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Endothelial phosphodiesterase 4B inactivation ameliorates endothelial-to-mesenchymal transition and pulmonary hypertension

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1726-1741页

作者： yanjiang xing Yangfeng Hou Tianfei Fan Ran Gao Xiaohang Feng Bolun Li Junling Pang Wenjun Guo Ting Shu Jinqiu Li Jie Yang Qilong Mao Ya Luo Xianmei Qi Peiran Yang Chaoyang Liang Hongmei Zhao Wenhui Chen Jing Wang Chen Wang State Key Laboratory of Respiratory Health and Multimorbidity Institute of Basic Medical SciencesChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100005China Department of Lung Transplantation National Center for Respiratory MedicineNational Clinical Research Center for Respiratory DiseasesChina–Japan Friendship HospitalInstitute of Respiratory MedicineChinese Academy of Medical SciencesBeijing 100029China Haihe Laboratory of Cell Ecosystem Chinese Academy of Medical Sciences and Peking Union Medical CollegeTianjin 300051China The State Key Laboratory of Complex Severeand Rare DiseasesInstitute of Basic Medical SciencesChinese Academy of Medical SciencesDepartment of PathophysiologyPeking Union Medical CollegeBeijing 100005China Department of Pharmacy West China HospitalSichuan UniversityChengdu 610044China

Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A–D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH;however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA–CREB–BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.

关键词： Phosphodiesterase 4B Pulmonary hypertension Endothelial-to-mesenchymal transition

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Gefitinib and fostamatinib target EGFR and SYK to attenuate silicosis:a multi-omics study with drug exploration

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Signal Transduction and Targeted Therapy 2022年第6期7卷 2066-2078页

作者： Mingyao Wang Zhe Zhang Jiangfeng Liu Meiyue Song Tiantian Zhang Yiling Chen Huiyuan Hu Peiran Yang Bolun Li Xiaomin Song Junling Pang yanjiang xing Zhujie Cao Wenjun Guo Hao Yang Jing Wang Juntao Yang Chen Wang State Key Laboratory of Medical Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijing 100005China Laboratory of Stem Cell and Tissue Engineering Orthopedic Research InstituteState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengdu 610041China Department of Pulmonary and Critical Care Medicine The First Hospital of Shanxi Medical UniversityTaiyuan 030001China NHC Key Laboratory of Pneumoconiosis Taiyuan 030001China Shanxi Province Key Laboratory of Respiratory Disease Taiyuan 030001China Department of Pulmonary and Critical Care Medicine Center of Respiratory MedicineChina-Japan Friendship HospitalBeijing 100029China Department of Respiratory and Critical Care Medicine The First Affiliated Hospital of Xi’an Jiao tong UniversityXi’an 710061China Key Lab of Transplant Engineering and Immunology MOHRegenerative Medical Research CenterWest China HospitalSichuan UniversityChengdu 610041China

Silicosis is the most prevalent and fatal occupational disease with no effective therapeutics,and currently used drugs cannot reverse the disease *** still,there are still challenges to be addressed to fully decipher the intricated ***,specifying the essential mechanisms and targets in silicosis progression then exploring anti-silicosis pharmacuticals are desperately *** this work,multi-omics atlas was constructed to depict the pivotal abnormalities of silicosis and develop targeted *** utilizing an unbiased and time-resolved analysis of the transcriptome,proteome and phosphoproteome of a silicosis mouse model,we have verified the significant differences in transcript,protein,kinase activity and signaling pathway level during silicosis progression,in which the importance of essential biological processes such as macrophage activation,chemotaxis,immune cell recruitment and chronic inflammation were ***,the phosphorylation of EGFR(p-EGFR)and SYK(pSYK)were identified as potential therapeutic targets in the progression of *** inhibit and validate these targets,we tested fostamatinib(targeting SYK)and Gefitinib(targeting EGFR),and both drugs effectively ameliorated pulmonary dysfunction and inhibited the progression of inflammation and ***,our drug discovery with multi-omics approach provides novel and viable therapeutic strategies for the treatment of silicosis.

