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Establishment of pseudovirus infection mouse models for in vivo pharmacodynamics evaluation of filovirus entry inhibitors

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Acta Pharmaceutica Sinica B 2018年第2期8卷 200-208页

作者： Qing Chen Ke Tang Xiaoyu Zhang Panpan Chen Ying Guo State Key Laboratory of Bioactive Substances and Function of Natural Medicines Department of Pharmacology Institute of Materia Medica Chinese Academy of Medical Sciences Peking Union Medical College

Filoviruses cause severe and fatal viral hemorrhagic fever in humans. Filovirus research has been extensive since the 2014 Ebola outbreak. Due to their high pathogenicity and mortality, live filoviruses require Biosafety Level-4(BSL-4) facilities, which have restricted the development of anti-filovirus vaccines and *** HIV-based pseudovirus cell infection assay is widely used for viral entry studies in BSL-2 conditions. Here,we successfully constructed nine in vitro pseudo-filovirus models covering all filovirus genera and three in vivo pseudo-filovirus-infection mouse models using Ebola virus, Marburg virus, and Lloviu virus as representative viruses. The pseudo-filovirus-infected mice showed visualizing bioluminescence in a dose-dependent manner. A bioluminescence peak in mice was reached on day 5 post-infection for Ebola virus and Marburg virus and on day4 post-infection for Lloviu virus. Two known filovirus entry inhibitors, clomiphene and toremiphene, were used to validate the model. Collectively, our study shows that all genera of filoviruses can be well-pseudotyped and are infectious in vitro. The pseudo-filovirus-infection mouse models can be used for in vivo activity evaluation of anti-filovirus drugs. This sequential in vitro and in vivo evaluation system of filovirus entry inhibitors provides a secure and efficient platform for screening and assessing anti-filovirus agents in BSL-2 facilities.

关键词： Filovirus Ebola Marburg Pseudovirus Entry inhibitor Mouse model

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Pharmacological effects of ginsenoside Rg1 in neuropsychopharmacology

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中国药理学与毒理学杂志 2019年第9期33卷 685-686页

作者： GAO Yan CHU Shi-feng ZHANG Zhao ZHANG Lan CHEN Nai-hong State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaNeuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Department of Pharmacy Xuanwu Hospital of Capital Medical UniversityBeijing 100053China Hunan University of Chinese Medicine Changsha 410208China

Panax Ginseng has been used for thousands of years in traditional Chinese medicine(TCM)as a tonic to improver stamina and *** Rg1(Rg1),a saponin extracted from Panax ginseng,is considered one of the most potent pharmacological candidates among *** various diseases related to nervous system,Rg1 has shown excellent pharmacological activities.①Stroke:Rg1 has been well documented to be effective against ischemic/reperfusion(I/R)neuronal injury.A systematic review and meta-analysis revealed a marked efficacy of Rg1 in experi⁃mental acute ischemic stroke,as manifested by its ability to reduce infract volume and improve neurological *** protective effects of Rg1 were abolished by injecting of AAV-HIF-miR-144-shRNA into the predicted ischemic penumbra.②Depression:In addition,Rg1 showed antidepressive effects in chronic unpredictable mild stress(CUMS)model of depression and in gonadectomized(GDX)model of neuroendocrine ***1 displayed antidepressant activity through the modulation of HPA and HPG axis,markedly alleviated depression-like behavior in ***-term Rg1 treat⁃ment of CUS-exposed rats also significantly prevented the decrease in dye diffusion and improved the ultrastructure of astrocyte gap junctions in the ***1 upregulated Cx43 expression in PFC reduced by CUS exposure,indicating beneficial effects on the functional activity of gap junction channels in the brain.③Parkinson disease(PD):Oral treatment with Rg1 significantly attenuated high MPTP-induced mortality,behavior defects,loss of dopamine neurons and abnormal unltrastructure changes in *** regulated MPTP-induced reactive astrocytes and microglia and decreased the release of cytokines such as TNF-alpha and IL-1βin ***1 also alleviated the unusual MPTP-induced increase in oligomeric,phosphorylated and disease-relatedα-synuclein in SNpc.④Alzheimer disease(AD):Okadaic acid(OKA)intracerebroventricular injection induced memory impairment,including changes in the abil

关键词： ginsenoside Rg1 neuropsychopharmacology multiple targets

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functions of connexin-43 in neural development and its relationship with neural diseases

Functions of connexin-43 in neural development and its relat...

