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Ailanthone ameliorates pulmonary fibrosis by suppressing JUN-dependent MEOX1 activation

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3543-3560页

作者： Lixin Zhao Yuguang Zhu Hua Tao Xiying Chen Feng Yin Yingyi Zhang Jianfeng Qin Yongyin Huang Bikun Cai Yonghao Lin Jiaxiang Wu Yu Zhang Lu Liang Ao Shen Xi-Yong Yu The Fifth Affiliated Hospital Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target and Clinical PharmacologyNMPA&State Key LaboratorySchool of Pharmaceutical SciencesGuangzhou Medical UniversityGuangzhou 511436China

Pulmonary fibrosis poses a significant health threat with very limited therapeutic options *** this study,we reported the enhanced expression of mesenchymal homobox 1(MEOX1)in pulmonary fibrosis patients,especially in their fibroblasts and endothelial cells,and confirmed MEOX1 as a central orchestrator in the activation of profibrotic *** high-throughput screening,we identified Ailanthone(AIL)from a natural compound library as the first small molecule capable of directly targeting and suppressing *** demonstrated the ability to inhibit both the activation of fibroblasts and endothelial-to-mesenchymal transition of endothelial cells when challenged by transforming growth factor-b1(TGF-b1).In an animal model of bleomycin-induced pulmonary fibrosis,AIL effectively mitigated the fibrotic process and restored respiratory ***,AIL acted as a suppressor of MEOX1 by disrupting the interaction between the transcription factor JUN and the promoter of MEOX1,thereby inhibiting MEOX1 expression and *** summary,our findings pinpointed MEOX1 as a cell-specific and clinically translatable target in ***,we demonstrated the potent anti-fibrotic effect of AIL in pulmonary fibrosis,specifically through the suppression of JUN-dependent MEOX1 activation.

关键词： Ailanthone MEOX1 Pulmonary fibrosis JUN TGF-b1 High-throughput screening Natural product

Inhibition of tubulin detyrosination:a novel strategy to promote central nervous system regeneration

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Neural Regeneration Research 2024年第12期19卷 2557-2558页

作者： Charlotte Zeitler Marco Leibinger Dietmar Fischer Center of pharmacology Institute for PharmacologyMedical Faculty and University of CologneCologneGermany

The adult mammalian central nervous system(CNS) coordinates essential functions such as sensation,movement,autonomic control,thought processes,and ***,injuries or diseases of the CNS are often associated with devastating and permanent functional impairments because damaged axons normally fail to *** insufficient neuron-intrinsic growth capacity and an inhibitory environment at the injury site are the leading causes of this regenerative failure.

关键词： injuries sensation diseases

Probiotics: Shaping the gut immunological responses

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World Journal of Gastroenterology 2024年第15期30卷 2096-2108页

作者： Eirini Filidou Leonidas Kandilogiannakis Anne Shrewsbury George Kolios Katerina Kotzampassi Faculty of Medicine Laboratory of PharmacologyDemocritus University of ThraceAlexandroupolis 68100Greece Department of Surgery Aristotle University of ThessalonikiThessaloniki 54636Greece

Probiotics are live microorganisms exerting beneficial effects on the host’s health when administered in adequate *** the most popular and adequately studied probiotics are bacteria from the families Lactobacillaceae,Bifidobacteriaceae and *** of them have been shown,both in vitro and in vivo studies of intestinal inflammation models,to provide favorable results by means of improving the gut microbiota composition,promoting the wound healing process and shaping the immunological *** intestinal conditions,such as inflammatory bowel diseases(IBD),are characterized by an imbalance in microbiota composition,with decreased diversity,and by relapsing and persisting inflammation,which may lead to mucosal *** the results of the clinical studies investigating the effect of probiotics on patients with IBD are still controversial,it is without doubt that these microorganisms and their metabolites,now named postbiotics,have a positive influence on both the host’s microbiota and the immune system,and ultimately alter the topical tissue *** influence is achieved through three axes:(1)By dis-placement of potential pathogens via competitive exclusion;(2)by offering protection to the host through the secretion of various defensive mediators;and(3)by supplying the host with essential *** will analyze and discuss almost all the in vitro and in vivo studies of the past 2 years dealing with the possible favorable effects of certain probiotic genus on gut immunological responses,highlighting which species are the most beneficial against intestinal inflammation.