关键词： silicosis SYK drugs

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嗜酸性粒细胞在心血管疾病中的作用

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中华心血管病杂志 2022年第4期50卷 415-419页

作者：张佳玮邢岩江舒婷王婧中国医学科学院基础医学研究所北京协和医学院基础学院北京100730

炎症反应是心血管疾病重要的病理生理过程,嗜酸性粒细胞(EOS)作为炎症反应的效应细胞,可分泌多种促炎因子、趋化因子以及毒性颗粒蛋白,并可与多种细胞相互作用。早期研究认为EOS主要参与寄生虫感染和过敏性疾病,近年来发现EOS与心血管... 详细信息

炎症反应是心血管疾病重要的病理生理过程,嗜酸性粒细胞(EOS)作为炎症反应的效应细胞,可分泌多种促炎因子、趋化因子以及毒性颗粒蛋白,并可与多种细胞相互作用。早期研究认为EOS主要参与寄生虫感染和过敏性疾病,近年来发现EOS与心血管疾病发生发展具有相关性,但现有研究有限,EOS在心血管疾病中的具体作用机制尚不清楚。该文对EOS在心血管疾病中的损伤/保护作用及研究中存在的争议进行了综述,以期进一步明确EOS在心血管疾病中的作用机制,为临床诊疗提供新思路。

关键词：细胞相互作用心血管疾病效应细胞寄生虫感染过敏性疾病促炎因子颗粒蛋白趋化因子

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尾翼楔角对通气超空泡特性影响试验研究

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哈尔滨工业大学学报 2013年第1期45卷 25-29页

作者：邢彦江张嘉钟曹伟王聪王柏秋哈尔滨工业大学航天学院哈尔滨150001

为优化通气超空泡航行体流体动力布局,通过水洞试验,研究了航行体尾翼对通气超空泡航行体流体动力的影响.细致分析了通气超空泡的生成和发展过程,给出了尾翼、尾翼楔角对通气超空泡航行体流体动力的影响规律.试验结果表明:航行体尾翼增... 详细信息

为优化通气超空泡航行体流体动力布局,通过水洞试验,研究了航行体尾翼对通气超空泡航行体流体动力的影响.细致分析了通气超空泡的生成和发展过程,给出了尾翼、尾翼楔角对通气超空泡航行体流体动力的影响规律.试验结果表明:航行体尾翼增大了通气超空泡航行体阻力系数与升力系数.通气超空泡航行体阻力系数与升力系数分别随自然空化数减小而减小.通气超空泡航行体阻力系数与升力系数随通气率增大先小幅增加后减小.尾翼楔角越大,通气超空泡航行体升力系数越大.

关键词：超空泡航行体流体动力升力系数阻力系数

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Functional and binding studies of gallic acid showing platelet aggregation inhibitory effect as a thrombin inhibitor

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Chinese Herbal Medicines 2022年第2期14卷 303-309页

作者： Yuxin Zhang xing Wang Binan Lu Yanbin Gao Yanling Zhang Yatong Li Hongjuan Niu Lu Fan Zongran Pang yanjiang Qiao Key Laboratory of Ethnomedicine of Ministry of Education School of PharmacyMinzu University of ChinaBeijing 100081China Beijing Key Lab of Traditional Chinese Medicine Collateral Disease Theory Research School of Traditional Chinese MedicineCapital Medical UniversityBeijing 100069China Key Laboratory of TCM-Information Engineer of State Administration of TCM School of Chinese Materia MedicaBeijing University of Chinese MedicineBeijing 100029China

