探讨柴金解郁安神片调控前扣带皮层(ACC)-腹侧海马(vHPC)谷氨酸能神经环路异常改善抑郁症大鼠腹侧海马神经元突触重塑的分子机制。首先运用化学遗传将谷氨酸能腺相关病毒(AAV)定位注射至大鼠ACC脑区,并通过慢性温和不可预知性应激(CUMS...探讨柴金解郁安神片调控前扣带皮层(ACC)-腹侧海马(vHPC)谷氨酸能神经环路异常改善抑郁症大鼠腹侧海马神经元突触重塑的分子机制。首先运用化学遗传将谷氨酸能腺相关病毒(AAV)定位注射至大鼠ACC脑区,并通过慢性温和不可预知性应激(CUMS)联合孤笼饲养复制大鼠抑郁模型,实验设正常组、模型组、AAV空载组、AAV病毒组、AAV病毒+糖皮质激素受体(GR)阻断剂组、AAV病毒+趋化因子受体1(CX3CR1)阻断剂组、AAV病毒+柴金解郁安神片组,采用水迷宫(Morris water maze)、旷场(open-field)和强迫游泳(forced-swimming)实验联合动物行为分析系统评估大鼠抑郁样行为;苏木素-伊红(HE)染色检测大鼠ACC及vHPC脑区神经元形态结构变化;免疫荧光及核磷酸蛋白(c-Fos)检测大鼠ACC-vHPC谷氨酸能神经环路激活情况;高尔基染色和透射电镜检测大鼠vHPC神经元树突、树突棘及突触亚微结构变化;免疫荧光、Western blot分别检测大鼠vHPC谷氨酸能神经元细胞内突触重塑相关蛋白谷氨酸受体2A(GRIN2A)、谷氨酸受体2B(GRIN2B)、Ca^(2+)/钙调蛋白依赖性蛋白激酶Ⅱ(CaMKⅡ)、丝裂原激活蛋白激酶激活蛋白激酶2(MK2)、丝切蛋白(cofilin)表达水平。结果表明,谷氨酸能AAV病毒激活后模型组大鼠抑郁样行为表型、ACC及vHPC神经元形态结构、突触超微结构损伤更加加重,而GR、CX3CR1阻断剂均能不同程度逆转其异常改变,提示ACC脑区内胶质细胞GR/CX3CR1双信号介导的ACC-vHPC谷氨酸能神经环路异常激活可能与抑郁的发生发展密切相关。有趣的是,柴金解郁安神片也能显著抑制AAV病毒诱导的ACC-vHPC神经环路激活及Glu含量异常升高,同时有效逆转模型组大鼠进一步加重的抑郁样行为和vHPC谷氨酸能神经元突触重塑,并揭示其改善腹侧海马神经元突触损伤的分子机制可能与调控突触重塑相关信号NR/CaMKⅡ、MK2/cofilin有关。综上,该文证实了柴金解郁安神片能有效调控ACC-vHPC谷氨酸能神经环路异常进而改善抑郁症大鼠腹侧海马谷氨酸能神经元突触重塑,其分子机制可能与调节突触相关NR/CaMKⅡ、MK2/cofilin信号通路有关,这可能是其发挥抗抑郁作用的重要机制。展开更多
The methylation of DNA is a prevalent epigenetic modification that plays a crucial role in the pathological progression of ocular diseases.DNA methylation can regulate gene expression,thereby affecting cell function a...The methylation of DNA is a prevalent epigenetic modification that plays a crucial role in the pathological progression of ocular diseases.DNA methylation can regulate gene expression,thereby affecting cell function and signal transduction.Ophthalmic diseases are a kind of complex diseases,and their pathogenesis involves many factors such as genetic,environmental and individual differences.In addition,inflammation,oxidative stress and lipid metabolism,which abnormal DNA methylation is closely related to,are also considered to be major factors in eye diseases.The current understanding of DNA methylation in eye diseases is becoming more complex and comprehensive.In addition to the simple suppression of gene expression by hypermethylation,factors such as hypomethylation or demethylation,DNA methylation in non-promoter regions,interactions with other epigenetic modifications,and dynamic changes in DNA methylation must also be considered.Interestingly,although some genes are at abnormal methylation levels,their expression is not significantly changed,which indirectly reflects the complexity of gene regulation.This review aims to summarize and compare some relevant studies,and provide with new ideas and methods for the prevention and treatment of different eye diseases,such as glaucoma,retinoblastoma,and diabetic retinopathy.展开更多
Periodontitis is a chronic inflammatory disease caused by oral pathogens,and the osteogenic potential of human periodontal ligament stem cells(hPDLSCs)is severely impaired under the inflammatory environment.Current cl...Periodontitis is a chronic inflammatory disease caused by oral pathogens,and the osteogenic potential of human periodontal ligament stem cells(hPDLSCs)is severely impaired under the inflammatory environment.Current clinical periodontitis treatment strategies such as surgical interventions and antibiotic delivery still suffer from poor antibacterial efficacy,difficulty in ameliorating excessive inflammatory