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中国药理学会第十五次全国学术大会

作者： YANG Xiong CHU Shi-feng CHEN Nai-hong 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

Connexin43(Cx43) is a kind of gap junction protein, which not only is expressed in astrocytes,but also in excitatory neurons of development stage. As we know, neurons and glial cells are vital parts in the brain, making contribution to function wel of central nervous system. Dysplastic astrocytes and neurons give rise to the occurrence of almost all neural diseases. Accruing evidence has indicated that Cx43 plays crucial roles in synaptic formation and transmission by the function and development of hemichannels in astrocytes. However,the exact roles of Cx43 in excitatory neurons of developmental stage and neural diseases are not very clear. In this review, we first describe the expression pattern of Cx43 in developmental central nervous system. Then,we address the roles of Cx43 in astrocytes. Further, the function of Cx43 in excitatory neurons are ***, we summarize the dominating mechanisms of Cx43 involved in the onset and progress of neural diseases,especially neurodegenerative disease. Clearly, the investigations on the functions of Cx43 in the progress of neural diseases will benefit not only the new understanding of pathogenesis, but also potential therapeutic targets to ameliorate the states of related neural diseases.

关键词： Cx43 excitatory neurons central nervous system neural diseases

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Corrigendum to "Impact of Codonopsis decoction on cerebral blood flow and cognitive function in rats with chronic cerebral ischemia" [J. Ethnopharmacol. 323 (2024) 117585]

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Journal of ethnopharmacology 2024年 335卷 118682页

作者： Jie Wang Qinqing Li Shifeng Chu Xin Liu Junlong Zhang Wenbin He Shanxi Key Laboratory of Chinese Medicine Encephalopathy Shanxi University of Chinese Medicine Jinzhong 030619 Shanxi China College of Traditional Chinese Medicine Shandong University of Traditional Chinese Medicine Jinan 250000 Shandong China. Shanxi Key Laboratory of Chinese Medicine Encephalopathy Shanxi University of Chinese Medicine Jinzhong 030619 Shanxi China. 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 Traditional Chinese Medicine Shandong University of Traditional Chinese Medicine Jinan 250000 Shandong China. Electronic address: zhangjl@***.

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Roles of calretinin interneurons in APP / PS1 mouse model

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中国药理学与毒理学杂志 2018年第9期32卷 695-696页

作者： YANG Xiong CHU Shi-feng CHEN Nai-hong 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

OBJECTIVE To explore the changes of calretinin interneurons in APP/PS1 mouse model and their correlation with the pathological features of Alzheimer *** The morphological differences between the brain regions of control and transgenic(TG) mice were detected by Nissl *** immunofluorescence histochemistry and western blotting,the expression of related proteins was detected,including GAD65/67,calretinin and Aβ*** the same time,in terms of behavioral experiments,the motor ability,the level of fear and cognitive level of control and transgenic mice were tested through open-field test,elevated plus maze and novel object recognition(NOR) *** According to Nissl staining results,compared with the control group,the number of cells in glomerular layer(GL) and granule cell layer(GCL) of olfactory bulb in the TG group was significantly ***,in the hippocampus,compared with the control group,the ventral CA1 and CA3 is dysplastic in APP/PS1 ***,the morphology of subgranular zone(SGZ) layer cells in the dorsal DG significantly changed and the number of cells in hilar regions significantly decreased in the TG *** brain regions associated with cognition,including the piriform cortex,entorhinal cortex and the prefrontal cortex,showed no significant changes between the control and TG *** Western blotting experiment,compared with the control mice,it was found that the expression of GAD65/67 and calretinin in the olfactory bulb and hippocampus was significantly decreased in the TG *** detail,the level of the protein in the relevant brain regions was detected by immunofluorescence histochemistry(IHC).The expression of calretinin in GL of the olfactory bulb and the hippocampal DG region was significantly decreased,which was correlated with the distribution of Aβ1-42 by *** the part of functional behavioral experiment,compared with the control mice,the total distance of movement in 6 M TG group mice was sign

关键词： calretinin interneuron olfactory bulb hippocampus Alzheimer disease

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Anti-diabetes effects and mechanisms of a Chinese herbal medicine preparation JQ-R in diabetic KKAy mice and in vitro

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中国药理学与毒理学杂志 2018年第4期32卷 294-295页

作者： Shuai-nan LIU Quan LIU Zhu-fang SHEN Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Key laboratory of Polymorphic Drugs of Beijing Diabetes Research Center of

