damage therapy,although the underlying molecular mechanisms are still not fully understood.To explore the underlining mechanisms of action for SWGJP in liver injury from a holistic view,in the present study,a systems pharmacology approach was developed,which involved drug target identification and multilevel data integration analysis.Using a comprehensive systems approach,we identified 43 candidate compounds in SWGJP and 408 corresponding potential targets.We further deciphered the mechanisms of SWGJP in treating liver injury,including compound-target network analysis,target-function network analysis,and integrated pathways analysis.We deduced that SWGJP may protect hepatocytes through several functional modules involved in liver injury integrated-pathway,such as Nrf2-dependent anti-oxidative stress module.Notably,systems pharmacology provides an alternative way to investigate the complex action mode of TCM.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 the National Natural Science Foundation of China(Nos.81603318,81473740,and 81673627)Guangdong Provincial Major Science and Technology for Special Program of China(No.2015A030302072)+2 种基金Guangdong Provincial Major Science and Technology for Special Program of China(No.2015A030302071)the Guangzhou Science Technology and Innovation Commission Technology Research Projects(No.201805010005)the Guangzhou Science Technology and Innovation Commission Technology Research Projects(No.201607010333)
文摘Liver injury remains a significant global health problem and has a variety of causes,including oxidative stress(OS),inflammation,and apoptosis of liver cells.There is currently no curative therapy for this disorder.Sanwei Ganjiang Prescription(SWGJP),derived from traditional Chinese medicine(TCM),has shown its effectiveness in long-term liver damage therapy,although the underlying molecular mechanisms are still not fully understood.To explore the underlining mechanisms of action for SWGJP in liver injury from a holistic view,in the present study,a systems pharmacology approach was developed,which involved drug target identification and multilevel data integration analysis.Using a comprehensive systems approach,we identified 43 candidate compounds in SWGJP and 408 corresponding potential targets.We further deciphered the mechanisms of SWGJP in treating liver injury,including compound-target network analysis,target-function network analysis,and integrated pathways analysis.We deduced that SWGJP may protect hepatocytes through several functional modules involved in liver injury integrated-pathway,such as Nrf2-dependent anti-oxidative stress module.Notably,systems pharmacology provides an alternative way to investigate the complex action mode of TCM.
