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Parishin C's prevention of Aβ_(1–42)-induced inhibition of long-term potentiation is related to NMDA receptors

Acta Pharmaceutica Sinica B 2016年第3期6卷 189-197页

作者： Zhihui Liu Weiping Wang Nan Feng Ling Wang Jiangong Shi Xiaoliang Wang State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences & Peking Union Medical College

The rhizome of Gastrodia elata(GE), a herb medicine, has been used for treatment of neuronal disorders in Eastern Asia for hundreds of years. Parishin C is a major ingredient of GE. In this study, the i.c.v. injection of soluble Aβ1–42oligomers model of LTP injury was used. We investigated the effects of parishin C on the improvement of LTP in soluble Aβ1–42oligomer–injected rats and the underlying electrophysiological mechanisms. Parishin C(i.p. or i.c.v.) significantly ameliorated LTP impairment induced by i.c.v. injection of soluble Aβ1–42oligomers. In cultured hippocampal neurons,soluble Aβ1–42oligomers significantly inhibited NMDAR currents while not affecting AMPAR currents and voltage-dependent currents. Pretreatment with parishin C protected NMDA receptor currents from the damage induced by Aβ. In summary, parishin C improved LTP deficits induced by soluble Aβ1–42oligomers. The protection by parishin C against Aβ-induced LTP damage might be related to NMDA receptors.

关键词： Parishin C Long-term potentiation Neuroprotection NMDA receptors Ion channels

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P20 The novel compound HLY effectively relieves ulcerative colitis by xbp1-myh9 pathway

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Biochemical Pharmacology 2017年 139卷 131-132页

作者： Haijing Zhang Guangmin Song HuaChen Song XiaoNan Tang WenJie Wang Lianqiu Wu State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China

Ulcerative colitis (UC) is a recurrent and chronic intestinal disease. Available drugs for UC are accompanied by poor effectiveness or severe adverse events and thus there is an urgent need to develop specific and effective drugs for UC treatment. HLY is a new compound synthesised from coptisine by our institute. HLY activates the transcriptional activity of X-box binding protein 1 (xbp1) and inhibits the expression of non-muscle myosin heavy chain 9 (myh9) in intestinal epithelial cells (IEC6). When the xbp1 gene was silenced by siRNA, HLY had no effect on myh9. HLY effectively reduced body weight loss and the percentage of colon contracture in vivo , decreased disease activity index (DAI) score, colon mucosal damage index (CMDI) and tissue histopathological index (THI) in dextran sulfate sodium (DSS)-induced UC mice. Furthermore, oral HLY effectively increased the expression of xbp1 and inhibited the expression of myh9 in vivo as demonstrated by western-blot and immunohistochemical assays. Taken together, HLY could alter ulcerative colitis via the xbp1-myh9 pathway. To our knowledge, this is the first report demonstrating that the monomer compound targets the xbp1-myh9 pathway in the treatment of UC. HLY may be developed as a possible therapeutic candidate for UC.

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Simultaneous quantification of ginsenoside Rg1 and its metabolites by HPLC–MS/MS:Rg1 excretion in rat bile, urine and feces

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Acta Pharmaceutica Sinica B 2016年第6期6卷 593-599页

作者： Chiyu He Ru Feng Yupeng Sun Shifeng Chu Ji Chen Chao Ma Jie Fu Zhenxiong Zhao Min Huang Jiawen Shou Xiaoyang Li Yuzhu Wang Jinfeng Hu Yan Wang Juntian Zhang State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences Beijing Analytical Application Center Shimadzu (China) Co. Ltd.

Ginsenoside Rg1(Rg1), the major effective component of ginseng, has been shown to have multiple bioactivities, but low oral bioavailability. The aim of this study was to develop a simple, sensitive and rapid high performance liquid chromatography–tandem mass spectrometry(LC–MS/MS) method, which could be used to validate and quantify the concentrations of Rg1 and its metabolites in Sprague-Dawley rat bile,urine, and feces after oral administration(25 mg/kg). Calibration curves offered satisfactory linearity(r40.995)within the determined ranges. Both intra-day and inter-day variances were less than 15%, and the accuracy was within 80–120%. The excretion recoveries of Rg1, ginsenoside Rh1(Rh1), and protopanaxatriol(Ppt) in bile,urine, and feces combined were all greater than 70%. The fecal excretion recoveries of Rg1, Rh1, and Ppt were40.11%, 22.19%, and 22.88%, respectively, whereas 6.88% of Rg1 and 0.09% of Rh1 were excreted in *** excretion accounted for only 0.04% of Rg1. In conclusion, the observed excretion profiles for Rg1 and its metabolites after oral administration are helpful for understanding the poor oral bioavailability of Rg1 and will aid further investigations of Rg1 as a pharmacologically active component.