Objective:This study was devoted to identifying natural thrombin inhibitors from traditional Chinese medicine(TCM)and evaluating its biological activity in vitro and binding ***:A combination strategy containing molecular docking,thrombin inhibition assay,surface plasmon resonance(SPR)and molecular dynamics simulation were applied to verify the study ***:Gallic acid was confirmed as a direct thrombin inhibitor with IC;of 9.07μmol/L and showed a significant inhibitory effect on thrombin induced platelet ***-based binding studies demonstrated that gallic acid interacted with thrombin with a KDvalue of 8.29μmol/*** dynamics and binding free energy analysis revealed that thrombin-gallic acid system attained equilibrium rapidly with very low fluctuations,the calculated binding free energies was-14.61 kcal/***230,Glu232,Ser235,Gly258 and Gly260 were the main amino acid residues responsible for thrombin inhibition by gallic acid,providing a mechanistic basis for further ***:This study proved that gallic acid is a direct thrombin inhibitor with platelet aggregation inhibitory effect,which could provide a basis for the follow-up research and development for novel thrombin inhibitors.

关键词： gallic acid molecular dynamics natural thrombin inhibitor platelet aggregation surface plasmon resonance

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Pharmacophore Model Generation of Thrombin Inhibitors

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Journal of Software Engineering and Applications 2012年第12期5卷 84-87页

作者： xing Wang Yanling Zhang Yuhong Xiang Zhenzhen Ren yanjiang Qiao Department of Chemistry Capital Normal University Beijing 100048 China School of Chinese Materia Medica Beijing University of Chinese Medicine Beijing 100102 China

Thrombin, an important factor of clotting system, take part in a variety of physiological actions, such as blood clotting, anticoagulation, thrombosis and fibrinolysis. Inhibiting thrombin is a pivotal and effective step for the prophylaxis of venous and arterial thrombosis, as well as prevent myocardial infarction for high-risk patients. In this study, a three dimensional pharmacophore model was generated for the molecules which are responsible for vasodilation activities targeting thrombin. Ten compounds with known thrombin-inhibiting activity values were selected as training set to generate the hypothesis using GALAHAD program in SYBYL 7.0 software. The best hypothesis comprises five pharmacophore features: four hydrophobes groups and one positively charged group. It has been further validated towards a test set including known activity compounds obtained from Binding Database, the values of effectively active hit A% and comprehensive evaluation index CAI are respectively 63.33% and 2.34, the pharmacophore was proven to be successful in discriminating active and inactive inhibitors. ?Furthermore, the pharmacophore model was used as a 3D query to screen TCMD (Version 2009) database and 6 hit compounds of higher predicted activity were the reported cardiovascular activities, which may be useful for further study.

关键词： Cardiovascular disease thrombin Pharmacophore Virtual screening

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杨树人工林土壤丛枝菌根真菌群落对氮添加的季节性动态响应

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浙江农林大学学报 2023年第4期40卷 792-800页

作者：彭思利张鑫武仁杰蔡延江邢玮葛之葳毛岭峰南京林业大学生物与环境学院南方现代林业协同创新中心江苏南京210037 浙江农林大学环境与资源学院浙江杭州311300 江苏省林业科学研究院江苏南京211153 江苏省林业科学研究院江苏盐城滨海湿地生态系统国家定位观测研究站江苏盐城224000

【目的】探究杨树Populus spp.人工林土壤丛枝菌根(arbuscular mycorrhizal,AM)真菌群落结构和多样性对氮添加的季节动态响应及其驱动因素。【方法】以江苏省东台林场杨树为对象,研究5种氮添加水平(0、5、10、15和30g·m^(-2)·a^(-1))... 详细信息

