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Inhibitory effect of compound NS5806 on cardiac transient outward potassium channel dependents on interaction between auxiliary subunits

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中国药理学与毒理学杂志 2017年第10期31卷 1027-1028页

作者： Hong-xue ZHANG Hua ZHANG Yu-hong WANG Yan-fang XU Department of pharmacology Hebei Medical University the Key Laboratory of New Drug pharmacology and Toxicolog Hebei Province the Key Laboratory of Neural and Vascular Biology Ministry of Education Institute of Masteria Medica Chinese Academy of Medical Sciences & Peking Union Medical College

OBJECTIVE Transient outward potassium current(I_(to)) plays a crucial role in cardiac phase 1 repolarization and the channels are assembled by pore-forming α-subunits(K_v4.2 or K_v4.3) and auxiliary subunits(KCh IP2 and DPP6).Previous studies have found that the compound NS5806 increases I_(to) in canine ventricular cardiomyocytes through slowing current ***,we reported that NS5806 produced an acute inhibitory action on I_(to) in mouse ventricular cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes(hi PS-CM).METHODS Whole-cell patch-clamp was used to record I_(to) in native myocytes and in HEK cells expressing cloned K_v4.x/KCh IP2/DPP6 channels;Western-blot detected the channel protein *** In isolated mouse ventricular cardiomyocytes,NS5806(0.1-30 μmol·L^(-1)) inhibited I_(to) in a concentration-dependent manner with IC50 of 6.6±1.9 μmol·L^(-1).The current decay was significantly accelerated with a time constant from 53.8±5.5 to 41.8±3.0 ms at +60 m V(P<0.01).Similarly,NS5806 concentration-dependently reduced the I_(to) peak current amplitude with an acceleration of current *** addition,NS5806 increased I Kv4.2/KCh IP2 and delayed current decay,but decreased I Kv4.2/KCh IP2/DPP6 with the acceleration of current *** inhibitory action on the current was more potent if DPP6 expression level was increased from K_v4.2/KCh IP2/DPP6 1∶1∶1 to 1∶1∶***-blot showed a higher expression of DPP6 protein in mouse heart and in hi PS-CM compared to canine ***,specific knock-down DPP6 expression by si RNA antagonized the inhibitory action of NS5806 in hi *** results pointed to an important role of DPP6 subunit in the regulation of NS5806 on the *** using molecular docking simulation,five interaction sites with high possibility between KCh IP2 and DPP6 were *** of those sites changed the inhibitory action of NS58056 into excitatory effect on the current with the delay of current

关键词： NS5806 Ito hiPS-CM molecular docking

Network mechanism on effective constituents from Polygala Tenuifolia for anti-Alzheimer Disease

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中国药理学与毒理学杂志 2018年第4期32卷 287-288页

作者： Hao JIA Xiao-cong PANG Bao-yue ZHANG Zhe WANG Ai-lin LIU Guan-hua DU Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100050 China

OBJECTIVE To clarify out the network pharmacology mechanism of Polygala tenuifolia against Alzheimer disease(AD).METHODS Firstly,we collected the chemical constituents from Polygala tenuifolia and key targets toward *** learning algorithms were applied to construct *** for predicting the effective ***,docking models were utilized for further ***,we built constituent-target,target-target network and target-biology pathway *** 104 chemical constituents Polygala tenuifolia from were *** prediction of bloodbrain penetration and validation,36 chemical constituents were selected among 100 chemical ***,their action targets mainly focused on AChE,COX-2,TNF-α,insulin-degrading enzyme and *** main structure types include Polygala saponins,Polygala glycosides,Polygala shrubby ketones,polygala xanthones and sterols,which acted on AchE,APP,M-TAU,GSK3β and 5 HT1A with high ***-Ontology and KEGG enrichment analysis showed that the main pathways of these *** involve in neurotransmitter release,synaptic conduction and synaptic plasticity,apoptosis ***,phosphorylation pathway,Ca^(2+) signaling pathway,and so *** This study *** a network mechanism of Polygala tenuifolia against Alzheimer disease,which may provide *** information for the further study and new drug development.

