作者机构：
1. College of Pharmacy,Hunan University of Chinese Medicine;2. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Institute of Materia Medica & Neuroscience Center,Chinese Academy of Medical Sciences and Peking Union Medical College
关键词：
抑郁症;治疗方法;心理健康;临床分析
摘要：
Depression is a devastating mental disorder and major depressive disorder（MDD） that afflicts 16% of the global population at some point in their lives.Currently available classical antide.pressants（SSRIs,SNRIs,TCAs and MOIs）,require a minimum of 2–4 weeks of continuous treat.ment to elicit therapeutic relief in depressed patients and are associated with high rates of non-respon.siveness,and limited duration of efficacy.Therefore,faster-acting antidepressant therapies are need.ed,particularly for patients at risk for suicide for current therapies for depression.Although the molecu.lar mechanisms underlying the pathogenesis of depression are still largely unclear,previous studies have suggested that modulators of mammalian target of rapamycin complex 1（mTORC1） signaling may have beneficial neuroprotective and antidepressant effects.Here,we review recent advances in understanding mTORC1 signaling in depression and potential therapeutic strategies resulting from modulation of the mTORC1 signaling network.We also highlight recent studies considered to support mTORC1 signaling modulation as a rapid-acting antidepressant therapy（e.g.ketamine,scopolamine,GLYX-13,（2R,6 R）-HNK,Ro-256891 etc.） and discuss future research directions.Studies on prospec.tive next-generation rapid-acting antidepressant therapies should focus on developing more selective glutamate receptors（e.g.α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors（AMPARs）agonists or activators） that activate the mTORC1 signaling pathway free of ketamine’s adverse effects.
摘要：
Myelin is a membrane wrapped around the axon of the nerve cell, which is composed of the mature oligodendrocytes. The role of myelin is to insulate and prevent the nerve electrical impulses from the axon of the neurons to the axons of the other neurons, which is essential for the proper functioning of the nervous system. Minor changes in myelin thickness could lead to substantial changes in conduction speed and may thus alter neural circuit function. Demyelination is the myelin damage, which characterized by the loss of nerve sheath and the relative fatigue of the neuronal sheath and axon. Studies have shown that myelin injury may be closely related to neurodegenerative diseases and may be an early diagnostic criteria and therapeutic target. Thus this review summarizes the recent result of pathologic effect and signal pathways of myelin injury in neurodegenerative diseases, especially the Alzheimer's disease to provide new and effective therapeutic targets.
作者机构：
[Wang, Zhen-Zhen; Lou, Yu-Xia; Gao, Yan; Chen, Nai-Hong; Xia, Cong-Yuan; Chen, Jiao; Ren, Qian; Zhang, Zhao; Du, Guo-Hua] Chinese Acad Med Sci, State Key Lab Bioact Subst & Funct Nat Med, Inst Mat Med, Beijing 100050, Peoples R China.;[Wang, Zhen-Zhen; Lou, Yu-Xia; Gao, Yan; Chen, Nai-Hong; Xia, Cong-Yuan; Chen, Jiao; Ren, Qian; Zhang, Zhao; Du, Guo-Hua] Chinese Acad Med Sci, Neurosci Ctr, Beijing 100050, Peoples R China.;[Wang, Zhen-Zhen; Lou, Yu-Xia; Gao, Yan; Chen, Nai-Hong; Xia, Cong-Yuan; Chen, Jiao; Ren, Qian; Zhang, Zhao; Du, Guo-Hua] Peking Union Med Coll, Beijing 100050, Peoples R China.;[Chen, Nai-Hong; Wang, Ying-Ying] Guangzhou Univ Chinese Med, Guangzhou 510000, Guangdong, Peoples R China.;[Chen, Nai-Hong; Luo, Piao] Hunan Univ Chinese Med, Coll Pharm, Changsha 410208, Hunan, Peoples R China.
通讯机构：
[Chen, Nai-Hong] C;[Chen, Nai-Hong] P;Chinese Acad Med Sci, State Key Lab Bioact Subst & Funct Nat Med, Inst Mat Med, Beijing 100050, Peoples R China.;Chinese Acad Med Sci, Neurosci Ctr, Beijing 100050, Peoples R China.;Peking Union Med Coll, Beijing 100050, Peoples R China.