responses and slow periodontal tissue regeneration.Here,we have innovatively developed a non-surgical treatment strategy based on a functional composite hydrogel.A composite hydrogel system(Pt@ZIF-8/ALN-ac/Gel)containing bioactive zeolite imidazolate framework-8(ZIF-8)integrated with platinum nanoparticles(Pt@ZIF-8)and alendronate acrylamide(ALN-ac)was constructed on the basis of gelatin methacryloyl(GelMA)to achieve enhanced antibacterial effect and reactive oxygen species(ROS)scavenging ability while promoting the osteogenic potential of hPDLSCs.We confirmed that Pt@ZIF-8/ALN-ac/Gel was able to continuously release Zn^(2+)and exerted an obvious antibacterial effect against Porphyromonas gingivalis.In vitro experiments proved that Pt@ZIF-8/ALN-ac/Gel had good biocompatibility,while efficiently featuring excellent reactive oxygen species(ROS)scavenging capacity,increasing alkaline phosphatase activity,and promoting extracellular matrix mineralization by hPDLSCs.In vivo,Pt@ZIF-8/ALN-ac/Gel significantly inhibited the alveolar bone deterioration and reduced osteoclast activation and inflammation,thereby promoting the regeneration of damaged tissues.These findings demonstrated superior therapeutic efficacy in the reported clinical periodontitis treatment,exhibiting great potential for application.展开更多
The androgenetic alopecia(AGA)is the most prevalent clinical manifestation of hair loss,believed to be associated with excessive dihydrotestosterone(DHT)caused by typeⅡ5α-reductase(5αR2).The utilization of oral fin...The androgenetic alopecia(AGA)is the most prevalent clinical manifestation of hair loss,believed to be associated with excessive dihydrotestosterone(DHT)caused by typeⅡ5α-reductase(5αR2).The utilization of oral finasteride(FNS),which selectively inhibits 5αR2,is frequently constrained by its adverse effects.Topical FNS formulations can mitigate adverse effects but often exhibit limited dermal permeability.Nanocarriers show great potential in augmenting the cutaneous permeation of loaded FNS due to their inherent properties of selective accumulation within the hair follicles(HFs).In this study,hollow mesoporous silica nanoparticles(HMSN)with varying sizes were utilized as the nanocarriers for FNS,following mixing with the Carbopol hydrogel(F@H/Gel)for direct topical application.Specifically,the influence of size on the targeted delivery of FNS to HFs,and its enhanced therapeutic efficacy for the AGA mice model was evaluated.Results showed that the HMSN,with a diameter of approximately 300 nm,exhibited significant enhancement in FNS retention within skin and HFs,as well as remarkably accelerated hair regrowth on an AGA mouse model.In conclusion,this FNS topical formulation has proved to be a viable approach in offering a secure and efficient treatment modality for AGA.展开更多