OBJECTIVE To investigate the effects and mechanisms by which JQ-R regulated the glucose metabolism and improves insulin sensitivity in diabetic KKAy mice and insulin-resistant L6 ***-R is a mixture of refined extracts from Coptis chinensis,Astragalus membranaceus and Lonicera japonica,three major herbs of JinQi-JiangTang *** Diabetic KKAy mice were *** JQ-R(100 mg·kg^(-1) or 200 mg·kg^(-1) BW) for 10 *** of fasting plasma glucose,lipids,insulin and hemoglobin A1c were *** insulin sensitivity was quantified using the *** *** effect of JQ-R on the expressions of the enzymes involved in insulin signaling,oxidative stress and inflammation(Akt,NFκB,IΚBα,JNK,Erk,p38 MAPK) were measured in L6 *** *** JQ-R showed beneficial effects on glucose homeostasis and insulin *** in diabetic KKAy mice after 10 weeks ***-R also ameliorated the plasma lipid ***,JQ-R can directly reverse the decreased activity of SOD and increased MDA levels as well as activity of iNOS in insulin resistant L6 cell induced with palmitic acid(PA).The expressions of *** of NF-κB p65,IκBα,JNK1/2 and Erk1/2 were also decreased after JQ-R *** was also shown that the insulin-stimulated glucose uptake increased significantly after JQ-R treatment,with upregulated expression of phosphorylation of *** JQ-R ameliorated the glucose and lipid metabolism and insulin sensitivity in diabetic KKAy *** vitro treatment with JQ-R directly enhanced insulin stimulated glucose uptake in insulin resistant myotubes with improved insulin *** and inflammatory response and oxidative stress state.

关键词：糖尿病胰岛素治疗方法临床分析

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Ursodeoxycholic acid protects interstitial Cajal-like cells in the gallbladder from undergoing apoptosis by inhibiting TNF-a expression

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中国药理学报（英文版） 2018年第9期39卷 1493-1500页

作者： Jiang-fan WAN Shi-feng CHU Xin ZHOU Yue-ting LI Wen-bin HE Feng TAN Piao LUO Qi-di Al Qi WANG Nai-hong CHEN Institute of Clinical Pharmacology Guangzhou University of Chinese Medicine Guangzhou 510080China 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 100050China 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 100050China Beijing Hospital of Integrated Traditional and Western Medicine Beijing 100039 China Institute of Clinical Pharmacology Guangzhou University of Chinese Medicine Guangzhou 510080China 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 100050China College of Pharmacy Hunan University of Chinese Medicine Changsha 410208China Institute of Clinical Pharmacology Guangzhou University of Chinese Medicine Guangzhou 510080China 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 100050China College of Pharmacy Hunan University of Chinese Medicine Changsha 410208China

Hypomotility is a common symptom of gallstone disease, which is accompanied by a loss of interstitial Cajal-like cells (ICLCs) in the gallbladder. Ursodeoxycholic acid (UDCA) is widely used in treating gallstone disease, and has shown anti-apoptotic and antiinflammatory effects apart from its ability to dissolve gallstones. In this study, we investigated the anti-apoptotic and anti-inflammatory effects of UDCA on ICLCs in guinea pigs with gallstones. Guinea pigs were fed a high-cholesterol diet for 8 weeks to induce the formation of gallstones. A group of animals was administered UDCA (50 mg·kg-1·d-11, ig) simultaneously. At the end of 8 weeks,the animals were euthanized with anesthesia, cholecystectomy was performed immediately and gallbladder was collected for further analysis. We showed that in the model group the contractility of gallbladder muscle strips in response to both acetylcholine (ACh) and CCK-8 was severely impaired, which was significantly improved by UDCA administration. Furthermore, UDCA administration significantly reduced the apoptotic ratio of ICLCs, based on the observation of co-localization imaging of apoptotic cells and c-kit-positive cells. Western blotting analysis and real-time PCR results revealed that the TNF-a/Caspase8/Caspase3 pathway was suppressed in the UDCA-treated animals, confirming the anti-apoptotic effect of UDCA in the gallbladder. The H&E staining showed that UDCA administration significantly attenuated inflammatory cell infiltration in the gallbladder wall. In conclusion, UDCA can protect ICLCs in the gallbladder from undergoing apoptosis by inhibiting the TNF-a/Caspase8/caspase3 pathway.

