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Inhibition of P2X7R modulates ECM deposition in HSCs and crosstalk with macrophages in liver fibrosis

中国药理学与毒理学杂志 2019年第10期 772-773页

作者： JIANG Min CUI Ben-wen ZHANG Yu WU Yan-ling NAN Ji-xing LIAN Li-hua key laboratory for Natural Resource of Changbai Mountain& functional Molecules Ministry of Education College of Pharmacy Yanbian University

OBJECTIVE Modulation of immune response and reduction of extracellular matrix(ECM)deposition are both essential in the therapy of liver *** P2 X7 R might be a potential therapeutic strategy to treat liver fibrosis, we investigated whether the blockade of P2 X7 R could reverse liver fibrosis and how P2 X7 R is involved in fibrogenesis during hepatic stellate cells(HSCs) and macrophages crosstalk. METHODS In vivo,liver fibrosis model was established by thioacetamide(TAA) intraperitoneal administration in male C57 BL/6 mice. In vitro, LX-2 cells were treated with TGF-β and LPS/ATP respectively. Supernatant from LPS/ATP stimulated THP-1 macrophages were supplemented to LX-2 cells to mimic cellular crosstalk between HSCs and macrophages. RESULTS Blockade of P2 X7 R with its selective antagonist A438079, not only decreased liver injury and ECM deposition but also ameliorated inflammation by inhibiting NLRP3 inflammasome, NF-κB activation and IL-1β production in TAA-induced liver fibrosis. And the recruitment of macrophages, monocytes and granulocytes were also inhibited. In TGF-β-stimulated LX-2 cells,ECM deposition was reduced by the inhibiting of P2 X7 RTLR4-NLRP3 axis. Protein synthesis and cleavage of IL-1β and its m RNA level was dramatically increased by LPS 4 h combined with ATP 30 min than those in HSC treated with LPS or ATP alone. Additionally, LX-2 cells primed with LPS/ATP greatly increased m RNA and protein expression of caspase-1, NLRP3 and P2 x7 R, as well as liver fibrosis markers, α-SMA and typeⅠ*** events were remarkably suppressed by A438079 pretreatment. si RNA against P2 x7 R reduced protein expression of NLRP3 and α-SMA, and suppressed deposition and secretion of type Ⅰ collagen induced by LPS/ATP. Ectopic overexpression of P2 X7 R reduced the threshold of ECM deposition in HSCs induced by TGF-β.Inhibiting upstream receptors of NLRP3 inflammasome,P2 X7 receptor-selective antagonist(A438079), TLR4 inhibitor(CLI-095) reduced

关键词： liver fibrosis hepatic stellate cells macrophages P2x7R IL-1β

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Enhancing the HSV-1-mediated antitumor immune response by suppressing Bach1

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cellular & Molecular Immunology 2022年第4期19卷 516-526页

作者： Chaohu Pan Qiaomei Cai Xiaorong Li Lili Li Liping Yang Yu Chen Junxiao Liu Wancheng Liu Meiling Gao Tianqi Sui Xiaoyang Wang Huiming Fan Jiayin Ruan Yueyue Shi Saihua Chen Lucy S.Cheng Jiayong Liu Heng Yang Genhong Cheng Institute of Basic Medical Sciences Chinese Academy of Medical Sciences School of Basic Medicine Peking Union Medical College100005BeijingChina Suzhou Institute of Systems Medicine Suzhou215123JiangsuChina Institute of Systems Medicine Chinese Academy of Medical Sciences&Peking Union Medical College100005BeijingChina The Second Affiliated Hospital Zhejiang University School of Medicine310009HangzhouChina Heze Vocational College 274008HezeChina Affiliated Tumor Hospital of Nantong University 226000NantongChina Department of Dermatology University of Pittsburgh Medical Center3708 Fifth AvenueSuite 500.68PittsburghPA15213USA key laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Department of Bone and Soft Tissue TumorPeking University Cancer Hospital&Institute52 Fucheng Rd100142BeijingChina Department of Molecular and Medical pharmacology and California NanoSystems Institute University of CaliforniaLos AngelesLos AngelesCA90095USA