AIM:To explore whether plasma proteins serve as potential therapeutic targets for primary open angle glaucoma(POAG)based on a Mendelian randomization(MR)study.METHODS:Large-scale protein quantitative trait loci(pQTLs)...AIM:To explore whether plasma proteins serve as potential therapeutic targets for primary open angle glaucoma(POAG)based on a Mendelian randomization(MR)study.METHODS:Large-scale protein quantitative trait loci(pQTLs)data from the Icelandic deCODE database and two large POAG Genome-Wide Association Study(GWAS)summary datasets were used in this study.Causal associations between plasma proteins and POAG were identified using summary-data-based MR(SMR)analysis and the heterogeneity in dependent instruments(HEIDI)test.Colocalization analysis was then conducted to assess the genetic associations between these two factors.Phenotype-wide MR analysis was performed to validate protein targets as potential drug targets and to evaluate potential side effects.Finally,protein-protein interactions(PPI)were studied,and the Drug-Gene Interaction Database(DGIDb)was used to identify associations between drugs and the identified proteins.RESULTS:Four proteins(SVEP1,TMEM190,ROBO1,and ENPP5)were identified as potential drug targets in this study.Phenome-wide MR analysis showed that SVEP1,ROBO1,and ENPP5 were not associated with adverse effects,while TMEM190 was linked to nerve root and plexus disorders,as well as subarachnoid hemorrhage.Ticagrelor was suggested as a potential new drug for the treatment of glaucoma by regulating SVEP1.CONCLUSION:Four plasma proteins—SVEP1,TMEM190,ROBO1,and ENPP5—are identified as potential therapeutic targets for POAG through an MR approach.Phenome-wide MR analysis reveals that SVEP1,ROBO1,and ENPP5 are not associated with adverse effects,while TMEM190 is linked to nerve root and plexus disorders,as well as subarachnoid hemorrhage.Ticagrelor is proposed as a potential therapeutic drug for glaucoma by regulating SVEP1.These findings highlight the potential of plasma proteins as drug targets for POAG and provide valuable insights for further research.展开更多
Colorectal cancer causes the third most common type of malignant tumors with high morbidity and mortality.Chemotherapy is currently one of the most effective and common treatments for colorectal cancer.However,the poo...Colorectal cancer causes the third most common type of malignant tumors with high morbidity and mortality.Chemotherapy is currently one of the most effective and common treatments for colorectal cancer.However,the poor water solubility of some chemotherapeutics,untargeted drug delivery,and the undesirable systemic side effects of conventional treatment remain the major issues for colorectal cancer chemotherapy.Fortunately,drug delivery systems(DDS)based on biomaterials have been widely investigated and found to be capable of resolving those issues with good performance.Therefore,the main goal of this review is to summarize and discuss the progress and potential advantages of different DDS for colorectal cancer chemotherapy.We not only reviewed the nanocarriers used to improve the solubility of chemotherapeutics,including liposomes,micelles,and nanoparticles,but also discussed targeted DDS based on specific ligand-receptor recognition and tumor microenvironmental stimulus responses.Furthermore,locally administered systems based on hydrogels and microspheres,which have been shown to increase drug accumulation at the tumor site while decreasing systemic toxicity,were also emphasized.DDS provides a good option for improving the efficacy of chemotherapy in the treatment of colorectal cancer.展开更多