关键词：阿尔茨海默病中药治疗方法临床分析

The antidepressive effect of the complex consisting of Radix Pseudostellariae,Radix Pueraria and Herba Epimedii:the involvement of NRSF/NRSE-TPH2 signaling

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Journal of Chinese Pharmaceutical Sciences 2021年第1期30卷 27-41页

作者： Xuan Yu Xinpei Wang Fan Lei Yugang Wang Wei Wang Yi Ding Dongming Xing Zhiyi Yuan Hong Sun Lijun Du Laboratory of Molecular pharmacology and Pharmaceutical Sciences School of Life SciencesTsinghua UniversityBeijing 100084China Institute of Medicinal Plant and Development Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100094China

Depression is a psychological disease with no particularly effective therapy currently *** the present study,we aimed to examine the antidepressive activity of a pharmaceutical Chinese medicine called TaiZi(TZ)capsule,consisting of total polysaccharides of Radix Pseudostellariae and total flavonoids of both Radix Pueraria and Herba Epimedii.A tail suspension test and forced swimming test were performed to assess the effect of TZ in vivo.A plasmid of TPH2(tryptophan hydroxylase-2)was constructed to determine the exact target of TZ in *** addition,mRNA expression was detected using a real-time PCR assay,and the protein expression was investigated using a Western blotting *** results showed that TZ had an anti-depression effect in mouse and rat models with increased serotonin in the brain,and in the upregulation of mRNA and protein expression of TPH2 in the brain simultaneously by inhibition of NRSF(neuron restrictive silencer factor)expression because NRSF could bind to NRSE(neuron restrictive silencer element)to repress TPH2 transcription during the depression *** could bind to NRSE directly and block NRSF protein toward to NRSE for TPH2 ***,we concluded that TZ had potential antidepressive effects because it could ameliorat the depression-like behavior in the animals,and the underlying mechanism of the effect was involved in NRSF/NRSE-TPH2 *** was identified as the active component of *** study provided a new perspective for the development of antidepression drugs(Chinese medicines)based on NRSF/NRSE-TPH2 signaling.

关键词： Depression TPH2 NRSF Icariin Pseudostellariae Pueraria Epimedii

S1PR1 serves as a viable drug target against pulmonary fibrosis by increasing the integrity of the endothelial barrier of the lung

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Acta Pharmaceutica Sinica B 2023年第3期13卷 1110-1127页

作者： Mengyao Hao Rong Fu Jun Tai Zhenhuan Tian Xia Yuan Yang Chen Mingjin Wang Huimin Jiang Ming Ji Fangfang Lai Nina Xue Liping Bai Yizhun Zhu Xiaoxi Lv Xiaoguang Chen Jing Jin State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100050China Department of Otolaryngology Head and Neck SurgeryChildren's Hospital Capital Institute of PediatricsBeijing 100020China Department of Thoracic Surgery Peking Union Medical College HospitalPeking Union Medical CollegeDong Cheng DistrictBeijing 100730China State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Department of pharmacology School of PharmaceuticalGuangzhou University of Chinese MedicineGuangzhou 510000China State Key Laboratory of Quality Research in Chinese Medicine Macao Institute for Applied Research in Medicine and HealthMacao University of Science and TechnologyTaipaMacao SAR 999078China

Idiopathic pulmonary fibrosis(IPF)is a progressive lung disease with unclear etiology and limited treatment *** median survival time for IPF patients is approximately 2–3 years and there is no effective intervention to treat IPF other than lung *** important components of lung tissue,endothelial cells(ECs)are associated with pulmonary ***,the role of endothelial dysfunction in pulmonary fibrosis(PF)is incompletely ***-1-phosphate receptor 1(S1PR1)is a G protein-coupled receptor highly expressed in lung *** expression is markedly reduced in patients with ***,we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin(BLM)*** activation of S1PR1 with an S1PR1 agonist,IMMH002,exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial *** results suggest that S1PR1 might be a promising drug target for IPF therapy.