Background In 2015,herpes simplex virus 1(HSV-1)-derived talimogene laherparepvec(T-VEC)was the first oncolytic virus approved by the US Food and Drug Administration as a therapeutic agent for cancer ***,its antitumor application is limited to local treatment of melanoma,and there is a lack of understanding of the mechanisms underlying the regulation of HSV-1 replication in cancer cells and the associated antitumor *** hypothesized that increasing the replication capacity of HSV-1 in tumor cells would enhance the antitumor effect of this *** We systematically identified IFN-stimulated genes induced by HSV-1 by performing functional screens and clarified the mechanism by which BACH1 acts against ***,we tested the effect of BACH1 deficiency on immunogenic cell death induced by ***,we investigated the antitumor effect of BACH1 deficiency on HSV-1 in MCA205 and B16 murine tumor *** We identified eight IFN-stimulated genes(ISGs)controlling HSV-1 replication,among which BTB and CNC homology 1(BACH1)suppressed HSV-1 replication by inhibiting the transcription of ICP4,ICP27,and *** of Bach1 function not only increased HSV-1 proliferation but also promoted HSV-1-induced cell apoptosis,HMGB1 secretion,and calreticulin exposure in tumor *** importantly,hemin,an FDA-approved drug known to downregulate BACH1,significantly enhanced HSV-1-mediated antitumor activity with increased T lymphocyte infiltration at the tumor *** Our studies uncovered a novel antiviral activity of BACH1 and provided a new strategy for improving the clinical efficiency of the oncolytic virus HSV-1.

关键词： IFN stimulated genes Bach1 HSV-1 Hemin Antitumor immunity

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The effect of apelin/APJ system on pathological and physiology function of vascular smooth muscle cell

The effect of apelin/APJ system on pathological and physiolo...

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2016年中国药学大会暨第十六届中国药师周

作者： Xuling Luo Jin Xu Lu Liqun Jingyong Jiang Mingzhu Tang Qionglin Zhou Jiaqi Liu Lu He LanFang Li Linxi Chen Institute of Pharmacy and pharmacology Hunan Province Cooperative innovation Center for Molecular Target New Drugs StudyUniversity of South China

Apelin is endogenous ligand of APJ which is an orphan G protein-coupled receptor. Apelin/APJ has a variety of biological effects about cells. Apelin treatment can increase endothelial cell proliferation and inhibits thrombin and collagen but not ADP and TXA2-induced platelet aggregation in vitro. As for vascular smooth muscle cell（VSMC）, an integral part of the vascular wall, takes part in normal physiological processes. VSMC dysfunction is linked to the progression of various cardiovascular diseases such as atherosclerosis and hypertension. This review offers a molecular insight into the effect of apelin in regulation of proliferation and anti-apoptotic, migration, contraction and relaxation, calcification of VSMC. What is more, apelin is a promising target for managing VSMC-related disease. This review demonstrates that apelin/APJ system plays a very important role in regulating VSMCs. Proliferation: Our laboratory first time founds that apelin enhances VSMC proliferation by PI3 K/Akt signaling transduction pathway and the regulation of cyclin D1. Anti-apoptotic: PI3 K/Akt signaling transduction pathway is a key role in treatment strategies of tumors, which involves the regulation of cellular functions, including proliferation, differentiation, apoptosis, migration and glucose transport. Further research shows that apelin suppresses serum deprivation-induced human VSMCs apoptosis. Migration: Through PI3 K/Akt signaling transduction pathway, apelin also protects VSMC from apoptosis and promote VSMC migration. The proliferation and migration of VSMCs may have effect on atherosclerosis and apelin may hopefully lead to treatment of cardiovascular diseases. Contraction and relaxation: Hypertension is a kind of cardiovascular diseases which is characterized by arterial hypertension. The emergence of apelin as an important regulator in vasodilatation has attracted increasing attention on the molecular mechanisms of nitric oxide-dependent pathways. But on the contrary, ap

关键词： Apelin VSMC Proliferation and anti-apoptotic Migration Contraction and relaxation Calcification Cardiovascular diseases Hypertension Atherosclerosis

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Preserving cognitive function in patients with Alzheimer's disease:The Alzheimer's disease neuroprotection research initiative(ADNRI)

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Neuroprotection 2023年第2期1卷 84-98页