OBJECTIVE:To investigate the effects of luteolin on chronic unpredictable mild stress(CUMS)-induced depressive rats and corticosterone(CORT)-induced depressive primary hippocampal neurons,and to elucidate the mechanis...OBJECTIVE:To investigate the effects of luteolin on chronic unpredictable mild stress(CUMS)-induced depressive rats and corticosterone(CORT)-induced depressive primary hippocampal neurons,and to elucidate the mechanism behind the action.METHODS:The antidepressant mechanism of luteolin was studied by using CUMS rat model and primary hippocampal neurons in fetal rats.In vivo,novelty suppressed feeding,open-field and sucrose preference tests as well as Morris water maze were evaluated.The content of brain derived neurotrophic factor(BDNF),5-hydroxytryptamine(5-HT),norepinephrine(NE),and dopamine(DA)in serum were detected by enzyme-linked immunosorbent assay.The mechanisms of luteolin were explored based on neurotrophin and hippocampal neurogenesis,and proliferation.Survival of the septotemporal axis in hippocampus was assayed using the 5-bromo-2-deoxyuridine(BrdU),the expression of BDNF,neurotrophin-3(NT-3),and nerve growth factor(NGF)in hippocampus dentate gyrus region were measured by Western-blotting.In vitro,BDNF,NT-3,tropomyosin receptor kinase B(TrkB),and phosphorylated cyclic adenosine monophosphate responsive element binding protein(p-CREB)were detected through the high content analysis(HCA)to investigate neurotrophin and apoptosis.RESULTS:Induction of CUMS in rats induced depressive symptoms,while luteolin significantly enhanced sucrose consumption,decreased feeding latency,increased locomotor activity,escape latency,distance of target quadrant and regulated the content of depressive-like biomarkers.Histology analysis revealed that luteolin increased the abundance of new born neurons that had been labeled with BrdU,BrdU+neuronal nuclear antigen,and BrdU+doublecortin in septo-temporal axis of S2(mid-septal)and T3(mid-temporal).Moreover,expression of BDNF,NT-3,and NGF increased significantly in the septo-temporal axis of S2 and T3.HCA showed increased expression of BDNF,NT-3,TrkB and p-CREB in primary hippocampal neurons.CONCLUSION:The results provided direct evidence that luteolin has an antidepressant effect and could effectively promote the regeneration of the septotemporal axis nerve and hippocampal neuronutrition,which suggested that the antidepressant effect of luteolin may be related to hippocampal neurogenesis.展开更多
文摘探讨柴金解郁安神片调控前扣带皮层(ACC)-腹侧海马(vHPC)谷氨酸能神经环路异常改善抑郁症大鼠腹侧海马神经元突触重塑的分子机制。首先运用化学遗传将谷氨酸能腺相关病毒(AAV)定位注射至大鼠ACC脑区,并通过慢性温和不可预知性应激(CUMS)联合孤笼饲养复制大鼠抑郁模型,实验设正常组、模型组、AAV空载组、AAV病毒组、AAV病毒+糖皮质激素受体(GR)阻断剂组、AAV病毒+趋化因子受体1(CX3CR1)阻断剂组、AAV病毒+柴金解郁安神片组,采用水迷宫(Morris water maze)、旷场(open-field)和强迫游泳(forced-swimming)实验联合动物行为分析系统评估大鼠抑郁样行为;苏木素-伊红(HE)染色检测大鼠ACC及vHPC脑区神经元形态结构变化;免疫荧光及核磷酸蛋白(c-Fos)检测大鼠ACC-vHPC谷氨酸能神经环路激活情况;高尔基染色和透射电镜检测大鼠vHPC神经元树突、树突棘及突触亚微结构变化;免疫荧光、Western blot分别检测大鼠vHPC谷氨酸能神经元细胞内突触重塑相关蛋白谷氨酸受体2A(GRIN2A)、谷氨酸受体2B(GRIN2B)、Ca^(2+)/钙调蛋白依赖性蛋白激酶Ⅱ(CaMKⅡ)、丝裂原激活蛋白激酶激活蛋白激酶2(MK2)、丝切蛋白(cofilin)表达水平。结果表明,谷氨酸能AAV病毒激活后模型组大鼠抑郁样行为表型、ACC及vHPC神经元形态结构、突触超微结构损伤更加加重,而GR、CX3CR1阻断剂均能不同程度逆转其异常改变,提示ACC脑区内胶质细胞GR/CX3CR1双信号介导的ACC-vHPC谷氨酸能神经环路异常激活可能与抑郁的发生发展密切相关。有趣的是,柴金解郁安神片也能显著抑制AAV病毒诱导的ACC-vHPC神经环路激活及Glu含量异常升高,同时有效逆转模型组大鼠进一步加重的抑郁样行为和vHPC谷氨酸能神经元突触重塑,并揭示其改善腹侧海马神经元突触损伤的分子机制可能与调控突触重塑相关信号NR/CaMKⅡ、MK2/cofilin有关。综上,该文证实了柴金解郁安神片能有效调控ACC-vHPC谷氨酸能神经环路异常进而改善抑郁症大鼠腹侧海马谷氨酸能神经元突触重塑,其分子机制可能与调节突触相关NR/CaMKⅡ、MK2/cofilin信号通路有关,这可能是其发挥抗抑郁作用的重要机制。
