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基于六味地黄丸新配方的LW-AFC对认知缺陷、突触可塑性损伤和神经免疫调节病变APP/PS1和SAMP8小鼠的作用(英文)

中国药理学与毒理学杂志 2015年第S1期29卷 8-9页

作者：周文霞王健辉程斌黄晏程肖蕊张永祥 State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology Beijing 100850 China

OBJECTIVE To investigate the effect of LW-AFC,a new formula of the main active components extracted from Liuwei Dihuang decoction,on treatment of Alzheimer′s disease in mouse models.METHODS The APP/PS1 transgenic mice and senescence-accelerated mouse prone 8(SAMP8)were administered orally by LW-AFC continuously for 3 months.The behavioral tests were conducted by the novel object recognition(recognition memory task),the Morris water maze(spatial memory test),the shuttle box and step-down tests(active and passive avoidance,associative learning task).The synaptic plasticity was evaluated by long-term potentiation(LTP)experiment in anesthetized mice.The cytokine profiles in serum were assayed by multiplex Luminex assay methods.The hormone levels associated with hypothalamo-pituitary-adrenal(HPA)and hypothalamo-pituitary-gonad(HPG)were measured by radioimmunoassay.The levels of Aβ1-40 and Aβ1-42 were assayed by AlphaLISA technique.RESULTS The administration of LW-AFC significantly improved the behavioral performances in novel object recognition tasks,spatial memory tasks,and associative learning tasks both in APP/PS1 transgenic mice and SAMP8 mice,and the inductions of LTP were also significantly facilitated.Meanwhile,the concentrations of Aβ1-40 and Aβ1-42 in cerebral cortex,hippocampus and serum were decreased in LW-AFC treated groups.The serum concentration of some proinflammatory cytokines,such as IL-1β,IL-2,IL-6,IL-17,IL-23,INF-γ,TNF-α,TNF-β,MCP-1 and MIP-1β were significantly decreased,while the anti-inflammatory cytokines,such as IL-4,IL-10,IL-5 and G-CSF were significantly increased.In addition,LW-AFC could also improved the abnormalities of the corticotropin releasing hormone(CRH)and gonadotropin-releasing hormone(GnRH)levels in hypothalamus,the adrenocorticotropic hormone(ACTH),luteinizing hormone(LH)and follicle stimulating hormone(FSH)levels in pituitary,the corticosterone and testosterone level in serum,respectively.CONCLUSION LW-AFC improves cognitive deficits and synaptic plasticity impairments in AD mo

关键词： LW-AFC Alzheimer′s disease cogonitive behavior lon

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Active fraction combination from Liuwei Dihuang decoction(LW-AFC)ameliorates corticosterone-induced long-term potentiation impairment in mice in vivo

Active fraction combination from Liuwei Dihuang decoction(LW...

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2019全国老年痴呆与认知障碍相关疾病学术大会

作者： HUANG Yan LI Dong CHENG Bin LIU Gang ZHANG Yong-xiang ZHOU Wen-xia Beijing Institute of Pharmacology and toxicology State Key Laboratory of Toxicology and Medical Countermeasures

Liuwei Dihuang decoction(LW),a classic formula in traditional Chinese medicine(TCM),has been used for nearly one thousand years for various diseases with characteristic features of kidney yin deficiency.LW consists of 6 herbs including Dihuang [prepared root of Rehmannia glutinosa(Gaertn) DC],Shanyao(rhizome of Dioscorea polystachya Turcz),Shanzhuyu(fruit of Cornus officinalis Siebold Zucc),Mudanpi(root bark of Paeonia × suffruticosa Andrews),Zexie(rhizome of Alisma plantago-aquatica L) and Fuling [scleorotia of Wolfiporia extensa(Peck) Ginns].LW-active fraction combination(LW-AFC) is extracted from LW,it is effective for the treatment of kidney yin deficiency in many animal models.There are 3 fractions in LW-AFC,a polysaccharide fraction(LWB-B),a glycoside fraction(LWD-b) and an oligosaccharide fraction(CA-30).Our previous results indicate that LW-AFC has similar pharmacological effects to LW,modulating the balance of the NIM network.LW-AFC has positive effects in many animal models of kidney deficiency or disturbance of the NIM network.LW-AFC could improve the cognitive ability in Alzheimer’s disease(AD) animal models(APP/PS1,SAMP8),where modulating immune function and balancing the NIM network may play an important role in its cognition improving effects.Our study also showed that LW-AFC had protective effects on stress-induced disturbances of the NIM network.However,the underlying mechanisms remain elusive and need further investigation.OBJECTIVE This study evaluated the effects of LW-AFC and the active fractions(polysaccharide,LWB-B;glycoside,LWD-b;oligosaccharide,CA-30) on corticosterone(Cort)-induced long-term potentiation(LTP) impairment in vivo.METHODS LTP was used to evaluate the synaptic plasticity.LW-AFC was orally administered for seven days.The active fractions were given by either chronic administration(ig,ip,7 d) or single administration(icv,ig,ip).Cort was injected subcutaneously 1 h before the high-frequency stimulation(HFS) to induce LTP impairment.Moreover,in order to research on the possible