作者： Jie Liu Heleen van Beusekom Xian-Le Bu Gong Chen Paulo Henrique Rosado de Castro Xiaochun Chen Xiaowei Chen Andrew N.Clarkson Tracy D.Farr Yuhong Fu Jianping Jia Jukka Jolkkonen Woojin Scott Kim Paula Korhonen Shen Li Yajie Liang Guang-Hui Liu Guiyou Liu Yu-Hui Liu Tarja Malm Xiaobo Mao Joaquim Miguel Oliveira Mike M.Modo Pedro Ramos-Cabrer Karsten Ruscher Weihong Song Jun Wang Xuanyue Wang Yun Wang Haitao Wu Lize Xiong Yi Yang Keqiang Ye Jin-Tai Yu Xin-Fu Zhou Marietta Zille Colin L.Masters Piotr Walczak Boltze Johannes Xunming Ji Yan-Jiang Wang Department of Neurology Daping HospitalThird Military Medical UniversityChongqingChina Chongqing key laboratory of Ageing and Brain Diseases ChongqingChina Division of Experimental Cardiology Department of CardiologyErasmus MCUniversity Medical CenterRotterdamThe Netherlands Institute of Brain and Intelligence Third Military Medical UniversityChongqingChina Guangdong-HongKong-Macao Institute of CNS Regeneration(GHMICR) Jinan UniversityGuangzhouGuangdongChina Institute of Biomedical Sciences Federal University of Rio de JaneiroRio de JaneiroRio de JaneiroBrazil Fujian key laboratory of Molecular Neurology Department of Neurology and GeriatricsFujian Institute of GeriatricsFujian Medical University Union HospitalInstitute of NeuroscienceFujian Medical UniversityFuzhouFujianChina Guangyang Bay laboratory Chongqing Institute for Brain and IntelligenceChongqingChina Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of SciencesShanghaiChina Department of Anatomy Brain Health Research Centre and Brain Research New ZealandUniversity of OtagoDunedinNew Zealand School of Life Sciences University of NottinghamNottinghamUK Brain and Mind Centre&School of Medical Sciences The University of SydneySydneyNew South WalesAustralia Innovation Center for Neurological Disorders and Department of Neurology Xuanwu HospitalNational Clinical Research Center for Geriatric DiseasesCapital Medical UniversityBeijingChina A.I.Virtanen Institute for Molecular Sciences University of Eastern FinlandKuopioFinland Department of Neurology and Psychiatry Beijing Shijitan HospitalCapital Medical UniversityBeijingChina Department of Diagnostic Radiology and Nuclear Medicine University of Maryland School of MedicineBaltimoreMarylandUSA University of Chinese Academy of Sciences BeijingChina State key laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijingChina Beijing Institute of Brain Disorders Laboratory of Brain DisordersMinistry of Sci

The global trend toward aging populations has resulted in an increase in the occurrence of Alzheimer's disease(AD)and associated socioeconomic *** metabolism of amyloid-β(Aβ)has been proposed as a significant pathomechanism in AD,supported by results of recent clinical trials using anti-Aβ***,the cognitive benefits of the current treatments are *** etiology of AD is multifactorial,encompassing Aβand tau accumulation,neuroinflammation,demyelination,vascular dysfunction,and comorbidities,which collectively lead to widespread neurodegeneration in the brain and cognitive ***,solely removing Aβfrom the brain may be insufficient to combat neurodegeneration and preserve *** attain effective treatment for AD,it is necessary to(1)conduct extensive research on various mechanisms that cause neurodegeneration,including advances in neuroimaging techniques for earlier detection and a more precise characterization of molecular events at scales ranging from cellular to the full system level;(2)identify neuroprotective intervention targets against different neurodegeneration mechanisms;and(3)discover novel and optimal combinations of neuroprotective intervention strategies to maintain cognitive function in AD *** Alzheimer's Disease Neuroprotection Research Initiative's objective is to facilitate coordinated,multidisciplinary efforts to develop systemic neuroprotective strategies to combat *** aim is to achieve mitigation of the full spectrum of pathological processes underlying AD,with the goal of halting or even reversing cognitive decline.

关键词： Alzheimer's disease early intervention neural regeneration neuroprotection systematic perspective

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Tetramethylpyrazine nitrone improved mitochondrial dysfunction, downregulated α-synuclein, and reduced neurodegeneration in Parkinson disease models

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中国药理学与毒理学杂志 2019年第10期 843-844页

作者： GUO Bao-jian ZHENG Cheng-you QIU Xiao-ling ZHANG Zai-jun Institute of New Drug Research and Guangzhou key laboratory of Innovative Chemical Drug Research in Cardiocerebrovascular Diseases Jinan University College of Pharmacy