文摘The methylation of DNA is a prevalent epigenetic modification that plays a crucial role in the pathological progression of ocular diseases.DNA methylation can regulate gene expression,thereby affecting cell function and signal transduction.Ophthalmic diseases are a kind of complex diseases,and their pathogenesis involves many factors such as genetic,environmental and individual differences.In addition,inflammation,oxidative stress and lipid metabolism,which abnormal DNA methylation is closely related to,are also considered to be major factors in eye diseases.The current understanding of DNA methylation in eye diseases is becoming more complex and comprehensive.In addition to the simple suppression of gene expression by hypermethylation,factors such as hypomethylation or demethylation,DNA methylation in non-promoter regions,interactions with other epigenetic modifications,and dynamic changes in DNA methylation must also be considered.Interestingly,although some genes are at abnormal methylation levels,their expression is not significantly changed,which indirectly reflects the complexity of gene regulation.This review aims to summarize and compare some relevant studies,and provide with new ideas and methods for the prevention and treatment of different eye diseases,such as glaucoma,retinoblastoma,and diabetic retinopathy.
基金financially supported by the National Natural Science Funds(NSFC,Nos.U21A20417 and 31930067)1·3·5 project for disciplines of excellence,West China Hospital,Sichuan University(No.ZYGD18002)。
文摘Periodontitis is a chronic inflammatory disease caused by oral pathogens,and the osteogenic potential of human periodontal ligament stem cells(hPDLSCs)is severely impaired under the inflammatory environment.Current clinical periodontitis treatment strategies such as surgical interventions and antibiotic delivery still suffer from poor antibacterial efficacy,difficulty in ameliorating excessive inflammatory responses and slow periodontal tissue regeneration.Here,we have innovatively developed a non-surgical treatment strategy based on a functional composite hydrogel.A composite hydrogel system(Pt@ZIF-8/ALN-ac/Gel)containing bioactive zeolite imidazolate framework-8(ZIF-8)integrated with platinum nanoparticles(Pt@ZIF-8)and alendronate acrylamide(ALN-ac)was constructed on the basis of gelatin methacryloyl(GelMA)to achieve enhanced antibacterial effect and reactive oxygen species(ROS)scavenging ability while promoting the osteogenic potential of hPDLSCs.We confirmed that Pt@ZIF-8/ALN-ac/Gel was able to continuously release Zn^(2+)and exerted an obvious antibacterial effect against Porphyromonas gingivalis.In vitro experiments proved that Pt@ZIF-8/ALN-ac/Gel had good biocompatibility,while efficiently featuring excellent reactive oxygen species(ROS)scavenging capacity,increasing alkaline phosphatase activity,and promoting extracellular matrix mineralization by hPDLSCs.In vivo,Pt@ZIF-8/ALN-ac/Gel significantly inhibited the alveolar bone deterioration and reduced osteoclast activation and inflammation,thereby promoting the regeneration of damaged tissues.These findings demonstrated superior therapeutic efficacy in the reported clinical periodontitis treatment,exhibiting great potential for application.
