作者机构：
[胥咏薇; 胡耀梅] Pharmacy School, Hunan University of Chinese Medicine, Changsha, 410208, China;Ctr. for Standardization and Funct. Engineering of Traditional Chinese Medicine in Hunan Province, Changsha, 410208, China;Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, 100050, China;[朱炎贞] College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, 410208, China;[陈乃宏] Pharmacy School, Hunan University of Chinese Medicine, Changsha, 410208, China, Ctr. for Standardization and Funct. Engineering of Traditional Chinese Medicine in Hunan Province, Changsha, 410208, China, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, 100050, China
作者机构：
Chinese Herbal Decoct Pieces, Hunan Engn Technol Ctr Standardizat & Funct, Changsha, Hunan, Peoples R China.;Hunan Univ Chinese Med, Class Disciple Construct Project Chinese Mat Med, Changsha, Hunan, Peoples R China.;[Chen, Naihong] Chinese Acad Med Sci, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China.;[Chen, Naihong] Chinese Acad Med Sci, Neurosci Ctr, Beijing 100050, Peoples R China.;[Chen, Naihong] Peking Union Med Coll, Beijing 100050, Peoples R China.
通讯机构：
[Chen, Naihong] C;[Chen, Naihong] P;Chinese Acad Med Sci, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat 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.
关键词：
ASC=apoptosis-associated speck-like protein containing a caspase activation recruitment domain;BCA=bicinchoninic acid;BSA=bovine serum albumin;CCA=common carotid artery;CCR4=C-C chemokine receptor type 4;CKLF1=chemokine-like factor 1;CO-IP=coimmunoprecipitation;ECA=external carotid artery;ELISA=enzyme-linked immunosorbent assay;FDA=Food and Drug Administration;I/R=ischemic/reperfusion;ICA=internal carotid artery;IL-18=interleukin 18;IL-1beta=interleukin 1beta;LDH=lactate dehydrogenase;NLRP3=NOD-like receptor protein 3;PBS=phosphate-buffered saline;SD=standard deviation;TNF-alpha=tumor necrosis factor alpha;TTC=2,3,5-triphenyltetrazolium-chloride;WT=wild-type;pMCAO=permanent middle cerebral artery occlusion;pro-Caspase-1=precursor Caspase-1;qPCR=quantitative real-time PCR;tMCAO=transient middle cerebral artery occlusion;tPA=tissue plasminogen activator
摘要：
Chemokine-like factor 1 (CKLF1) is a potential target for ischemic stroke therapy. The NOD-like receptor protein 3 (NLRP3) inflammasome has been postulated to mediate inflammatory responses during ischemic/reperfusion (I/R) injury. The compound IMM-H004 is a novel coumarin derivative that can improve cerebral I/R injury. This study aims to investigate the effects of IMM-H004 on ischemia stroke injury and further elucidate the molecular mechanisms. The standard pMCAO model of focal ischemia was used in this paper. Drugs were administered at 6 hours after ischemia, and behavioral assessment, euthanasia, and outcome measures were evaluated at 9 hours after ischemia. The effects of IMM-H004 on ischemic stroke injury were determined using 2,3,5-triphenyltetrazolium chloride (TTC) staining, behavioral tests, enzyme-linked immunosorbent assay (ELISA), and Nissl staining. Immunohistologic staining, immunofluorescence staining, quantitative RT-PCR (qPCR), western blotting, and coimmunoprecipitation (CO-IP) assays were used to elucidate the underlying mechanisms. IMM-H004 treatment provided significant protection against ischemia stroke through a CKLF1-dependent anti-inflammatory pathway in rats. IMM-H004 downregulated the amount of CKLF1 binding with C-C chemokine receptor type 4, further suppressing the activation of NLRP3 inflammasome and the following inflammatory response, ultimately protecting the ischemic brain. This preclinical study established the efficacy of IMM-H004 as a potential therapeutic medicine for permanent cerebral ischemia. These results support further efforts to develop IMM-H004 for human clinical trials in acute cerebral ischemia, particularly for patients who are not suitable for reperfusion therapy.