OBJECTIVE The peroxisome proliferatoractivated receptor γ co-activator 1α(PGC-1α) and nuclear factor(erythroid-derived 2)-like 2(Nrf2) are key regulators controlling antioxidant defense, mitochondrial biogenesis and cellular proteostasis. Dysfunction of any of these processes has been implicated in the pathogenesis of Parkinson disease(PD). Activation of PGC-1α/Nrf2 might improve mitochondrial dysfunction, promote α-synuclein(α-syn) clearance, and attenuate degeneration of nigral dopaminergic neurons in PD. To test this, we used tetramethylpyrazine nitrone(TBN), a potent free radical scavenger, to activate PGC-1α/Nrf2 pathway. METHODS 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine(MPTP)-induced mouse model, unilateral intrastriatal injection of 6-hydroxydopamine(6-OHDA)-induced rat model, and transgenic mice overexpression of human A53 T mutant α-synuclein were used to evaluate TBN's therapeutic efficacy and to explore its mechanisms of action. RESULTS TBN protected against 1-methyl-4-phenylpyridinium(MPP+) and 6-OHDA insult in cultured primary midbrain neurons. TBN promoted α-syn clearance by autophagy and proteasomal pathways in the cell models overexpressed human A53 T mutant α-syn. In MPTP-treated mouse and unilateral 6-OHDA-lesioned rat, as well as in α-syn transgenic mouse model, TBN improved motor impairment, increased survive of nigra dopaminergic neurons, and elevated striatal dopamine level, while decreased the products of oxidative ***, TBN down-regulated α-syn level in the brain and serum of α-syn transgenic mice. These improvements in vitro and in vivo were associated with activation of PGC-1α/Nrf2 signal pathway, resulting in reduced oxidative stress, enhanced mitochondrial function, and increased protein clearance. CONCLUSION Our work demonstrates that activation of PGC-1α/Nrf2 by TBN can maintain the survival of nigral dopaminergic neurons, and might be disease-modifying in PD models, providing the critical rationale for further devel

关键词： tetramethylpyrazine nitrone Parkinson disease peroxisome proliferator-activated receptor γ co-activator 1α nuclear factor(erythroid-derived 2)-like 2 α-synuclein

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Ticagrelor inhibits the NLRP3 inflammasome to protect against inflammatory disease independent of the P2Y_(12 ) signaling pathway

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cellular & Molecular Immunology 2021年第5期18卷 1278-1289页

作者： Bo Huang Yufeng Qian Shujun Xie Xianhua Ye Hanwen Chen Zhifeng Chen Lihuan Zhang Jinming Xu Hu Hu Shenglin Ma Paul Héroux Di Wang Han-Ming Shen Yihua Wu Dajing Xia Department of Toxicology of School of Public Health and Department of Gynecologic Oncology of Women’s HospitalZhejiang University School of MedicineHangzhouChina Department of Cardiology Affiliated Hangzhou First People’s HospitalZhejiang University School of MedicineHangzhouChina Translational Medicine Research Center and Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang ProvinceAffiliated Hangzhou First People’s HospitalZhejiang University School of MedicineHangzhouChina Department of Thoracic Surgery The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina Department of Pathology and Pathophysiology Zhejiang University School of MedicineHangzhouChina Department of Oncology Affiliated Hangzhou First People’s HospitalZhejiang University School of MedicineHangzhouChina Department of Epidemiology Biostatistics and Occupational HealthMcGill UniversityMontrealQCCanada Institute of Immunology Zhejiang University School of MedicineHangzhouChina Department of Physiology Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore

Ticagrelor is the first reversibly binding oralP2Y_(12) receptor antagonist to inhibit platelet activation and has been approved by the Food and Drug Administration for the treatment of coronary artery disease. At present, the other pharmacological functions of ticagrelor remain poorly understood. The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome plays a critical role in the innate immune system, but its excessive activation also contributes to the pathogenesis of complex diseases. In this study, we systematically examined the effects of ticagrelor on the NLRP3 inflammasome and found that ticagrelor inhibits NLRP3 inflammasome activation in macrophages independent of its classic inhibitory effect on theP2Y_(12) signaling pathway. Further mechanistic studies demonstrate that ticagrelor attenuates the oligomerization of apoptosis-associated speck-like protein containing a CARD (ASC) by blocking chloride efflux, an effect achieved through the degradation of chloride intracellular channel proteins (CLICs) and blockade of the translocation of CLICs to the plasma membrane. Moreover, experiments on lipopolysaccharide-induced sepsis and alum-induced peritonitis in mice confirmed that ticagrelor mitigates the severity of systemic inflammation independent ofP2Y_(12) receptor antagonism. Importantly, oral administration of ticagrelor rapidly and strongly inhibited NLRP3 inflammasome activation in peripheral blood mononuclear cells from patients with acute coronary syndrome. Overall, our study reveals a novel pharmacological function of ticagrelor in addition to its classic antiplatelet properties, which suggests that ticagrelor may serve as a potential therapeutic agent for use in NLRP3-associated diseases.