【目的】探究杨树Populus spp.人工林土壤丛枝菌根(arbuscular mycorrhizal,AM)真菌群落结构和多样性对氮添加的季节动态响应及其驱动因素。【方法】以江苏省东台林场杨树为对象,研究5种氮添加水平(0、5、10、15和30g·m^(-2)·a^(-1))处理6 a后土壤理化性质、AM真菌群落结构和多样性随季节的动态变化,并分析了AM真菌群落特征与土壤环境因子的关系。【结果】(1)高通量测序共获得AM真菌有效序列1307513条,196个分类操作单元(OTU)分属于4目8科10属,其中球囊霉属Glomus和多胞囊霉属Diversispora相对丰度之和平均达99.3%;(2)氮添加处理对AM真菌多样性指数影响不显著,但随着氮添加水平的增加多胞囊霉属的相对丰度逐渐降低,其中高氮(30 g·m^(-2)·a^(-1))处理球囊霉属的相对丰度显著(P<0.05)高于低氮处理(5和10 g·m^(-2)·a^(-1));(3)季节对AM真菌群落结构(基于OTUs,r=0.695)及Chao指数、Simpson指数均有显著影响,且秋季和春季的AM真菌多样性指数均显著高于夏季(P<0.01);(4)冗余分析结果表明:土壤pH、总磷和总氮等9个环境因子对AM真菌群落组成变化的解释量为57.6%(P=0.001),其中AM真菌群落组成与土壤温度的相关性最大(r=0.766),另外群落组成和多样性指数均与pH、总磷、总碳和铵态氮有显著相关关系(P<0.05)。【结论】氮添加下,杨树人工林土壤AM真菌群落具有季节性响应,土壤温度、pH、总磷、总碳和铵态氮是影响AM真菌群落动态变化的主要驱动因素。

关键词：氮沉降季节动态丛枝菌根真菌群落结构多样性杨树人工林

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Polymorphisms at cholesterol 7α-hydroxylase,apolipoproteins B and E and low density lipoprotein receptor genes in patients with gallbladder stone disease

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World Journal of Gastroenterology 2004年第10期10卷 1508-1512页

作者： Zhao-yanjiang Tian-QuanHan Guang-JunSuo Dian-XuFeng ShengChen xing-xingCai Zhi-HongJiang JunShang YiZhang YuJiang Sheng-DaoZhang DepartmentofSurgery RuijinHospitalShanghaiSecondMedicalUniversityShanghaiInstituteofDigestiveSurgeryShanghai200025China

AIM: To investigate the relationship between gallbladder stone disease (GSD) and single nucleotide polymorphisms of cholesterol 7α-hydroxylase (CYP7A) gene promoter,apolipoprotein (APO) B gene exon 26, APOEgene exon 4 or microsatellite polymorphism of low density lipoprotein receptor (LDLR) gene exon ***: Genotypes of CYP7A, APOB, APOE and LDLR genes were determined in 105 patients with GSD diagnosed by B-mode ultrasonography and 274 control *** lipids were analyzed with HITACHI 7060 automaic biochemical ***: Body mass index (BMI) was significantly higher in patients with GSD (24.47±3.09) than in controls (23.50±2.16).Plasma total cholesterol was lower in patients with GSD (4.66±0.92 mmol/L) than in controls (4.91±0.96 mmol/L),P<0.01 after adjusted for age, sex and BMI. The significantly higher frequency of A allele of CYP7A gene polymorphism and X+ allele of APOBgene polymorphism was seen in GSD patients. Percentages of A allele in patients and controls were 62.86% and 54.38% (P <0.05) and those of X+ allele 8.57% and 4.01% (P<0.01). Subjects with A allele had significantly lower plasma total cholesterol and LDL cholesterol than subjects with CC homozygote. In a multiple variable logistic regression model, the BMI (OR=1.13, 95% CI: 1.05-1.22), A allele (OR=1.48, 95% CI: 1.05-2.09) and X+ allele (OR=2.28, 95% CI: 1.14-4.59) were positively associated with GSD (P <0.05). Plasma total cholesterol (OR=0.69, 95% CI: 0.64-0.74) was negatively related to GSD (P<0.05).CONCLUSION: With an association analysis, it was determined that A allele of CYP7A gene and X+ allele of APOB gene might be considered as risk genes for GSD. These alleles are related with differences of serum lipids among ***-variable logistic regression model analysis showed that besides BMI, GSD was affected by polygenetic *** the mechanism for these two alleles responsible for GSD requires further investigations.