基金funded by the National Natural Science Foundation of China Regional Innovation and Development Joint Fund(Sichuan)(No.U21A20417)the National Natural Science Foundation of China(No.31930067)。
文摘The androgenetic alopecia(AGA)is the most prevalent clinical manifestation of hair loss,believed to be associated with excessive dihydrotestosterone(DHT)caused by typeⅡ5α-reductase(5αR2).The utilization of oral finasteride(FNS),which selectively inhibits 5αR2,is frequently constrained by its adverse effects.Topical FNS formulations can mitigate adverse effects but often exhibit limited dermal permeability.Nanocarriers show great potential in augmenting the cutaneous permeation of loaded FNS due to their inherent properties of selective accumulation within the hair follicles(HFs).In this study,hollow mesoporous silica nanoparticles(HMSN)with varying sizes were utilized as the nanocarriers for FNS,following mixing with the Carbopol hydrogel(F@H/Gel)for direct topical application.Specifically,the influence of size on the targeted delivery of FNS to HFs,and its enhanced therapeutic efficacy for the AGA mice model was evaluated.Results showed that the HMSN,with a diameter of approximately 300 nm,exhibited significant enhancement in FNS retention within skin and HFs,as well as remarkably accelerated hair regrowth on an AGA mouse model.In conclusion,this FNS topical formulation has proved to be a viable approach in offering a secure and efficient treatment modality for AGA.
基金Supported by the National Natural Science Foundation of China(No.81770920)Open Project of State Key Laboratory of Ophthalmology(No.303060202400383).
文摘AIM:To explore whether plasma proteins serve as potential therapeutic targets for primary open angle glaucoma(POAG)based on a Mendelian randomization(MR)study.METHODS:Large-scale protein quantitative trait loci(pQTLs)data from the Icelandic deCODE database and two large POAG Genome-Wide Association Study(GWAS)summary datasets were used in this study.Causal associations between plasma proteins and POAG were identified using summary-data-based MR(SMR)analysis and the heterogeneity in dependent instruments(HEIDI)test.Colocalization analysis was then conducted to assess the genetic associations between these two factors.Phenotype-wide MR analysis was performed to validate protein targets as potential drug targets and to evaluate potential side effects.Finally,protein-protein interactions(PPI)were studied,and the Drug-Gene Interaction Database(DGIDb)was used to identify associations between drugs and the identified proteins.RESULTS:Four proteins(SVEP1,TMEM190,ROBO1,and ENPP5)were identified as potential drug targets in this study.Phenome-wide MR analysis showed that SVEP1,ROBO1,and ENPP5 were not associated with adverse effects,while TMEM190 was linked to nerve root and plexus disorders,as well as subarachnoid hemorrhage.Ticagrelor was suggested as a potential new drug for the treatment of glaucoma by regulating SVEP1.CONCLUSION:Four plasma proteins—SVEP1,TMEM190,ROBO1,and ENPP5—are identified as potential therapeutic targets for POAG through an MR approach.Phenome-wide MR analysis reveals that SVEP1,ROBO1,and ENPP5 are not associated with adverse effects,while TMEM190 is linked to nerve root and plexus disorders,as well as subarachnoid hemorrhage.Ticagrelor is proposed as a potential therapeutic drug for glaucoma by regulating SVEP1.These findings highlight the potential of plasma proteins as drug targets for POAG and provide valuable insights for further research.
基金financial support from the National Natural Science Foundation of China(Nos.U21A20417,31930067,and 31800797)the Sichuan Science and Technology Program(Nos.2022YFS0333 and 2022YFS0203)+1 种基金the 1·3·5 project for disciplines of excellence,West China Hospital,Sichuan University(No.ZYGD18002)the Post-Doctor Research Project,West China Hospital,Sichuan University(No.2018HXBH066)。
文摘Colorectal cancer causes the third most common type of malignant tumors with high morbidity and mortality.Chemotherapy is currently one of the most effective and common treatments for colorectal cancer.However,the poor water solubility of some chemotherapeutics,untargeted drug delivery,and the undesirable systemic side effects of conventional treatment remain the major issues for colorectal cancer chemotherapy.Fortunately,drug delivery systems(DDS)based on biomaterials have been widely investigated and found to be capable of resolving those issues with good performance.Therefore,the main goal of this review is to summarize and discuss the progress and potential advantages of different DDS for colorectal cancer chemotherapy.We not only reviewed the nanocarriers used to improve the solubility of chemotherapeutics,including liposomes,micelles,and nanoparticles,but also discussed targeted DDS based on specific ligand-receptor recognition and tumor microenvironmental stimulus responses.Furthermore,locally administered systems based on hydrogels and microspheres,which have been shown to increase drug accumulation at the tumor site while decreasing systemic toxicity,were also emphasized.DDS provides a good option for improving the efficacy of chemotherapy in the treatment of colorectal cancer.