关键词： Ticagrelor NLRP3 inflammasome P2Y_(12) Chloride efflux ASC

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Structural and functional insights into sorting nexin 5/6 interaction with bacterial effector IncE

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Signal Transduction and Targeted Therapy 2017年第1期2卷 175-181页

作者： Qingxiang Sun Xin Yong Xiaodong Sun Fan Yang Zhonghua Dai Yanqiu Gong Liming Zhou Xia Zhang Dawen Niu Lunzhi Dai Jia-Jia Liu Da Jia Department of Pathology State Key Laboratory of BiotherapyWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduChina key laboratory of Birth Defects and Related Diseases of Women and Children of MOE Department of PaediatricsWest China Second University HospitalSichuan UniversityChengduChina Department of pharmacology West China School of Preclinical and Forensic MedicineSichuan UniversityChengduChina State key laboratory of Molecular Developmental Biology Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijingChina

The endosomal trafficking pathways are essential for many cellular *** are also important targets by many intracellular *** regulators of the endosomal trafficking include the retromer complex and sorting nexins(SNXs).Chlamydia trachomatis effector protein IncE directly targets the retromer components SNX5 and SNX6 and suppresses retromer-mediated transport,but the exact mechanism has remained *** present the crystal structure of the PX domain of SNX5 in complex with IncE,showing that IncE binds to a highly conserved hydrophobic groove of *** unique helical hairpin of SNX5/6 is essential for binding,explaining the specificity of SNX5/6 for *** SNX5/6–IncE interaction is required for cellular localization of IncE and its inhibitory ***,IncE inhibits the association of CI-MPR cargo with retromer-containing endosomal *** study provides new insights into the regulation of retromer-mediated transport and illustrates the intricate competition between host and pathogens in controlling cellular trafficking.

关键词： function. insight interaction

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Study on the Mechanism of Mulberry Root Bark Decoction in the Treatment of Chronic Obstructive Pulmonary Disease based on Network pharmacology

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Journal of Clinical and Nursing Research 2021年第5期5卷 90-95页

作者： Jie Meng Xuanguo Zhang Shaanxi University of Chinese Medicine Xianyang 712046Shaanxi ProvinceChina Shaanxi Provincial Hospital of Chinese Medicine Xi'an 710000Shaanxi ProvinceChina

Objective:Study the mechanism of Mulberry Root Bark Decoction in the treatment of COPD based on network ***:The active components and predictive targets of Mulberry Root Bark Decoction were screened by TCMSP *** disease targets of COPD were collected by searching GeneCards,DisGeNET,PhamGKB and TTD *** R language to draw Venn diagram,and get the key target of Mulberry Root Bark Decoction in the treatment of *** was used to construct the regulatory network of drug active ingredient disease *** key targets were imported into string database to construct protein-protein interaction network,and the core targets were obtained by network topology analysis with Cytoscape ***,the Bioconductor platform and R language were used for GO and KEGG enrichment analysis・Results:There were 142 active components and 255 drug targets in Mulberry Root Bark Decoction.1941 COPD targets were *** were 129 common targets of Mulberry Root Bark Decoction and COPD;Eight core targets of PPI network were *** function analysis is involved in oxidative stress,cellular chemical stress and other biological *** components such as cell membrane raft and membrane region involve molecular functions such as ubiquitin like protein ligase and DNA binding transcription *** mainly includes PI3K-Akt signal pathway,tumor necrosis factor signal pathway,IL-17 signal pathway,***:Quercetin,luteolin,kaempferol,wogonin and other active components in Mulberry Root Bark Decoction act on PI3K/Akt,TNF,IL-17,TCR and other signal pathways through Jun,TP53,MAPK1,IL6 and other targets to play an anti-inflammatory and reduce oxidative stress response *** results of this study can provide a reference for further study on the mechanism of Mulberry Root Bark Decoction in the treatment of chronic obstructive pulmonary disease.

关键词： Mulberry Root Bark Decoction Network pharmacology COPD Action mechanism

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