摘要：
Increasing evidence has implicated astrocyte pathology in the etiopathology of major depressive disorder (MDD). In particular, dysfunction of gap junctions in astrocytes is a potential target for MDD treatment. However, the mechanism underlying stress-induced dysfunction of gap junctions is still unknown. We therefore studied the mechanism of stress-induced dysfunction of gap junctions in prefrontal cortical and hippocampal astrocytes. Corticosterone (CORT) was used to induce stress conditions; CORT damaged the function of gap junctions, which resulted from less distribution of connexin43 (Cx43) on membranes and the enhanced phosphorylation of Cx43 at 5368. Moreover, CORT downregulated the biosynthesis of Cx43 but increased the degradation of Cx43. Interestingly, both autophagy and the proteasome system were involved in the degradation of Cx43 in prefrontal cortical astrocytes, but only the proteasome system was involved in the degradation of Cx43 in hippocampal astrocytes. CORT significantly induced the formation of annular gap junction vesicles in prefrontal cortical astrocytes; however, Cx43 mainly presented as small dots in the hippocampal astrocytes. Furthermore, CORT increased N-Cadherin expression and the interactions of Cx43 with ZO-1/idrebrin in prefrontal cortical astrocytes, but these interactions were oppositely modulated in hippocampal astrocytes. In conclusion, this study clarified the alternations of the Cx43 life cycle in the prefrontal cortical and hippocampal astrocytes exposed to CORT, which may contribute to our understanding of the mechanisms underlying stress-induced dysfunction of gap junctions. (C) 2017 Elsevier Ltd. All rights reserved.
期刊：
British Journal of Pharmacology,2018年175(4):590-605 ISSN：0007-1188
通讯作者：
Chen, Nai-Hong
作者机构：
[Yang, Peng-Fei; Gao, Yan; Chen, Nai-Hong; Zhang, Zhao; Wang, Sha-Sha; Chu, Shi-Feng] Peking Union Med Coll, Beijing 100050, Peoples R China.;[Yang, Peng-Fei; Gao, Yan; Chen, Nai-Hong; Zhang, Zhao; Wang, Sha-Sha; Chu, Shi-Feng] Chinese Acad Med Sci, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing, Peoples R China.;[Yang, Peng-Fei; Gao, Yan; Chen, Nai-Hong; Zhang, Zhao; Wang, Sha-Sha; Chu, Shi-Feng] Chinese Acad Med Sci, Neurosci Ctr, Beijing, Peoples R China.;[Ai, Qi-Di; Chen, Nai-Hong; Jiang, Yi-Na] Hunan Univ Chinese Med, Coll Pharm, Changsha, Hunan, Peoples R China.;[Chen, Nai-Hong] Guangzhou Univ Chinese Med, Inst Clin Pharmacol, Guangzhou, Guangdong, Peoples R China.
通讯机构：
[Chen, Nai-Hong] C;[Chen, Nai-Hong] P;Chinese Acad Med Sci, Inst Mat Med, Beijing 100050, Peoples R China.;Peking Union Med Coll, Beijing 100050, Peoples R China.