关键词： Ginsenoside Rg1 Ginsenoside Rh1 Protopanaxatriol Excretion LC–MS/MS

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Antidepressive effects of ginsenoside Rg1 via regulation of HPA and HPG axis

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Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2017年 92卷 962-971页

作者： Zheng Mou Qian Huang Shi-Feng Chu Mei-Jin Zhang Jin-Feng Hu Nai-Hong Chen Jun-Tian Zhang 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 Beijing 100050 China. College of Pharmacy Hunan University of Chinese Medicine Changsha Hunan 410208 China. 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 Beijing 100050 China College of Pharmacy Hunan University of Chinese Medicine Changsha Hunan 410208 China. Electronic address: chennh@***. 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 Beijing 100050 China. Electronic address: zhangjt@***.

BACKGROUND:Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity is a well-established pathological feature of major depression, accompanied by the persistent increase of glucocorticoid level and the dysfunction of hypothalamic-pituitary-gonadal (HPG) axis. Ginsenoside Rg1 (Rg1) is one of the most active ingredients of Panax ginseng, which has various biological activity. OBJECTIVE:This study aimed to investigate the antidepressive effects of Rg1 and elucidate its impact on neuroendocrine system. METHODS:The antidepressive effects of Rg1 were first analysed in mice, and was further identified in the chronic-unpredictable-mild-stress (CUMS) model and the gonadectomized (GDX) model. The effects of Rg1 on depression-like behaviour were analysed by the forced swimming test (FST), tail suspension test (TST), sucrose preference test, and measurement of pentobarbital-induced sleep. The serum corticosterone and testosterone levels were detected by ELISA. The protein levels of glucocorticoid receptor (GR) and androgen receptor (AR) were analysed by western blot and immunohistochemistry analysis. RESULTS:Rg1 significantly decreased the immobility time of mice in FST and TST. Furthermore, Rg1 alleviated anhedonia and hopelessness, decreased serum corticosterone level, and increased serum testosterone level, and the GR protein level in the PFC and hippocampus of the CUMS-treated rats. Moreover, Rg1 improved sleep disruption, down-regulated the serum corticosterone level, and increased AR protein level in the PFC of the GDX-treated mice. CONCLUSION:Together, these studies suggest that Rg1 displayed antidepressant activity through the modulation of the HPA and the HPG axis. These findings provide new mechanism involved in the antidepressive effects of Rg1 and propose theoretical clues for clinical therapies.

关键词： AR Depression GR Ginsenoside rg1 Testosterone

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Corrigendum to "Anti-neuroinflammatory effects of 20C from Gastrodia elata via regulating autophagy in LPS-activated BV-2 cells through MAPKs and TLR4/Akt/mTOR signaling pathways" [Molecular Immunology 99 (2018) 115-123]

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Molecular immunology 2018年 101卷 640页

作者： Qian-Hang Shao Xiao-Ling Zhang Ying Chen Cheng-Gen Zhu Jian-Gong Shi Yu-He Yuan Nai-Hong Chen 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 Beijing 100050 China. 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 Beijing 100050 China. Electronic address: yuanyuhe@***. 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 Beijing 100050 China College of Pharmacy Hunan University of Chinese Medicine Changsha Hunan 410208 China. Electronic address: chennh@***.

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A nucleophilic 1,3-rearrangement leading to 3,4-disubstituted 3,4-dihydroquinolines

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Chinese Chemical Letters 2016年第7期27卷 1036-1039页

作者： Chun-Xian He Zhi-Bo Jiang Hua-Qing Cui Da-Li Yin State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica Peking Union Medical College and Chinese Academy of Medical Sciences Department of Medicinal Chemistry Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation Institute of Materia Medica Peking Union Medical College and Chinese Academy of Medical Sciences

A new nucleophilic 1,3-rearrangement is observed when treating 2-methoxyquinolino-3-lithium with an α-C substituted deoxybenzoin,and this rearrangement yielded an unusual 3,4-disubstituted 3,*** similar reactions were designed and executed to investigate this novel 1,3-rearrangement,and a mechanism involving a nucleophilic addition and a following 1,3-rearrangement with an unusual dearomatization on the quinoline ring is proposed.