关键词： LW-active fraction combination active fractions corticosterone long-term potentiation synaptic plasticity stress

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Construction of NIM sub-network regulated by Liuwei Dihuang decoction and its characteristics

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中国药理学与毒理学杂志 2018年第4期32卷 306-307页

作者： Tong-xing WANG Lu HAN Xiao-rui CHENG Wen-xia ZHOU Yong-xiang ZHANG Beijing Institute of Pharmacology and toxicology Beijing 100850 China The State Key Laboratory of Toxicology and Medical Countermeasures Beijing 100850 China

OBJECTIVE To construct the neuroendocrine immunomodulation(NIM) sub-network regulated by Liuwei Dihuang decoction(LW) and analyze its characteristics.METHODS We took the GSE57273 in GEO database and screened the differentially expressed genes(DEGs)(P10).Among them,there were 19 NIM signaling molecules in which only ESR1 changed significantly and 3 non-DEGs(NFATC2,RARA,TP53).However,the down.stream of the hub nodes were significantly changes.CONCLUSION The results suggested that LW might mainly regulate the non-hub nodes to recovery of the network imbalance of the body in the state of disease.

关键词：六味地黄汤神经内分泌治疗方法临床分析

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Antibacterial and angiogenic chitosan microneedle array patch for promoting wound healing

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Bioactive Materials 2020年第2期5卷 253-259页

作者： Junjie Chi Xiaoxuan Zhang Canwen Chen Changmin Shao Yuanjin Zhao Yongan Wang Department of Clinical laboratory The Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing210008China State Key Laboratory of Toxicology and Medical Countermeasures Institute of Pharmacology and ToxicologyAcademy of Military Medical SciencesBeijing100850China state key laboratory of Bioelectronics School of Biological Science and Medical EngineeringSoutheast UniversityNanjing210096China

A patch with the capability of avoiding wound infection and promoting tissue remolding is of great value for wound healing.In this paper,we develop a biomass chitosan microneedle array(CSMNA)patch integrated with smart responsive drug delivery for promoting wound healing.Chitosan possesses many outstanding features such as the natural antibacterial property and has been widely utilized for wound healing.Besides,the microstructure of microneedles enables the effective delivery of loaded drugs into the target area and avoids the excessive adhesion between the skin and the patch.Also,vascular endothelial growth factor(VEGF)is encapsulated in the micropores of CSMNA by temperature sensitive hydrogel.Therefore,the smart release of the drugs can be controllably realized via the temperature rising induced by the inflammation response at the site of wounds.It is demonstrated that the biomass CSMNA patch can promote inflammatory inhibition,collagen deposition,angiogenesis,and tissue regeneration during the wound closure.Thus,this versatile CSMNA patch is potentially valuable for wound healing in clinical applications.

关键词： Microneedle Chitosan Drug delivery Wound healing Patch

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CA-30,An Oligosaccharide Fraction Derived from Liuwei Dihuang Decoction,Ameliorates Cognitive Deterioration Via the Intestinal Microbiome in the Senescence-Accelerated Mouse Prone 8 Strain

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神经药理学报 2019年第Z1期 82-83页

作者： ZHOU Wen-xia WANG Jian-hui LEI Xi ZHANG Xiao-rui CHENG Xiao-rui ZHANG Yong-xiang Beijing Institute of Pharmacology and toxicology State Key Laboratory of Toxicology and Medical Countermeasures