关键词： Probiotics Lactobacillaceae Bifidobacteriaceae Saccharomyces Intestinal inflammation Immune responses

m^(6)A reader YTHDF1 promotes cardiac fibrosis by enhancing AXL translation

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Frontiers of Medicine 2024年第3期18卷 499-515页

作者： Han Wu Weitao Jiang Ping Pang Wei Si Xue Kong Xinyue Zhang Yuting Xiong Chunlei Wang Feng Zhang Jinglun Song Yang Yang Linghua Zeng Kuiwu Liu Yingqiong Jia Zhuo Wang Jiaming Ju Hongtao Diao Yu Bian Baofeng Yang Department of pharmacology(National Key laboratory of Frigid Zone Cardiovascular Diseases the State-Province Key Laboratories of Biomedicine-Pharmaceutics of ChinaKey Laboratory of Cardiovascular ResearchMinistry of Education)College of PharmacyHarbin Medical UniversityHarbin150081China

Cardiac fibrosis caused by ventricular remodeling and dysfunction such as post-myocardial infarction(MI)can lead to heart *** N6-methyladenosine(m^(6)A)methylation has been shown to play a pivotal role in the occurrence and development of many *** investigating the biological function of the m^(6)A reader YTHDF1 in cardiac fibrosis,adeno-associated virus 9 was used to knock down or overexpress the YTHDF1 gene in mouse hearts,and MI surgery in vivo and transforming growth factor-β(TGF-β)-activated cardiac fibroblasts in vitro were performed to establish fibrosis *** results demonstrated that silencing YTHDF1 in mouse hearts can significantly restore impaired cardiac function and attenuate myocardial fibrosis,whereas YTHDF1 overexpression could further enhance cardiac dysfunction and aggravate the occurrence of ventricular pathological remodeling and fibrotic ***,zinc finger BED-type containing 6 mediated the transcriptional function of the YTHDF1 gene ***1 augmented AXL translation and activated the TGF-β-Smad2/3 signaling pathway,thereby aggravating the occurrence and development of cardiac dysfunction and myocardial ***,our data indicated that YTHDF1 was involved in activation,proliferation,and migration to participate in cardiac fibrosis in *** results revealed that YTHDF1 could serve as a potential therapeutic target for myocardial fibrosis.

关键词： cardiac fibrosis YTHDF1 AXL ZBED6 heart failure

GRK2 inhibits Flt-1^(+)macrophage infiltration and its proangiogenic properties in rheumatoid arthritis

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Acta Pharmaceutica Sinica B 2024年第1期14卷 241-255页

作者： Xuezhi Yang Yingjie Zhao Qi Wei Xuemin Zhu Luping Wang Wankang Zhang Xiaoyi Liu Jiajie Kuai Fengling Wang Wei Wei Institute of Clinical pharmacology Anhui Medical UniversityKey Laboratory of Anti-Inflammatory and Immune MedicineAnhui Collaborative Innovation Center of Anti-Inflammatory and Immune MedicineMinistry of EducationHefei 230032China Department of Clinical pharmacology the Second Affiliated Hospital of Anhui Medical UniversityHefei 230601China