关键词： Idiopathic pulmonary fibrosis Endothelial barrier Tight junction Sphingosine-1-phosphate receptor 1 Sphingosine-1-phosphate receptor 1 agonist FTY720 IMMH002 Protein stability

Protective Effect of Effective Composite of Chinese Medicine Prescription Naodesheng(脑得生) against Focal Cerebral Ischemia in Rats

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Chinese Journal of Integrative Medicine 2009年第5期15卷 377-383页

作者：张莉程新锐陈若芸竺晓鸣杜冠华 National Center for Pharmaceutical Screening Institute of Materia MedicaChinese Academy of Medical Science & Peking Union Medical College Department of pharmacology Institute of Basic Medical ScienceChinese Academy of Medical Science & Peking Union Medical College

Objective： To study the effects and possible mechanisms of effective composite of Naodesheng （脑得生, NDS） on permanent cerebral ischemia-induced injury in rats. Methods： Male Sprague-Dawley rats with middle cerebral artery occlusion （MCAO） were established with the modified suture method, and they were randomly divided into the following groups： the sham-operated group, the model group, the Nimodipine group （0.012 g/kg）, the NDS group （1.075 g/kg）, the total extracts group （0.23 g/kg）, the high-dose NEC group （0.07 g/kg）, the middle-dose NEC group （0.02 g/kg）, and the low-dose NEC group （0.007 g/kg）. The aforesaid medicines were administered at the 2nd, 4th, and 24th h after focal cerebral ischemia, and the infarction size and water content in the brain were evaluated at the 26th h after MCAO. Then, after oral administration once daily for 7 successive days, the changes in the degree of neurological deficit, oxidative stress, and apoptosis were measured on the 7th day. Results： NEC could significantly reduce the infarction size after focal cerebral ischemia, and slightly relieve water content in the brain, significantly alleviate neurological function impairment, increase the levels of superoxide dismutase （SOD） and adenosine triphosphate enzyme （ATPase） activity, and decrease the content of malondialdehyde （MDA）. NEE; could also extenuate Bax and caspase-3 expression in the hippocampus tissue of the ischemic region. As compared with the three NEE; treated groups, the highdose NEC showed better efficacy. Conclusions： NEE; could significantly reduce brain injury induced by ischemia; its mechanism was closely associated with hindering oxidative stress and apoptosis. The effective compositeguided methodology is a feasible tool to improve the neuro-protective properties of the Chinese medicine prescription NDS against focal cerebral ischemia in rats.

关键词： effective composite Naodesheng ischemia neuro-protection apoptosis

Equisetin is an anti-obesity candidate through targeting 11β-HSD1

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2358-2373页

作者： Zhenlu Xu Dongyun Liu Dong Liu Xue Ren Haibo Liu Guihong Qi Yue Zhou Chongming Wu Kui Zhu Zhongmei Zou Jing Yuan Wenhan Lin Peng Guo pharmacology and Toxicology Research Center Institute of Medicinal Plant DevelopmentChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100193China Capital Institute of Pediatrics Beijing 100020China State Key Laboratory of Natural and Biomimetic Drugs Peking UniversityBeijing 100191China National Center for Veterinary Drug Safety Evaluation College of Veterinary MedicineChina Agricultural UniversityBeijing 100193China

Obesity is increasingly prevalent globally, searching for therapeutic agents acting on adipose tissue is of great importance. Equisetin(EQST), a meroterpenoid isolated from a marine sponge-derived fungus, has been reported to display antibacterial and antiviral activities. Here, we revealed that EQST displayed anti-obesity effects acting on adipose tissue through inhibiting adipogenesis in vitro and attenuating HFD-induced obesity in mice, doing so without affecting food intake, blood pressure or heart *** demonstrated that EQST inhibited the enzyme activity of 11β-hydroxysteroid dehydrogenase type 1(11β-HSD1), a therapeutic target of obesity in adipose tissue. Anti-obesity properties of EQST were all offset by applying excessive 11β-HSD1’s substrates and 11β-HSD1 inhibition through knockdown in vitro or 11β-HSD1 knockout in vivo. In the 11β-HSD1 bypass model constructed by adding excess11β-HSD1 products, EQST’s anti-obesity effects disappeared. Furthermore, EQST directly bond to11β-HSD1 protein and presented remarkable better intensity on 11β-HSD1 inhibition and better efficacy on anti-obesity than known 11β-HSD1 inhibitor. Therefore, EQST can be developed into anti-obesity candidate compound, and this study may provide more clues for developing higher effective 11β-HSD1 inhibitors.