摘要：
Fractalkine (CX3C chemokine ligand 1, CX3CL1) is an essential chemokine, for regulating adhesion and chemotaxis through binding to CX3CR1, which plays a critical role in the crosstalk between glial cells and neurons by direct or indirect ways in the central nervous system (CNS). Fractalkine/CX3CR1 axis regulates microglial activation and function, neuronal survival and synaptic function by controlling the release of inflammatory cytokines and synaptic plasticity in the course of the neurological disease. The multiple functions of fractalkine/CX3CR1 make it exert neuroprotective or neurotoxic effects, which determines the pathogenesis. However, the role of fractalkine/CX3CR1 in the CNS remains controversial. Whether it can be used as a therapeutic target for neurological diseases needs to be further investigated. In this review, we summarize the studies highlighting fractalkine/CX3CR1-mediated effects and discuss the potential neurotoxic and neuroprotective actions of fractalkine/CX3CR1 in brain injury for providing useful insights into the potential applications of fractalkine/CX3CR1 in neurological diseases.
作者机构：
[Wang, Shuo; Shao, Qian-hang; Chen, Ying; Chen, Nai-hong; Zhang, Xiao-ling; Yuan, Yu-he; Li, Fang-fang; Chen, NH] Chinese Acad Med Sci & Peking Union Med Coll, State Key Lab Bioact Subst & Funct Nat Med, Inst Mat Med, Beijing 100050, Peoples R China.;[Wang, Shuo; Shao, Qian-hang; Chen, Ying; Chen, Nai-hong; Zhang, Xiao-ling; Yuan, Yu-he; Li, Fang-fang; Chen, NH] Chinese Acad Med Sci & Peking Union Med Coll, Neurosci Ctr, Beijing 100050, Peoples R China.;[Chen, Nai-hong] Hunan Univ Chinese Med, Coll Pharm, Changsha 410208, Hunan, Peoples R China.
通讯机构：
[Yuan, YH; Chen, NH] C;[Chen, Nai-hong] H;Chinese Acad Med Sci & Peking Union Med Coll, State Key Lab Bioact Subst & Funct Nat Med, Inst Mat Med, Beijing 100050, Peoples R China.;Chinese Acad Med Sci & Peking Union Med Coll, Neurosci Ctr, Beijing 100050, Peoples R China.;Hunan Univ Chinese Med, Coll Pharm, Changsha 410208, Hunan, Peoples R China.
作者机构：
[Yan, Wen-Fen; Shao, Qian-Hang; Peng, Shan-Ying; Cao, Ying-Li; Chen, Nai-Hong; Yuan, Yu-He; Zhang, Zhao] Chinese Acad Med Sci, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China.;[Yan, Wen-Fen; Shao, Qian-Hang; Peng, Shan-Ying; Cao, Ying-Li; Chen, Nai-Hong; Yuan, Yu-He; Zhang, Zhao] Chinese Acad Med Sci, Neurosci Ctr, Beijing 100050, Peoples R China.;[Yan, Wen-Fen; Shao, Qian-Hang; Peng, Shan-Ying; Cao, Ying-Li; Chen, Nai-Hong; Yuan, Yu-He; Zhang, Zhao; Chen, NH] Peking Union Med Coll, 1 Xiannongtan St, Beijing 100050, Peoples R China.;[Chen, Nai-Hong] Hunan Univ Chinese Med, Coll Pharm, Changsha 410208, Hunan, Peoples R China.;[Ma, Kai-Li] Chinese Acad Med Sci, Inst Med Biol, Kunming 650118, Yunnan, Peoples R China.
通讯机构：
[Yuan, YH; Chen, NH] P;[Yuan, YH; Chen, NH] C;Peking Union Med Coll, 1 Xiannongtan St, Beijing 100050, Peoples R China.;Chinese Acad Med Sci, Inst Mat Med, Dept Pharmacol, 1 Xiannongtan St, Beijing 100050, Peoples R China.