Alzheimer’s Disease（AD） is a progressive complex neurodegenerative disorder with an unknown etiopathogenesis. Mounting evidence points to alterations in the gut microbiotaneuroendocrine immunomodulation（NIM） network that might drive AD pathology and contribute to its exacerbation. In previous studies,we found that Liuwei Dihuang decoction（LW） and its active fractions had beneficial effects on the cognitive impairments and gastrointestinal microbiota dysbiosis in an AD mouse model. In particular,CA-30 is an oligosaccharide fraction derived from LW. We sought to determine the effects of CA-30 on the composition and function of the intestinal microbiome in the senescence-accelerated mouse prone 8（SAMP8） mouse strain,an AD mouse model. Treatment with CA-30 decreased the degree of senescence;increased nest building and locomotor activity;ameliorated impairments in object recognition,spatial learning,and memory;and decreased the active avoidance response in SAMP8 mice. Moreover,CA-30 ameliorated abnormal cytokine and hormone secretion and lymphocyte subset dysregulation in SAMP8 mice. In addition,we found that CA-30 mainly altered the abundance of 4 genera in the SAMR1 and CA-30 groups（Thermomonas,Paramesorhizobium,Alicycliphilus,and Candidatus;idichloria） and 10 newborn genera in the CA-30 group alone（Xylophilus,Serpens,Hathewaya,Tanticharoenia,Wigglesworthia,et al.）. Advantageous changes in carbohydrate-active enzymes of SAMP8 mice following CA-30 treatment,especially GH85,were also noted. We further found that 7 genera（Ruminococcus,Acidiphilium,Bacteroides,Prevotella,et al.） were significantly correlated with the NIM network and cognitive performance. CA-30 influenced the relative abundance of these intestinal microbiomes in SAMP8 mice and restored them to SAMR1 mouse levels. CA-30 ameliorated the intestinal microbiome,rebalanced the NIM network,improved the AD-like cognitive impairments in SAMP8 mice,and can thus be a potential therapeutic agent for AD.

关键词： Alzheimer’s disease CA-30 oligosaccharide SAMP8 intestinal microbiome cognition neuroendocrine immunomodulation

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Using distinguishable dissolution curve to select the optimal preparation technique of generic riociguat tablets

Using distinguishable dissolution curve to select the optima...

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2018年第十二届中国药物制剂大会

作者：张雨 Qidong Hu Jiang Li Xueying Huang Jing Gao Aiping Zheng State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology

＜正＞Objective:Riociguat is a soluble guanosine cyclase（sGC）agonist to treat pulmonary arterial hypertension（PAH）clinically.It’s an insoluble BCSII Drug.In this study,we constructed four dissolution curves in different mediums and select a critical dissolution condition to find the optimal preparation technique of riociguat generic tablets.

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Modulating balance of synaptic and extrasynaptic NMDA receptors as strategy for Alzheimer disease drug discovery

Modulating balance of synaptic and extrasynaptic NMDA recept...

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2019全国老年痴呆与认知障碍相关疾病学术大会

作者： ZHOU Wen-xia Beijing Institute of Pharmacology and toxicology State Key Laboratory of Toxicology and Medical Countermeasures

The unbalance between synaptic(GluN2 A,mediating the protective pathway) and extrasynaptic NMDA receptors(NMDARs)(GluN2 B,mediating the excitotoxic pathway) has been found in Alzheimer disease(AD),indicating restoring the balance of GluN2 A and GluN2 B should be beneficial for AD therapy.In this study,the GluN2 B-selective antagonist,ifenprodil,and the non-selective NMDAR agonist,NMDA,had little effects on amyloid-beta(Abeta)-induced long-term potentiation(LTP) deficits.Enhancing the activity of GluN2 A had a protective effect against Abeta,and specific activation of GluN2 A and inhibition of GluN2 B showed a better protective effect.The combination of ifenprodil and D-cycloserine(a co-activator of NMDRs similar to D-serine) led to greater improvement in behavior tests than ifenprodil or D-cycloserine alone,meanwhile,the combination of ifenprodil and D-cycloserine reversed the signal pathway more significantly than ifenprodil or D-cycloserine alone.These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed protective effects against Abeta-induced neurotoxicity,suggesting that modulation of the balance between GluN2 A and GluN2 B might be a good strategy for drug discovery against AD.

关键词： Alzheimer disease GluN2A GluN2B ifenprodil D-cycloserine drug discovery

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LW-AFC,a new formula derived from Liuwei Dihuang decoction,ameliorates behavioral and pathological deterioration via modulating the neuroendocrineimmune system in Alzheimer disease mouse models

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中国药理学与毒理学杂志 2018年第4期32卷 303-304页

作者： Jian-hui WANG Xi LEI Xiao-rui CHENG Xiao-rui ZHANG Gang LIU Jun-ping CHENG Yi-ran XU Ju ZENG Wen-xia ZHOU Yong-xiang ZHANG Department of Neuroimmunopharmacology Beijing Institute of Pharmacology and Toxicology Beijing 100850 State Key Laboratory of Toxicology and Medical Countermeasures Beijing 100850 China