关键词： 1,3-Rearrangement Dihydroquinoline derivatives Reaction mechanism

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Upregulating the Expression of Survivin-HBXIP Complex Contributes to the Protective Role of IMM-H004 in Transient Global Cerebral Ischemia/Reperfusion

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Molecular neurobiology 2017年第1期54卷 524-540页

作者： Shi-Feng Chu Zhao Zhang Wei Zhang Mei-Jin Zhang Yan Gao Ning Han Wei Zuo Hui-Yong Huang Nai-Hong Chen Key Laboratory of Diagnostics of Traditional Chinese Medicine Collaborative Innovation Center of Digital Traditional Chinese Medicine College of Pharmacy Hunan University of Chinese Medicine Changsha China. 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 Beijing China. Key Laboratory of Diagnostics of Traditional Chinese Medicine Collaborative Innovation Center of Digital Traditional Chinese Medicine College of Pharmacy Hunan University of Chinese Medicine Changsha China. chennh@***. 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 Beijing China. chennh@***.

IMM-H004, a 3-piperazinylcoumarin compound derived from coumarin, has been proved effective against CA1 cell loss and spatial learning impairments resulting from transient global ischemia/reperfusion (TGCI/R), while the mechanism is still largely unknown. Here, we confirmed that treatment of rats with IMM-H004 immediately after TGCI/R ameliorated delayed neuronal death (DND) in the CA1 of hippocampus and cortex. Further study suggested that IMM-H004 contributed to the expression of antiapoptotic protein survivin through the activation of PI3K-dependent protein kinase B (PKB/Akt), which led to the phosphorylation of forkhead box O1 (FoxO1), then relieved the inhibiting effect on survivin promoter. Additionally, IMM-H004 also enhanced the expression of hepatitis B X-interacting protein (HBXIP), which formed a complex with survivin to prevent the activation of caspase death cascade, thereby halting apoptotic cell death. Finally, we injected a HBXIP siRNA into hippocampus and performed microelectroporation before ischemia/reperfusion, which abolished the protective effect of IMM-H004. Further study revealed that HBXIP maintained the high expression of Akt and survivin. Collectively, our findings demonstrated that DND after TGCI/R was alleviated by IMM-H004 through promoting the formation of survivin-HBXIP complex, which further emphasized the importance of endogenous protein involved in self-repair after stroke.

关键词： Akt Delayed neuronal death Global cerebral ischemia HBXIP IMM-H004 Neuroprotective role Survivin

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Regulation of microRNAs in cell signaling pathways-mediated vascular remodeling

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中国药理学与毒理学杂志 2016年第10期30卷 1010-1011页

作者： CHEN Ying SUN Lan DU Guan-hua Beijing Key Laboratory of Drug Target Research and Drug Screening State Key Laboratory for Bioactive Substances and Functions of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Science and Peking Union Medical College

Vascular remodeling,which can be found in atherosclerosis,restenosis after angioplasty,hypertension,and some other frequent and serious chronic *** muscle cell(SMC)phenotype change,which has been described as converting from a contractile state into a synthetic phenotype,is a crucial event during vascular ***,micro RNAs(mi RNAs)a kind of small non-coding RNA molecules,has been proven to target critical genes of cell signaling pathways to regulate SMC phenotypic *** searching the Pub Med,Embase,reviews,and reference listsof relevant papers,we systematically carried out a review of the literature to provide an overview of the mi RNAs and their target genes in cell signaling pathways,focus inthe pathways involving in SMC phenotype *** be specific,mi RNAs that regulate genes involved in the MAPK signaling pathways(such as:mi R-155,mi R-92a,mi R-424/503,mi R-133,mi R-181b,mi R-31,mi R-1298,mi R-132,mi R-200c and mi R-483-3p),mi RNAs target genes involved in the TGF-βsignaling pathways(including mi R-24,mi R-17/92 cluster,mi R-599,mi R-21 and mi R-143/145),mi RNAs target the genes involved in the AMPK signaling pathways including mi R-144/451 and mi R-195,mi RNAs target the genes involved in the PI3K-Akt signaling pathways(including mi R-138,mi R-34c,mi R-223,mi R-761,mi R-10a,mi R-146a),mi R-199a-5ptargets the genes involved in the Wnt signaling pathways mi RNAs(mi R-221/222,mi R-15b,mi R-24/29a,mi R-224)involved in the PDGF signaling pathways and some mi RNAs(mi R-638,mi R-328,mi R-365,mi R-663,mi R-29b,mi R-130,mi R-142-5p,mi R-424/322)which regulate SMC phenotype change by other corresponding targets were in detailed discussed in our *** the regulation of miR NAs in key cellsignaling pathways-mediatedvascular remodeling wil have momentous impact on identifying novel therapeutic targets for its associated disease.