作者机构：
1. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Institute of Materia Medica & Neuroscience Center,Chinese Academy of Medical Sciences and Peking Union Medical College;2. College of Pharmacy,Hunan University of Chinese Medicine
摘要：
20C,a bibenzyl compound isolated from Gastrodia elata,possesses antioxidative properties in PC12 cells,but its in-depth molecular mechanisms against rotenone-induced neurotoxicity remains unknown.Recent studies indicate that without intact DJ-1,nuclear factor erythroid 2-related factor（Nrf2）protein becomes unstable,and the activity of Nrf2-mediated downstream antioxidant enzymes are thereby suppressed.Therefore,increasing the nuclear translocation of Nrf2 by DJ-1 may present a helpful means for the prevention and treatment of chronic diseases related to oxidative stress.Our results showed that 20C clearly protected PC12 and SH-SY5Y cells against rotenone-induced oxidative injury in a concentration-dependent manner.Furthermore,20C markedly up-regulated the levels of DJ-1,which in turn activated phosphoinositide-3-kinase（PI3K）/Akt signaling and inhibited glycogen synthase kinase 3β（GSK3β）activation,eventually promoting Nrf2 nuclear translocation and inducing the expression of Nrf2-mediated downstream antioxidative enzymes such as HO-1.The antioxidative effects of 20C could be partially blocked by ShR NA-mediated knockdown of DJ-1 and inhibition of the PI3K/Akt pathways with Akt1/2 kinase inhibitor in PC12 and SH-SY5Y cells,respectively.Conclusively,our findings confirm that DJ-1 is necessary for 20C-mediated protection against rotenone-induced oxidative damage,at least in part,by activating PI3K/Akt signaling,and subsequently enhancing the nuclear accumulation of Nrf2.The findings from our investigation suggest that 20C should be developed as a novel candidate for preventing or alleviating the consequences of PD in the future.
期刊：
Journal of Stroke & Cerebrovascular Diseases,2017年26(10):2065-2073 ISSN：1052-3057
通讯作者：
Chen, Nai-Hong
作者机构：
[Niu, Fei; Song, Xiu-Yun; Han, Ning; Kong, Ling-Lei; Hu, Jin-Feng; Chen, Nai-Hong; Zuo, Wei; Wang, Xiao-Feng] Chinese Acad Med Sci, Peking Union Med Coll, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, 2 Nanwei Rd, Beijing 100050, Peoples R China.;[Niu, Fei; Song, Xiu-Yun; Han, Ning; Kong, Ling-Lei; Hu, Jin-Feng; Chen, Nai-Hong; Zuo, Wei; Wang, Xiao-Feng] Chinese Acad Med Sci, Peking Union Med Coll, Neurosci Ctr, 2 Nanwei Rd, Beijing 100050, Peoples R China.;[Niu, Fei] Capital Med Univ, Beijing Neurosurg Inst, Beijing 100050, Peoples R China.;[Chen, Nai-Hong] Hunan Univ Chinese Med, Coll Pharm, Changsha 410208, Hunan, Peoples R China.
通讯机构：
[Chen, Nai-Hong] C;Chinese Acad Med Sci, Peking Union Med Coll, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, 2 Nanwei Rd, Beijing 100050, Peoples R China.;Chinese Acad Med Sci, Peking Union Med Coll, Neurosci Ctr, 2 Nanwei Rd, Beijing 100050, Peoples R China.
摘要：
OBJECTIVE: IMM-H004 (7-hydroxy-5-methoxy-4-methyl-3-[4-methylpiperazin-1-yl]-2H-chromen-2-one) is a novel coumarin derivative that showed better effect in improving global cerebral ischemia in rats. However, the effects and mechanisms in focal cerebral ischemia were not clear. Blood-brain barrier (BBB) protection is a vital strategy for the treatment of cerebral ischemia. This study is to investigate whether IMM-H004 improves brain ischemia injury via BBB protection. METHODS: Focal brain ischemia model was induced by middle cerebral artery occlusion for 1 hour and reperfusion (MCAO/R) for 24 hours in rats. IMM-H004 (1.5, 3, 6 mg/kg) and edaravone (positive drug, 6 mg/kg) were administered after 5 minutes of occlusion. Neurological score and TTC staining were used to evaluate the effect of IMM-H004. Evans Blue (EB) staining and electron microscopy were used to assess BBB permeability. Western blot, reverse transcription-polymerase chain reaction, and immunohistochemistry were used to detect the expression of BBB structure-related proteins. RESULTS: Compared with the model group, IMM-H004 in the focal brain ischemia model improved neurological function and reduced cerebral infarction size and edema content. IMM-H004 sharply reduced the EB content and alleviated BBB structure. In addition, IMM-H004 increased the level of zonula occludens (ZO-1) and occluding, decreased the level of aquaporin 4 and matrix metalloproteinase 9, either in cortex or in hippocampus. And all of these changed were related to BBB protection. CONCLUSION: IMM-H004 improved cerebral ischemia injury via BBB protection. For a potential therapy drug of cerebral ischemia, IMM-H004 merits further study.