Rheumatoid arthritis(RA)is an autoimmune disease with a complex ***-derived macrophages(MDMs)infiltration are associated with RA *** have reported the deletion of G-protein-coupled receptor kinase 2(GRK2)reprograms macrophages toward an anti-inflammatory phenotype by recovering G-protein-coupled receptor ***,as more GRK2-interacting proteins were discovered,the GRK2 interactome mechanisms in RA have been ***,in the collagen-induced arthritis mouse model,we performed genetic GRK2 deletion using GRK2^(f/f)Lyz2-Cre^(+/−)*** inflammation and M1 polarization were improved in GRK2^(f/f)Lyz2-Cre^(+/−)*** experiments with RNA-seq and dual-luciferase reporter assays identified peroxisome proliferator-activated receptorγ(PPARγ)as a new GRK2-interacting *** further confirmed that fms-related tyrosine kinase 1(Flt-1),which promoted macrophage migration to induce angiogenesis,was inhibited by GRK2-PPARγ***,excess GRK2 membrane recruitment in CIA MDMs reduced the activation of PPARγligand-binding domain and enhanced Flt-1 ***,the treatment of mice with GRK2 activity inhibitor resulted in significantly diminished CIA pathology,Flt-1^(+)macrophages induced-synovial inflammation,and ***,we anticipate to facilitate the elucidation of previously unappreciated details of GRK2-specific intracellular *** GRK2 activity is a viable strategy to inhibit MDMs infiltration,affording a distinct way to control joint inflammation and angiogenesis of RA.

关键词： GRK2 Monocyte-derived macrophages Rheumatoid arthritis PPARg Flt-1

Na^(+)/K^(+)-ATPase:ion pump,signal transducer,or cytoprotective protein,and novel biological functions

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Neural Regeneration Research 2024年第12期19卷 2684-2697页

作者： Songqiang Huang Wanting Dong Xiaoqian Lin Jinsong Bian Department of pharmacology Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and DiseasesSchool of MedicineSouthern University of Science and TechnologyShenzhenGuangdong ProvinceChina Department of pharmacology School of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei ProvinceChina

Na^(+)/K^(+)-ATPase is a transmembrane protein that has important roles in the maintenance of electrochemical gradients across cell membranes by transporting three Na^(+)out of and two K^(+)into ***,Na^(+)/K^(+)-ATPase participates in Ca^(2+)-signaling transduction and neurotransmitter release by coordinating the ion concentration gradient across the cell ***^(+)/K^(+)-ATPase works synergistically with multiple ion channels in the cell membrane to form a dynamic network of ion homeostatic regulation and affects cellular communication by regulating chemical signals and the ion balance among different types of *** re,it is not surprising that Na^(+)/K^(+)-ATPase dysfunction has emerged as a risk factor for a variety of neurological ***,published studies have so far only elucidated the important roles of Na^(+)/K^(+)-ATPase dysfunction in disease development,and we are lacking detailed mechanisms to clarify how Na^(+)/K^(+)-ATPase affects cell *** recent studies revealed that membrane loss of Na^(+)/K^(+)-ATPase is a key mechanism in many neurological disorders,particularly stroke and Parkinson's *** of plasma membrane Na^(+)/K^(+)-ATPase with an antibody is a novel strategy to treat these *** this reason,Na^(+)/K^(+)-ATPase acts not only as a simple ion pump but also as a sensor/regulator or cytoprotective protein,participating in signal transduction such as neuronal autophagy and apoptosis,and glial cell ***,the present review attempts to summarize the novel biological functions of Na^(+)/K^(+)-ATPase and Na^(+)/K^(+)-ATPase-related *** potential for novel strategies to treat Na^(+)/K^(+)-ATPase-related brain diseases will also be discussed.

关键词： antibody biological functions cellular communication electrochemical gradient ion balance ion channels Na^(+)/K^(+)-ATPase neurological diseases neurotransmitter release signal transduction

Discovery of first-in-class DOT1L inhibitors against the R231Q gain-of-function mutation in the catalytic domain with therapeutic potential of lung cancer

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3605-3623页

作者： Zehui Tan Ning Guo Zhi Cao Shuyu Liu Jiayu Zhang Deyi Ma Jiahao Zhang Wencai Lv Nan Jiang Linghe Zang Lihui Wang Xin Zhai Key laboratory of Structure-Based Drug Design and Discovery Ministry of EducationShenyang Pharmaceutical UniversityShenyang 110016China Department of pharmacology Shenyang Pharmaceutical UniversityShenyang 110016China