关键词：胆固醇基因多态性 7α-羟化酶载脂蛋白B 低密度脂蛋白受体胆囊结石

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In silico investigation of the association of the TRPM8 ion channel with the pungent flavor of Chinese herbs

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中医科学杂志（英文） 2016年第4期3卷 248-255页

作者： Yuxin Zhang xing Wang Shifeng Wang Qiao Zhang Sha Peng Xi Li Yanling Zhang yanjiang Qiao Key Laboratory of TCM-Information Engineer of State Administration of TCM School of Chinese Materia MedicaBeijing University of Chinese MedicineBeijing 100102China Beijing Key Lab of Traditional Chinese Medicine(TCM)Collateral Disease Theory Research School of Traditional Chinese MedicineCapital Medical UniversityBeijing 100069China

Objective:Explicating the property and action of traditional Chinese medicine(TCM)in the perspectives of modern science deepens the insight into the property of TCM,and provides the basis for new drug discovery and clinical *** this study,we investigated the relationship between transient receptor potential melastatin 8(TRPM8)and pungent flavor using three-dimensional pharmacophores based on virtual screening ***:Firstly,an inhouse database was established to identify the related pharmacological action according to the traditional Chinese herbs expressing an action of promoting blood ***,several therapeutic targets,3-hydroxy-3-methylglutaryl-coenzyme A reductase(HMG-CoAR),cholesteryl ester transfer protein(CETP),Niemann-Pick C1-Like 1(NPC1L1)and platelet-activating factor receptor(PAFR),were selected to screen traditional Chinese herbs,and the common virtual screening hits with various hit scores providing data to reveal the correlation among TRPM8 and therapeutic ***:According to the screening results,TRPM8 agonists were able to identify the effective components of pungent herbs and TRPM8,which shares the common virtual screening hits with the therapeutic targets,was considered to be related to the action of pungent ***:The novel ideas and methods in this study are beneficial to unveil the scientific relationship between a TCM property and its action.

关键词： Five flavors Pungent flavor TRPM8 Pharmacophore Pharmacological action

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基于XGBoost的测井解释规则库自动获取方法

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石油物探 2022年第2期61卷 356-363页

作者：邢强张晋言王镇方马睿姜文宗刘宝弟王延江中石化经纬有限公司胜利测井公司山东东营257096 中国石油大学(华东)海洋与空间信息学院山东青岛266580 中国石油大学(华东)控制科学与工程学院山东青岛266580

传统的测井解释规则库的获取需专业研究人员以手工方式进行,存在繁琐、耗时等缺点,且技术熟练程度直接影响到解释评价效果,为此,提出了一种基于XGBoost的测井解释规则库自动获取或建立测井解释专家规则库的方法,将多种物理信息和地质参... 详细信息

传统的测井解释规则库的获取需专业研究人员以手工方式进行,存在繁琐、耗时等缺点,且技术熟练程度直接影响到解释评价效果,为此,提出了一种基于XGBoost的测井解释规则库自动获取或建立测井解释专家规则库的方法,将多种物理信息和地质参数作为输入特征,储层类别作为输出标签,通过引入XGBoost算法,经过学习得出地质参数与储层类别之间的关系模型。利用该模型,可以自动预测储层类别,进而建立测井解释规则库。胜利油田盐家永安地区某砂砾岩油气藏的砂砾岩测井解释评价结果表明,与支持向量机(SVM)算法和梯度提升决策树(GBDT)算法相比,本文方法具有更高的准确率和更高的计算效率。研究区老井复查结果表明:与手工获取规则库方法相比,本文方法较完整地提取了研究区内的知识规则,提升了测井解释的准确率。

关键词： XGBoost 测井解释决策树模式识别规则库 GBDT

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