关键词： ursodeoxycholic acid gallstones interstitial Cajal-like cells

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1,25-Dihydroxyvitamin D3 protects obese rats from metabolic syndrome via promoting regulatory T cell-mediated resolution of inflammation

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Acta Pharmaceutica Sinica B 2018年第2期8卷 178-187页

作者： Wen Jin Bing Cui Pingping Li Fang Hua Xiaoxi Lv Jichao Zhou Zhuowei Hu Xiaowei Zhang Institute of Medicinal Plant Development Chinese Academy of Medical Sciences & Peking Union Medical College Molecular Immunology and Pharmacology Group State Key Laboratory of Bioactive Substances and Functions of Natural MedicinesInstitute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical College

Vitamin D_3 has been found to produce therapeutic effects on obesity-associated insulin resistance and dyslipidemia through its potent anti-inflammatory activity, but the precise immunomodulatory mechanism remains poorly understood. In the present study we found that 1,25-dihydroxyvitamin D_3[1,25(OH)_2D_3], the biologically active form of vitamin D_3, significantly attenuated monosodium glutamate(MSG)-induced obesity and insulin resistance as indicated by body weight reduction, oral glucose tolerance improvement, and a glucose infusion rate increase as detected with hyperinsulinemiceuglycemic clamp. Moreover, 1,25(OH)_2D_3 not only restored pancreatic islet functions but also improved lipid metabolism in insulin-targeted tissues. The protective effects of 1,25(OH)_2D_3 on glycolipid metabolism were attributed to its ability to inhibit an obesity-activated inflammatory response in insulin secretory and targeted tissues, as indicated by reduced infiltration of macrophages in pancreas islets and adipose tissue while enhancing the expression of Tgf-β1 in liver tissue, which was accompanied byincreased infiltration of Treg cells in immune organs such as spleen and lymph node as well as in insulintargeted tissues such as liver, adipose, and muscle. Together, our findings suggest that 1,25(OH)_2D_3 serves as a beneficial immunomodulator for the prevention and treatment of obesity or metabolic syndrome through its anti-inflammatory effects.

关键词： Insulin resistance Dyslipidemia MSG-obese rat Treg cell Vitamin D3 1,25-Dihydroxyvitamin D3

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A potential strategy for treating atherosclerosis: improving endothelial function via AMP-activated protein kinase

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中国科学（生命科学） 2018年第9期61卷 1024-1029页

作者： Feng Gao Jiemei Chen Haibo Zhu State Key Laboratory for Bioactive Substances and Functions of Natural Medicines Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study Institute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing 100050 China

Endothelial dysfunction is caused by many factors,such as dyslipidemia,endoplasmic reticulum (ER) stress,and *** has been demonstrated that endothelial dysfunction is the initial process of ***-activated protein kinase (AMPK) is an important metabolic switch that plays a crucial role in lipid metabolism and ***,recent evidence indicates that AMPK could be a target for atherosclerosis by improving endothelial *** instance,activation of AMPK inhibits the production of reactive oxygen species induced by mitochondrial dysfunction,ER stress,and NADPH ***,activation of AMPK inhibits the production of pro-inflammatory factors induced by dyslipidemia and hyperglycemia and restrains production of perivascular adipose tissue-released *** activation prevents endothelial dysfunction by increasing the bioavailability of nitric ***,we focused on the primary risk factors involved in endothelial dysfunction,and summarize the features of AMPK in the protection of endothelial function,by providing signaling pathways thought to be important in the pathological progress of risk factors.

关键词： atherosclerosis AMP-activated protein kinase cardiovascular diseases inflammation autophagy

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The regulation effect of AMPK in immune related diseases

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Science China(Life Sciences) 2018年第5期61卷 523-533页

作者： Jing Wang Zhenyu Li Li Gao Yanshuang Qi Haibo Zhu Xuemei Qin Modern Research Center for Traditional Chinese Medicine Shanxi University Taiyuan 030006 China State Key Laboratory for Bioactive Substances and Functions of Natural Medicines，Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study，Institute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050 China

AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that plays a key role in energetic metabolism *** changes in immune cells, such as dendritic cell (DC), macrophages, neutrophils and lymphocytes that participate in the signal directed programs that promote or inhibit immune mediated diseases, including cancer, atherosclerosis and inflammatory diseases. Multiple pathogenic mechanisms are involved in the initiation and progression of disease, and many pathways have been uncovered. The mechanistic overlap in the metabolic changes and inflammation could indicate that some of the targets they have are in common, whereas AMPK could be useful in treatment of both disorders. The insight into identification of AMPK responsible for specific immune regulation, anti-inflammatory actions and understanding of the underlying molecular mechanism will promote the generation of novel AMPK activators, and provide novel therapy strategy.

关键词： AMPK metabolic changes immune cells atherosclerosis cancer inflammation

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