期刊：
Journal of Cellular Biochemistry,2017年118(10):3130-3141 ISSN：0730-2312
通讯作者：
Chen, Naihong
作者机构：
[Xia, Congyuan; Gao, Yan; Chen, Naihong; Zuo, Wei; Zhang, Zhao] Chinese Acad Med Sci, Inst Mat Med, Dept Pharmacol, State Key Lab Bioact Subst & Funct Nat Med, Beijing, Peoples R China.;[Xia, Congyuan; Gao, Yan; Chen, Naihong; Zuo, Wei; Zhang, Zhao] Peking Union Med Coll, Beijing, Peoples R China.;[Ai, Qidi; Chen, Naihong; Chu, Shifeng; Luo, Piao] Hunan Univ Chinese Med, Coll Pharm, Changsha, Hunan, Peoples R China.;[Cao, Peng] Jiangsu Acad Tradit Chinese Med, Lab Cellular & Mol Biol, 100 Shizi St,Hongshan Rd, Nanjing, Jiangsu, Peoples R China.;[Chen, Naihong] Chinese Acad Med Sci, Inst Mat Medica, Dept Pharmacol,Peking Union Med Coll, State Key Lab Bioact Subst & Funct Nat Med, Beijing, Peoples R China.
通讯机构：
[Chen, Naihong] C;Chinese Acad Med Sci, Inst Mat Medica, Dept Pharmacol,Peking Union Med Coll, State Key Lab Bioact Subst & Funct Nat Med, Beijing, Peoples R China.
作者机构：
Shandong University of Chinese Medicine, Ji Nan Shandong, 250355, China;[龙倩; 张欣; 郭蕾] Shanxi University of Chinese Medicine, Tai Yuan Shanxi, 030619, China;Chinese Academy of Medical Science, Peking Union Medical College, Beijing, 100500, China;College of Pharmacy, Hunan University of Chinese Medicijve, Changsha Hunan, 410208, China;[贺文彬] Shanxi University of Chinese Medicine, Tai Yuan Shanxi, 030619, China, Chinese Academy of Medical Science, Peking Union Medical College, Beijing, 100500, China
期刊：
Journal of Ethnopharmacology,2017年206:178-183 ISSN：0378-8741
通讯作者：
Chen, Naihong
作者机构：
[Gao, Yan; Chen, Naihong; Zhang, Zhao; Chu, Shifeng] Chinese Acad Med Sci, Inst Mat Med, Beijing 100050, Peoples R China.;[Gao, Yan; Chen, Naihong; Zhang, Zhao; Chu, Shifeng] Peking Union Med Coll, Beijing 100050, Peoples R China.;[Chen, Naihong; Chu, Shifeng] Hunan Univ Chinese Med, Changsha 410208, Hunan, Peoples R China.
通讯机构：
[Chen, Naihong] C;[Chen, Naihong] P;Chinese Acad Med Sci, Inst Mat Med, Beijing 100050, Peoples R China.;Peking Union Med Coll, Beijing 100050, Peoples R China.
摘要：
Background and ethnopharmacological relevance: Ginseng has been used as efficient tonic and for the treatment of various diseases including hepatic disorders. Ginseng saponins, also known as ginsenosides, are principal constituents and have been treated to be responsible for disparate ginseng health benefits. The current review mainly focuses on ginsenoside Rg1, a compound isolated from traditional Chinese herbal medicine Panax ginseng Meyer. Aims: To summary the hepataprotective effects and related mechanisms of ginsenoside Rg1, we conclude this review by combining the literature and our own researches. Methods: As evidenced, we organized the pharmacological function of ginsenoside Rg1 by searching the pubmed. It has been deeply studied and summarized in the field of neurobiology, however, in this paper we described the pharmacological function of Rg1 in liver related to antioxidative stress and anti-inflammation. R&D: Individual ginsenoside could be used since it shows a wide array of beneficial functions in the regulation and disorders of acute and chronic hepatotoxicity, hepatitis, hepatic fibrosis and cirrhosis in various pathways and different mechanisms. Of note, the antioxidant hepatic protection of ginsenoside Rg1 is mainly through the induction of Keap1-Nrf2-ARE signaling pathway. Conclusion: The multi-target actions of Rg1 substantiates it as a promising drug candidate for the treatment of hepatic impairment in different factors induced liver diseases.