关键词： EQST Obesity Adipocyte Lipid accumulation Preadipocyte differentiation Adipose tissue 11β-HSD1 11β-HSD1 inhibitor

Effect of active components group of Xiaoxuming decoction on cerebral mitophagy after focal cerebral ischemia/reperfusion injury

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中国药理学与毒理学杂志 2019年第10期 841-842页

作者： BAI Xue DU Xiao HE Xiao-li Institute of Medicinal Plant Development Chinese Academy of Medical Sciences and Peking Union Medical College

OBJECTIVE To explore the effect of the active components group of Xiaoxuming decoction(XXMD)on mitophagy after cerebral ischemia/reperfusion(I/R) in MCAO rats. METHODS Male Sprague-Dawley rats were randomly divided into 4 groups: sham group, XXMD and rapamycin group. The I/R models were induced by middle cerebral artery occlusion. The effects of XXMD and rapamycin on behavioral study of focal cerebral I/R in rats were measured by Zea-Longa′ s level standard scoring method and neurological defect score(m NSS). The volume percentage and hemispheric swelling of rat cerebral infarction were detected by TTC staining. Proteins in the mitophagy were detected by Western blotting. RESULTS The behavioral results showed that compared with the model group, XXMD decoction and rapamycin could significantly alleviate the neurological deficit scores after I/R, decreased the m NSS score(P<0.05) of the MCAO rats. TTC results showed that XXMD and rapamycin could significantly reduce the percentage of infarct volume and hemispheric swelling(P<0.05) of MCAO rats. Compared with the model group, the XXMD could significantly inhibit the expression of P62, Beclin-1 and BNIP3 and decrease LC3-Ⅱ/LC3-Ⅰ ratio(P<0.05, P<0.01) in isolated cerebral mitochondrial proteins at 24 h after cerebral I/R. However, the expression of P62,Beclin-1, BNIP3(P<0.05, P<0.01) and the ratio of LC3-Ⅱ/LC3-Ⅰin purified mitochondrial proteins can be significantly elevated by XXMD at 96 h after cerebral I/R. CONCLUSION Autophagy and mitophagy were activated at 24 h after cerebral I/R, and then it was inhibited. XXMD can protect mitochondrial structures, regulate the level of mitophagy at different points after cerebral I/R, inhibit the excessive activation of mitophagy in 24 h after I/R, and improve the level of mitophagy in the later stage of I/R.

关键词： active components Xiaoxuming decoction cerebral ischemic reperfusion mitochondrial function mitophagy

Ganoderma triterpenes slow cyst growth in polycystic kidney disease

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中国药理学与毒理学杂志 2017年第10期31卷 1006-1007页

作者： Bao-xue YANG Li-min SU Li-ying LIU Hong ZHOU Ruo-yun CHEN State Key Laboratory of Natural and Biomimetic Drugs Department of PharmacologySchool of Basic Medical SciencesPeking University State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences & Peking Union Medical College