关键词：
Nurr1;alpha-Synuclein;Neuroinflammation;Toll-like receptor 4;Nuclear factor kappa B
摘要：
Parkinson's disease (PD) is a multi-factorial neurodegenerative disease. Abnormal alpha-synuclein protein aggregate and sustained microglia activation contribute to the pathogenic processes of PD. However, the relationship between alpha-synuclein and microglia-mediated neuroinflammation remains unclear. We purified alpha-synuclein after overexpression in Escherichia coli and then used it to stimulate BV-2 cells or primary microglia cells from wild type or toll-like receptor 4 (TLR4)-defective mice. Enzyme linked immunosorbent assay (ELISA) and real-time PCR results confirmed that alpha-synuclein could enhance the production of tumor necrosis factor alpha (TNF-alpha) through TLR4 activation. Western blotting results confirmed the involvement of the TLR4/PI3K/AKT/GSK3 beta signal pathway in the inflammatory response. Nuclear factor kappa B (NF-kappa B) could translocate to the nucleus, promoting the expression of TNF-alpha when stimulated by alpha-synuclein in BV-2 cells. Nurr1 suppressed the production of TNF-alpha via interaction with NF-kappa B/p65 and inhibiting its nuclear translocation. In addition, both NF-kappa B and Nurr1 appeared to be regulated by the TLR4-mediated signal pathway. Our work demonstrated that TLR4 recognized alpha-synuclein and activated downstream signaling mechanisms leading to the release of pro-inflammatory mediators that are contra-balanced by Nurr1 expression. In conclusion, Nurr1 is a novel participant in the neuroinflammation stimulated by alpha-synuclein, thus the regulation of Nurr1 may be a novel neuroprotective target for PD treatment. (C) 2018 Elsevier Ltd. All rights reserved.
作者机构：
[Wang, Yingying; Chen, Naihong; Song, Xiuyun] Chinese Acad Med Sci & Peking Union Med Coll, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China.;[Wang, Yingying; Chen, Naihong; Song, Xiuyun] Chinese Acad Med Sci & Peking Union Med Coll, Neurosci Ctr, Beijing 100050, Peoples R China.;[Wang, Yingying; Wang, Qi] Guangzhou Univ Chinese Med, Inst Clin Pharmacol, 12 Airport Rd, Guangzhou 510405, Guangdong, Peoples R China.;[Lou, Yu-Xia; Liu, Dandan] Tianjin Univ Tradit Chinese Med, Tianjin 300193, Peoples R China.;[Chen, Naihong; Luo, Piao; Zhu, Tianbi] Hunan Univ Chinese Med, Changsha 410208, Hunan, Peoples R China.
通讯机构：
[Wang, Qi] G;[Chen, Naihong] C;Guangzhou Univ Chinese Med, Inst Clin Pharmacol, 12 Airport Rd, Guangzhou 510405, Guangdong, Peoples R China.;Chinese Acad Med Sci & Peking Union Med Coll, Inst Mat Med, Xiannongtan St, Beijing 100050, Peoples R China.
关键词：
*Alzheimer's disease;*IMM-H004;*Neuroprotection;*Okadaic acid;*Tau protein
摘要：
This study aimed to explore effects and mechanisms of 004 (IMM-H004), a novel coumarin derivative, in OKA (okadaic acid)-induced AD (Alzheimer's disease)-like model. In vitro, MTT, LDH, and Annexin V/FITC flow cytometry assay were used to test cell survival. In vivo, OKA microinjection was conducted to simulate AD-like neuropathology. Morris water maze and Nissl staining were used to detect spatial memory function and neuronal damage respectively. Western blot and immunohistochemistry were used to study the mechanisms of 004 in Tau pathology. The results showed that 004 reduced cell death and increased survival in PC12 cells, and decreased neuronal injury in the hippocampus in rats. 004 improved learning and memory functions in OKA-treated rats. The mechanistic studies indicated that 004 inhibited phosphorylation of Tau protein by down-regulating the activity of protein kinases CDK5 and GSK3beta and increasing PP2A activity. Overall, 004 improved spatial memory impairments and neuron cells injury induced by OKA; on the other hand, 004 inhibited Tau hyperphosphorylation by regulating CDK5, GSK3beta and PP2A.