基金Outstanding Youth Project of Natural Science Foundation of Hunan Province:Mechanisms of Emotional-behavioural and Cognitive Impairment in Depression and Intervention with Traditional Chinese Medicine(No.2020JJ3027)the Training Plan of Outstanding Innovative Youth of Changsha(No.kq2009018)+2 种基金Key Projects of Hunan Provincial Department of Education:Hspa5/Pr Pcbased Study on the Mechanism of Lymphoid System Damage in Cerebral Small Vessel Disease with Depression and Intervention with Traditional Chinese Medicine(23A0281)Traditional Chinese Medicine Research Program Project of Hunan Province:Mechanisms of Impairment of Ventral and Dorsal Hippocampal Differential Function in Depression based on Sonic Hedgehog/Brain-Derived Neurotrophic Factor Signalling-Mediated Synaptogenesis in Newborn Neurons and Intervention with Traditional Chinese Medicine(B2023021)Open Fund Project of State Key Laboratory of Traditional Chinese Medicine Powder and Innovative Drugs:Mechanisms of Glymphatic Iinjury in Cerebral Small Vessel Disease with Depression Based on Aquaporin Protein-4 Signalling-Mediated Astrocyte-Responsive Hyperplasia and Intervention with Traditional Chinese Medicine(23PTKF1013)。
文摘OBJECTIVE:To investigate the effects of luteolin on chronic unpredictable mild stress(CUMS)-induced depressive rats and corticosterone(CORT)-induced depressive primary hippocampal neurons,and to elucidate the mechanism behind the action.METHODS:The antidepressant mechanism of luteolin was studied by using CUMS rat model and primary hippocampal neurons in fetal rats.In vivo,novelty suppressed feeding,open-field and sucrose preference tests as well as Morris water maze were evaluated.The content of brain derived neurotrophic factor(BDNF),5-hydroxytryptamine(5-HT),norepinephrine(NE),and dopamine(DA)in serum were detected by enzyme-linked immunosorbent assay.The mechanisms of luteolin were explored based on neurotrophin and hippocampal neurogenesis,and proliferation.Survival of the septotemporal axis in hippocampus was assayed using the 5-bromo-2-deoxyuridine(BrdU),the expression of BDNF,neurotrophin-3(NT-3),and nerve growth factor(NGF)in hippocampus dentate gyrus region were measured by Western-blotting.In vitro,BDNF,NT-3,tropomyosin receptor kinase B(TrkB),and phosphorylated cyclic adenosine monophosphate responsive element binding protein(p-CREB)were detected through the high content analysis(HCA)to investigate neurotrophin and apoptosis.RESULTS:Induction of CUMS in rats induced depressive symptoms,while luteolin significantly enhanced sucrose consumption,decreased feeding latency,increased locomotor activity,escape latency,distance of target quadrant and regulated the content of depressive-like biomarkers.Histology analysis revealed that luteolin increased the abundance of new born neurons that had been labeled with BrdU,BrdU+neuronal nuclear antigen,and BrdU+doublecortin in septo-temporal axis of S2(mid-septal)and T3(mid-temporal).Moreover,expression of BDNF,NT-3,and NGF increased significantly in the septo-temporal axis of S2 and T3.HCA showed increased expression of BDNF,NT-3,TrkB and p-CREB in primary hippocampal neurons.CONCLUSION:The results provided direct evidence that luteolin has an antidepressant effect and could effectively promote the regeneration of the septotemporal axis nerve and hippocampal neuronutrition,which suggested that the antidepressant effect of luteolin may be related to hippocampal neurogenesis.
