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Targeting deubiquitinase OTUB1 protects vascular smooth muscle cells in atherosclerosis by modulating PDGFRβ

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Frontiers of Medicine 2024年第3期18卷 465-483页

作者： Fei Xu Han Chen Changyi Zhou Tongtong Zang Rui Wang Shutong Shen Chaofu Li Yue Yu Zhiqiang Pei Li Shen Juying Qian Junbo Ge Department of Cardiology and Laboratory of Heart Valve disease West China HospitalSichuan UniversityChengdu610041China Department of Cardiology Zhongshan HospitalFudan UniversityResearch Unit of Cardiovascular Techniques and DevicesChinese Academy of Medical SciencesShanghai200032China Shanghai institute of cardiovascular diseases Shanghai200032China National Clinical research Center for Interventional Medicine&Shanghai Clinical research Center for Interventional Medicine(19MC1910300) Shanghai200032China

Atherosclerosis is a chronic artery disease that causes various types of cardiovascular dysfunction.Vascular smooth muscle cells(VSMCs),the main components of atherosclerotic plaque,switch from contractile to synthetic phenotypes during atherogenesis.Ubiquitylation is crucial in regulating VSMC phenotypes in atherosclerosis,and it can be reversely regulated by deubiquitinases.However,the specific effects of deubiquitinases on atherosclerosis have not been thoroughly elucidated.In this study,RNAi screening in human aortic smooth muscle cells was performed to explore the effects of OTU family deubiquitinases,which revealed that silencing OTUB1 inhibited PDGF-BB-stimulated VSMC phenotype switch.Further in vivo studies using Apoe−/−mice revealed that knockdown of OTUB1 in VSMCs alleviated atherosclerosis plaque burden in the advanced stage and led to a stable plaque phenotype.Moreover,VSMC proliferation and migration upon PDGF-BB stimulation could be inhibited by silencing OTUB1 in vitro.Unbiased RNA-sequencing data indicated that knocking down OTUB1 influenced VSMC differentiation,adhesion,and proliferation.Mass spectrometry of ubiquitinated protein confirmed that proteins related to cell growth and migration were differentially ubiquitylated.Mechanistically,we found that OTUB1 recognized the K707 residue ubiquitylation of PDGFRβwith its catalytic triad,thereby reducing the K48-linked ubiquitylation of PDGFRβ.Inhibiting OTUB1 in VSMCs could promote PDGFRβdegradation via the ubiquitin–proteasome pathway,so it was beneficial in preventing VSMCs’phenotype switch.These findings revealed that knocking down OTUB1 ameliorated VSMCs’phenotype switch and atherosclerosis progression,indicating that OTUB1 could be a valuable translational therapeutic target in the future.

关键词： atherosclerosis vascular smooth muscle cell ubiquitylation deubiquitinase OTUB1 PDGFRβ

Molecular mechanisms underlying microglial sensing and phagocytosis in synaptic pruning

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Neural Regeneration research 2024年第6期19卷 1284-1290页

作者： Anran Huo Jiali Wang Qi Li Mengqi Li Yuwan Qi Qiao Yin Weifeng Luo Jijun Shi Qifei Cong Clinical research Center of Neurological disease The Second Affiliated Hospital of Soochow UniversityInstitute of Neuroscience and Jiangsu Key Laboratory of Neuropsychiatric Diseases Soochow University Department of Neurology and Clinical research Center of Neurological disease The Second Affiliated Hospital of Soochow University

Microglia are the main non-neuronal cells in the central nervous system that have important roles in brain development and functional connectivity of neural circuits. In brain physiology, highly dynamic microglial processes are facilitated to sense the surrounding environment and stimuli. Once the brain switches its functional states, microglia are recruited to specific sites to exert their immune functions, including the release of cytokines and phagocytosis of cellular debris. The crosstalk of microglia between neurons, neural stem cells, endothelial cells, oligodendrocytes, and astrocytes contributes to their functions in synapse pruning, neurogenesis, vascularization, myelination, and blood-brain barrier permeability. In this review, we highlight the neuron-derived “find-me,” “eat-me,” and “don’t eat-me” molecular signals that drive microglia in response to changes in neuronal activity for synapse refinement during brain development. This review reveals the molecular mechanism of neuron-microglia interaction in synaptic pruning and presents novel ideas for the synaptic pruning of microglia in disease, thereby providing important clues for discovery of target drugs and development of nervous system disease treatment methods targeting synaptic dysfunction.