OBJECTIVE Alzheimer disease(AD),the most common cause of dementia among older people,could not be prevented,halted,or reversed up till now.A large body of pharmacological study has revealed that Liuwei Dihuang(LW) possesses potential therapeutic effects on AD.LW-AFC is key fractions fromLW.In the present study,we investigated the effect of LW-AFC on AD mouse models.METHODS PrP-hAβPPswe/PS1ΔE9(APP/PS1) mice and senescence-accelerated mouse prone 8 strain(SAMP8),classic AD animal models,were employed.After the treatment of LW-AFC,mice were cognitively evaluated in behavioral experiments.Neuron loss,amyloid-β(Αβ)deposition,and Αβ level were analyzed using Nissl staining,immunofluorescence,and an AlphaLISA assay,respectively.Multiplex bead analysis,a radioimmunoassay,immunochemiluminometry,and an ELISA were used to measure cytokine and hormone levels.Lymphocyte subsets were detected using fl ow cytometry.RESULTS LW-AFC ameliorated the cognitive impairment observed in APP/PS1 and SAMP8 mice,including the impairment of object recognition memory,spatial learning and memory,and active and passive avoidance.In addition,LW-AFC alleviated the neuron loss in the hippocampus,suppressed amyloid-β(Αβ) deposition in the brain,and reduced the concentration of Aβ1-42 in the hippo.campus and plasma of APP/PS1 mice.LW-AFC treatment also significantly restored the imbalance of hypothalamic-pituitary-adrenal(HPA) and hypothalamic-pituitary-gonadal(HPG) axis,enhanced the proliferation of splenocytes,corrected the disorder of lymphocyte subsets,and regulated the abnormal production of cytokine in APP/PS1 and SAMP8 mice.Effects of LW-AFC on pharmacodynamics and neuroendocrine immunomodulation network in APP/PS1 and SAMP8 mice were better than meman.tine and donepezil.CONCLUSION LW-AFC ameliorated the behavioral and pathological deterioration of AD mouse models via the restoration of the NIM network,which supports the use of LW-AFC as a potential agent for AD therapy.

关键词：阿尔茨海默病药理学临床分析药物化学

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Oral Capsule Containing Progesterone Nanocrystal: In Vivo and In Vitro Study

Oral Capsule Containing Progesterone Nanocrystal: In Vivo an...

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2018年第十二届中国药物制剂大会

作者：卢雪瑞 Yabing Hua Jing Gao Xi Yang Jianxu Sun Hui Zhang Aiping Zheng State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology

＜正＞Progesterone（PG）has been extensively studied in the treatment of different gynecological pathologies,as a contraceptive and in assisted reproductive technologies.At present,PG soft capsulesare mainly used in clinical,but the bioavailability is low,only 6%～8%of progesterone injection.The object of this study was to develop progesterone nanocrystal（PG/NC）for oral administration,which could enhance

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Effects of LW-AFC on anxiety-like behavior and immune function in corticosterone-induced mice

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中国药理学与毒理学杂志 2019年第9期33卷 678-679页

作者： ZENG Ju CHENG Xiao-rui ZHOU Wen-xia ZHANG Yong-xiang Beijing Institute of Pharmacology and toxicology Beijing 100850China State Key Laboratory of Toxicology and Medical Countermeasures Beijing 100850China

OBJECTIVE Chronic stress is one of the important factors in the development of many mental and neurological diseases,and cause damage to the central nervous system,affect animal emotions and damage the immune function of the body.The purpose of this study was to investigate the effects of LW-AFC which extracting from traditional Chinese medicine prescription Liuwei Dihuang decoctionon the anxiety-like behaviorand immune dysfunction abnormalities caused by chronic stress,and whether immune intervention affect the action of LW-AFC.METHODS Male BALB/c mice were subcutaneously injected with corticosterone(25 mg·kg^-1)for 28 d to establish a chronic stress model.Cyclophos⁃phamide(Cy,80 mg·kg^-1)was injected continuously for the initial three days,followed by once a week,LW-AFC(1.6 g·kg^-1)was given continuously for 28 d.Then investigate the emotion changes by open field and elevated plus maze tests,and detected the lymphocyte proliferation,lymphocyte subsets in peripheral blood,microglia and astrocyte expression,and inflammatory cytokines in peripheral blood and brain tissue.RESULTS The mice showed obvious depressive-like behaviorafter 28 d of continuous corticosterone injection.LW-AFC could significantly improve the anxietybehavior induced by corticosterone injection,but LW-AFC could not improve the anxietybehavior of mice by Cy intervention.The expression of glial cells in hippocampus of corticosterone-induced mice showed an upward trend,and the activation of microglia and astrocytes have significantly increase in corticosterone and Cy injected mice.LW-AFC significantly decreased the activation of microglia and astrocytes in corticosterone-induced mice with Cy intervention.This suggested that LW-AFC can reduce the damage of stress on the immune function of central nervous system under immunosuppres⁃sive state.Furthermore,LW-AFC could significantly up-regulate the proliferation of splenic lymphocyte stimulated by LPS and ConA,up-regulate the proportion of CD3+CD8+cells,reduce the proportion of CD4+/CD8+cells,decrease

关键词： LW-AFC corticosterone cyclophosphamide anxiety-like behavior glia cells lymphocyte inflammatory factors

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