OBJECTIVE Autosomal dominant polycystic kidney disease(ADPKD)is a common inherited disease with a high morbidity around 1/1000-1/400,characterized by progressive enlargement of fluid-fil ed cysts derived from renal tubular epithelial *** cysts gradually compress renal parenchyma destroying normal renal structures and compromising renal ***,it will cause end-stage renal disease in most of the patients but without effective therapy now,who have to live on hemodialysis or kidney *** on this present situation,it is of great significance to find early intervention to inhibit renal cyst *** projective of this study was to investigate whether Ganoderma triterpenes(GT)can inhibit renal cyst development and study the related *** and RESULTS First,we used MDCK cyst model,cultivated MDCK cells in vitro to form fluid-filled cysts surrounded by monolayer *** inhibited MDCK cyst formation significantly,and inhibited cyst enlargement dose-dependently proving GT cyst inhibition in *** we used an embryonic kidney cyst model,wile-type mice kidneys were taken out on embryonic day 13.5 to form renal cysts stimulated with 8-Br-c *** inhibited embryonic kidney cyst development significantly in a dosedependent and reversible manner proving GT cyst inhibition at organ ***,we used two ADPKD mouse models with severe cystic kidney disease *** dramatically inhibited renal cyst development,decreased ADPKD mouse kidney volume and the cyst index inside proving GT cyst inhibition in *** Western blot,we proved GT down-regulated Ras/MAPK signal pathway without detectable effect on m TOR signal pathway both in MDCK cells and two ADPKD mouse *** GT retard renal cyst development both in vitro and in vivo *** related mechanisms were involved in GT promoting renal tubular epithelial cell differentiation,down-regulating intracellular c AMP level and Ras/MAPK sig

关键词： polycystic kidney disease Ganoderma triterpenes mTOR signal pathway

Microdosing cocktail study on the determination and pharmacokinetics of six hepatic cytochrome probes and their metabolites in rat

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中国药理学与毒理学杂志 2016年第10期30卷 1045-1046页

作者： YANG Zhi-hong XU Li-yun YOU Yu-yang Institute of Medicinal Plant Development Chinese Academy of Medical Sciences and Peking Union Medical College Beijing Institute of Technology

OBJECTIVE To describe a highly sensitive LC-ESI MSnmethod that was developed to simultaneously detect six CYP isoform-specific probes and their metabolites in rat plasma for microdosing cocktail *** After administration of a mixture of six probes(i.e.,a cocktail approach with caffeine 100μg·kg-1,tolbutamide100μg·kg-1,omeprazole 500μg·kg-1,dextromethorphan 500μg·kg-1,chlorzoxazone 50μg·kg-1and midazolam 100μg·kg-1)to SD *** plasma samples were extracted using ethyl acetate with diazepam and gliclazide as the *** assay was performed on an Agilent Eclipse Plus C18 column(2.1×50 mm,3.5μm).The mobile phase consisted of 0.01%formic acid(1 mmol·L-1ammonium formate)and *** flow rate was0.3 m L·*** samples were analyzed by LC-20A&5500Qtrap ESI MSnin MRM *** MS/MS reaction selected 181.2/124.0 m/z ions for caffeine,195.2/138.2m/z for paraxanthine,269.1/170.0 m/z for tolbutamide,285.1/186.0 m/z for 4-hydroxytolbutamide,346.1/198.1m/z for omeprazole,362.2/214.2 m/z for 5-hydroxyomeprazole,272.3/147.1 m/z for dextromethorphan,258.2/157.0 m/z for dextrorphan,168.1/132.1 m/z for chlorzoxazone,326.1/291.2 m/z for midazolam,and 342.1/324.2m/z for 1′-*** The datashowed that the method was with good linearity in the range of 0.2-200 ng·m L-1for caffeine,0.1-25 ng·m L-1for paraxanthine,0.05-100 ng·m L-1for omeprazole,0.01-25 ng·mL-1for 5-hydroxyomeprazole,0.1-200 ng·mL-1for dextromethorphan,0.05-12.5 ng·mL-1for dextrophan,0.2-200 ng·mL-1for midazolam,and 0.2-25 ng·mL-1for 1′-hydroxymidazolam,*** stability%RSD for al probes was less than 15%and matrix effects in plasma on the ionization were *** This highly sensitive and quantitative method allowed a pharmacokinetic study in subjects receiving doses 10-100 times lower than typical therapeutic *** established LCMS/MS method was suitable for pharmacokinetic study of this mixture cocktail probe group and could be applied deeply to CYP isofor

关键词： microdosing cocktail hepatic cytochrome drug metabolism probes and metabolites