期刊：
International Immunopharmacology,2017年49(10):155-160 ISSN：1567-5769
通讯作者：
Yuan, Yu-he;Chen, Nai-hong
作者机构：
[Yang, Peng-fei; Shao, Qian-hang; Chen, Nai-hong; Zhang, Xiao-ling; Yuan, Yu-he] Chinese Acad Med Sci, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China.;[Yang, Peng-fei; Shao, Qian-hang; Chen, Nai-hong; Zhang, Xiao-ling; Yuan, Yu-he] Chinese Acad Med Sci, Neurosci Ctr, Beijing 100050, Peoples R China.;[Yang, Peng-fei; Shao, Qian-hang; Chen, Nai-hong; Zhang, Xiao-ling; Yuan, Yu-he; Chen, NH] Peking Union Med Coll, I Xiannongtan St, Beijing 100050, Peoples R China.;[Chen, Nai-hong] Hunan Univ Chinese Med, Coll Pharm, Changsha 410208, Hunan, Peoples R China.;[Yuan, Yu-he; Chen, NH] Chinese Acad Med Sci, Inst Mat Med, Dept Pharmacol, I Xiannongtan St, Beijing 100050, Peoples R China.
通讯机构：
[Yuan, YH; Chen, NH] P;[Yuan, YH; Chen, NH] C;Peking Union Med Coll, I Xiannongtan St, Beijing 100050, Peoples R China.;Chinese Acad Med Sci, Inst Mat Med, Dept Pharmacol, I Xiannongtan St, Beijing 100050, Peoples R China.
摘要：
Neuroinflammation has been shown as an essential factor in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, and Multiple Sclerosis. Furthermore, activated microglia and increased pro-inflammatory cytokines are the major hallmarks in neurodegenerative diseases. A multimolecular complex named as inflammasome is involved in the process of inflammatory response, which can activate inflammatory caspases, leading to the cleavage and secretion of inflammatory cytokines, and finally generates a potent inflammatory response. In neurodegenerative diseases, it has been widely assumed that some types of amyloid proteins might be the triggers to activate the NLRP3 inflammasome. In this review, we summarize the current researches about the role of NLRP3 inflammasome, by reviewing the main studies in vitro and in vivo experiments and discuss the potential for new therapeutic interventions in neurodegenerative diseases.
摘要：
Oxidative stress is thought to be involved in the development of Parkinson's disease (PD). We previously reported that 20C, a bibenzyl compound isolated from Gastrodia elata, possesses antioxidative properties, but its in-depth molecular mechanisms against rotenone-induced neurotoxicity remains unknown. Recent studies indicate that without intact DJ-1, nuclear factor erythroid 2-related factor (Nrf2) protein becomes unstable, and the activity of Nrf2-mediated downstream antioxidant enzymes are thereby suppressed. In this study, we showed that 20C clearly protected PC12 and SH-SY5Y cells against rotenone-induced oxidative injury. Furthermore, 20C markedly up-regulated the levels of DJ-1, which in turn activated phosphoinositide-3-kinase (PI3K)/Akt signaling and inhibited glycogen synthase kinase 3 beta (GSK3 beta) activation, eventually promoted the nuclear translocation of Nrf2 and induced the expression of hemeoxygenase-1 (HO-1). The antioxidant effects of 20C could be partially blocked by ShRNA-mediated knockdown of DJ-1 and inhibition of the PI3K/Akt pathways with Akt1/2 kinase inhibitor, respectively. Conclusively, our findings confirm that DJ-1 is necessary for 20C-mediated protection against rotenone-induced oxidative damage, at least in part, by activating PI3K/Akt signaling, and subsequently enhancing the nuclear accumulation of Nrf2. The findings from our investigation suggest that 20C should be developed as a novel candidate for alleviating the consequences of PD in the future. (C) 2017 Elsevier B.V. All rights reserved.