关键词： microRNA vascular remodeling smooth muscle cell cell signaling pathway

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Possible target-related proteins of stress-resistant rats suggested by label-free proteomic analysis

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RSC Advances 2017年第65期7卷 40957-40964页

作者： Jiao Chen Zhenzhen Wang Shuai Zhang Qidi Ai Shifeng Chu Nai-hong Chen 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 Beijing 100050 China Hunan University of Chinese Medicine Changsha Hunan 410208 China Guangzhou University of Chinese Medicine Guangzhou 510000 China

Stress plays a crucial role in the development of major depressive disorder, but the molecular mechanism underlying the susceptibility vs. resilience to stress remains unclear. To better understand these mechanisms, w...

Stress plays a crucial role in the development of major depressive disorder, but the molecular mechanism underlying the susceptibility vs. resilience to stress remains unclear. To better understand these mechanisms, we used chronic unpredictable mild stress to develop a depressive rat model. We categorized them into stress resistant rats and stress sensitive rats by their performance in behavioral tests, including forced swim test and sucrose preference test. Brain regions were dissected, and prefrontal cortex (PFC) proteins extracted from stress resistant and stress sensitive rats were analyzed using label-free liquid chromatography-tandem mass spectrometry. Three hundred and four proteins were up-regulated and 323 proteins were down-regulated among the 1482 different proteins from stress resistant rats compared with that of the stress sensitive rats. Western blotting, immunohistochemical staining and electron microscopy were used to validate the results of the proteomic analysis. Some proteins differentially expressed in stress resistant and sensitive rats were found to be associated with several neurobiological processes, particularly with neurotransmission regulation. The results provide possible novel insights into the molecular mechanisms for stress resilience.

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IMM-H004, a coumarin derivative, attenuated brain ischemia/reperfusion injuries and subsequent inflammation in spontaneously hypertensive rats through inhibition of VCAM-1

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RSC Advances 2017年第44期7卷 27480-27495页

作者： Peng-Fei Yang Xiu-Yun Song Ting Zeng Qi-Di Ai Dan-Dan Liu Wei Zuo Shuai Zhang Cong-Yuan Xia Xin He Nai-Hong Chen Department of State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica & Neuroscience Center Chinese Academy of Medical Sciences Peking Union Medical College Beijing 100050 China College of Pharmacy Hunan University of Chinese Medicine Changsha Hunan China Tianjin University of Traditional Chinese Medicine Tianjin China

Strokes are the leading cause of death and disability all over the world, however, there are few satisfactory therapies. IMM-H004 citrate (004), 7-hydroxy-5-methoxy-4-methyl-3-(4-methylpiperazin-1-yl)-coumarin, is a coumarin derivative which has potential therapeutic effects in brain ischemia with ambiguous mechanisms. We aim to study the anti-brain ischemia effect and mechanism of 004 in spontaneously hypertensive (SHR) rats. Adult male Wistar-Kyoto (WKY) rats and SHR rats were subjected to 24 h reperfusion after transient middle cerebral artery occlusion (tMCAO) for 1 h and were intravenously injected with 004 or Edaravone at the time of reperfusion. Behavioral scores, magnetic resonance imaging (MRI) and TTC staining were used to test the therapeutic effect of 004. To study the mechanism, the infiltration of leukocytes, the activation of microglia, blood viscosity, the expression of VCAM-1, MMPs and proteins involved in the MAPK/NF-κB pathway were researched. The results indicated that tMCAO/R induced serious injury, while 004 significantly alleviated the infarct volume and improved neurological deficits. 004 improved inflammatory processes, such as the enhancement of blood viscosity, expression of VCAM-1 and MMP2, release of TNF-α, IL-1β, IL-6 and IL-23, phosphorylation of JNK and p38 and translocation of NF-κB, which play crucial roles in brain I/R in SHR rats. An in vitro study also proved that 004 regulated JNK and NF-κB pathways and decreased the expression of VCAM-1, which eventually led to the suppression of neuroinflammation.

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