Recent research certified that DOT1L and its mutations represented by R231Q were potential targets for the treatment of lung ***,a series of adenosine-containing derivatives were identified with DOT1LR231Q inhibition through antiproliferation assay and Western blot analysis in the H460R231Q *** most promising compound 37 significantly reduced DOT1LR231Q mediated H3K79 methylation and effectively inhibited the proliferation,self-renewal,migration,and invasion of lung cancer cell lines at low micromolar *** cell permeability and cellular target engagement of 37 were verified by both CETSA and DARTS *** the H460R231Q OE cell-derived xenograft(CDX)model,37 displayed pronounced tumor growth inhibition after intraperitoneal administration at 20 mg/kg dose for 3 weeks(TGI=54.38%),without obvious toxicities.A pharmacokinetic study revealed that 37 possessed tolerable properties(t_(1/2)=1.93±0.91 h,F=97.2%)after intraperitoneal administration in *** study confirmed that 37 suppressed malignant phenotypes of lung cancer carrying R231Q gain-of-function mutation via the MAPK/ERK signaling ***,analysis of the binding modes between molecules and DOT1LWT/R231Q proteins put forward the“Induced-fit”allosteric model in favor to the discovery of potent DOT1L candidates.

关键词： DOT1L R231Q mutation Lung cancer Adenosine-containing inhibitors Epigenetics

Dual-targeting AAV9P1-mediated neuronal reprogramming in a mouse model of traumatic brain injury

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Neural Regeneration Research 2024年第3期19卷 629-635页

作者： Jingzhou Liu Xin Xin Jiejie Sun Yueyue Fan Xun Zhou Wei Gong Meiyan Yang Zhiping Li Yuli Wang Yang Yang Chunsheng Gao State Key laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and ToxicologyBeijingChina Academy of Medical Engineering and Translational Medicine Medical CollegeTianjin UniversityTianjinChina

Traumatic brain injury results in neuronal loss and glial scar *** neurons and eliminating the consequences of glial scar formation are essential for treating traumatic brain *** reprogramming is a promising strategy to convert glial scars to neural ***,previous studies have reported inconsistent *** this study,an AAV9P1 vector incorporating an astrocyte-targeting P1 peptide and glial fibrillary acidic protein promoter was used to achieve dual-targeting of astrocytes and the glial scar while minimizing off-target *** results demonstrate that AAV9P1 provides high selectivity of astrocytes and reactive ***,neuronal reprogramming was induced by downregulating the polypyrimidine tract-binding protein 1 gene via systemic administration of AAV9P1 in a mouse model of traumatic brain *** summary,this approach provides an improved gene delivery vehicle to study neuronal programming and evidence of its applications for traumatic brain injury.

关键词： AAV9P1 astrocytes astrocyte-to-neuron conversion GFAP promoter glial scar induced neurons neuronal reprogramming P1 peptide PTBP1 traumatic brain injury

1,12-cyclic apelin-12 ameliorates Ang II and Apelin-13-induced cardiac hypertrophy by reducing mitochondrial oxidative damage

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Chinese Medical Journal 2024年第6期137卷 749-751页

作者： Xueqian Ouyang Wei Chen Guolong Peng Huimei Liu Sisi Fan Qin Li Liwen Wang Linxi Chen Lanfang Li The Institute of Pharmacy and pharmacology Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug ResearchUniversity of South ChinaHengyangHunan 421001China

To the Editor:Pathological cardiac hypertrophy is commonly stimulated by stress or induced by cardiovascular diseases,such as hypertension and myocardial infarction.A sustained pathological hypertrophic response can lead to declines in diastolic and systolic functions and eventually develop heart *** II(Ang II)can mediate cardiac hypertrophy through the angiotensin II type 1 receptor(AT1R).^([1])

关键词： hypertrophy cardiac Ang