作者机构：
1. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Institute of Materia Medica& Neuroscience Center,Chinese Academy of Medical Sciences and Peking Union Medical College;2. College of Pharmacy,Hunan University of Chinese Medicine
摘要：
OBJECTIVE（1） To estimate the value of the subacute MPTP mouse model in aspects of behavioral performance,biochemical changes and pathological abnormalities.（2） To find effective positive drugs.METHODS Male C57 BL/6 mice were injected with MPTP(30 mg·kg-1·d-1,ip) for 5 consecutive days.Three days before MPTP injection,the mice were orally administered selegiline(3 mg·kg-1·d-1),pramipexole(3 mg·kg-1·d-1),or medopar(100 mg·kg-1·d-1) for 18 d.Behavioral performance was assessed in the open field test,pole test and rotarod test.Neurotransmitters in the striatum were detected using HPLC.Protein levels were measured by Western blot.Pathological characteristics were examined by immunohistochemistry.Ultrastructure changes were observed by electron microscopy.RESULTS The subacute MPTP treatment did not induce evident motor defects despite severe injuries in the dopaminergic system.Additionally,MPTP significantly increased the α-synuclein levels and the number of astrocytes in the striatum,and destroyed the blood-brain barrier（BBB） in the substantianigra pars compacta.Both selegiline and pramipexole were able to protect the mice against MPTP injuries.CONCLUSION The subacute MPTP mouse model does not show visible motor defects;it is not enough to evaluate the validity of a candidate just based on behavioral examination,much attention should also be paid to the alterations in neurotransmitters,astrocytes,α-synuclein and the BBB.In addition,selegiline or pramipexole is a better choice than medopar as an effective positive control for the subacute MPTP model.
作者机构：
1. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Institute of Materia Medica & Neuroscience Center,Chinese Academy of Medical Sciences and Peking Union Medical College;2. College of Pharmacy,Hunan University of Chinese Medicine
摘要：
OBJECTIVE To evaluate these activities of Rg1 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（MPTP）/probenecid（MPTP/p）-induced PD mouse model for the first time and to elucidate the underlying mechanisms.METHODS Male C57BL/6 mice were randomly assigned to six groups.One hour prior to MPTP/p injection,GroupⅢ-Ⅵmice received 10 mg·kg-1,20 mg·kg-1,or 40 mg·kg-1 Rg1 or 3 mg·kg-1 selegiline,respectively,orally from D（-3） to D49.GroupⅠ-Ⅱmice received solvent water.Subsequently,GroupⅡ-Ⅵmice received by injection MPTP-HCl(25 mg·kg-1 bw dissolved in0.9%saline,sc)on a 40-d schedule at intervals of 4 d between consecutive doses in combination with an adjuvant drug,probenecid(250 mg·kg-1 bw in 0.03 mL of DMSO,ip);GroupⅠmice were injected with saline and probenecid.Behavioral performance was assessed in the open field test,pole test and rotarod test.Neurotransmitters in the striatum were detected using HPLC.Protein levels were measured by Western blot.Pathological characteristics were examined by immunohistochemistry.Ultrastructure changes were observed by electron microscopy.RESULTS Oral treatment with Rg1 significantly attenuated the high MPTP-induced mortality,behavior defects,loss of dopamine neurons and abnormal ultrastructure changes in the SNpc.Other assays indicated that the protective effect of Rg1 may be mediated by its anti-neuroinflammatory properties.Rg1 regulated MPTP-induced reactive astrocytes and microglia and decreased the release of cytokines such as tumor necrosis factor-α（TNF-α）and interleukin-1b(IL-1b)in the SNpc.Rg1 also al eviated the unusual MPTP induced increase in oligomeric,phosphorylated and disease-related a-synuclein in the SNpc.CONCLUSION Rg1 protects dopaminergic neurons,most likely by reducing aberrant a-synuclein-mediated neuroinflammation,and holds promise for Parkinson disease therapeutics.