关键词： complement immune signals microglia molecular signal synapse elimination synapse formation synapse refinement synaptic pruning

Atorvastatin, etanercept and the nephrogenic cardiac sympathetic remodeling in chronic renal failure rats

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Journal of Geriatric Cardiology 2024年第4期21卷 443-457页

作者： Jing-Yue XU Zheng-Kai XUE Ya-Ru ZHANG Xing LIU Xue ZHANG Xi YANG Tong LIU Kang-Yin CHEN Tianjin Key Laboratory of Ionic-Molecular Function of cardiovascular disease Department of CardiologyTianjin Institute of Cardiologythe Second Hospital of Tianjin Medical UniversityTianjinChina

BACKGROUND Chronic renal failure(CRF) patients are predisposed to arrhythmias, while the detailed mechanisms are unclear. We hypothesized the chronic inflammatory state of CRF patients may lead to cardiac sympathetic remodeling, increasing the incidence of ventricular arrhythmia(VA) and sudden cardiac death. And explored the role of atorvastatin and etanercept in this process.METHODS A total of 48 rats were randomly divided into sham operation group(Sham group), CRF group, CRF + atorvastatin group(CRF + statin group), and CRF + etanercept group(CRF + rhTNFR-Fcgroup). Sympathetic nerve remodeling was assessed by immunofluorescence of growth-associated protein 43(GAP-43) and tyrosine hydroxylase positive area fraction. Electrophysiological testing was performed to assess the incidence of VA by assessing the ventricular effective refractory period and ventricular fibrillation threshold. The levels of tumor necrosis factor-alpha(TNF-α) and interleukin-1beta were determined by Western blotting and enzyme-linked immunosorbent assay.RESULTS Echocardiogram showed that compared with the Sham group, left ventricular end-systolic diameter and ventricular weight/body weight ratio were significantly higher in the CRF group. Hematoxylin-eosin and Masson staining indicated that myocardial fibers were broken, disordered, and fibrotic in the CRF group. Western blotting, enzyme-linked immunosorbent assay,immunofluorescence and electrophysiological examination suggested that compared with the Sham group, GAP-43 and TNF-α proteins were significantly upregulated, GAP-43 and tyrosine hydroxylase positive nerve fiber area was increased, and ventricular fibrillation threshold was significantly decreased in the CRF group. The above effects were inhibited in the CRF + statin group and the CRF + rhTNFR-Fcgroup.CONCLUSIONS In CRF rats, TNF-α was upregulated, cardiac sympathetic remodeling was more severe, and the nephrogenic cardiac sympathetic remodeling existed. Atorvastatin and etanercept could downregulate the expression of TNF-α or inh

关键词： remodeling cardiac inhibited

Bile acids,gut microbiota,and therapeutic insights in hepatocellular carcinoma

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Cancer Biology & Medicine 2024年第2期21卷 144-162页

作者： Yang Song Harry CH Lau Xiang Zhang Jun Yu institute of Digestive disease and Department of Medicine and Therapeutics State Key Laboratory of Digestive DiseaseLi Ka Shing Institute of Health SciencesCUHK Shenzhen Research InstituteThe Chinese University of Hong KongHong KongChina Department of Gastroenterology Zhongshan Hospital Xiamen UniversityXiamen 361004China

Hepatocellular carcinoma(HCC)is a prevalent and aggressive liver malignancy.The interplay between bile acids(BAs)and the gut microbiota has emerged as a critical factor in HCC development and progression.Under normal conditions,BA metabolism is tightly regulated through a bidirectional interplay between gut microorganisms and BAs.The gut microbiota plays a critical role in BA metabolism,and BAs are endogenous signaling molecules that help maintain liver and intestinal homeostasis.Of note,dysbiotic changes in the gut microbiota during pathogenesis and cancer development can disrupt BA homeostasis,thereby leading to liver inflammation and fibrosis,and ultimately contributing to HCC development.Therefore,understanding the intricate interplay between BAs and the gut microbiota is crucial for elucidating the mechanisms underlying hepatocarcinogenesis.In this review,we comprehensively explore the roles and functions of BA metabolism,with a focus on the interactions between BAs and gut microorganisms in HCC.Additionally,therapeutic strategies targeting BA metabolism and the gut microbiota are discussed,including the use of BA agonists/antagonists,probiotic/prebiotic and dietary interventions,fecal microbiota transplantation,and engineered bacteria.In summary,understanding the complex BA-microbiota crosstalk can provide valuable insights into HCC development and facilitate the development of innovative therapeutic approaches for liver malignancy.

关键词： Bile acid gut microbiota hepatocellular carcinoma therapeutics microbiota modulation

M6PR interacts with the HA2 subunit of influenza A virus to facilitate the fusion of viral and endosomal membranes

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Science China(Life Sciences) 2024年第3期67卷 579-595页

作者： Yuzhen Hu Li Jiang Guangwen Wang Yangming Song Zhibo Shan Xuyuan Wang Guohua Deng Jianzhong Shi Guobin Tian Xianying Zeng Liling Liu Hualan Chen Chengjun Li State Key Laboratory for Animal disease Control and Prevention Harbin Veterinary Research InstituteChinese Academy of Agricultural SciencesHarbin 150069China

Influenza A virus(IAV) commandeers numerous host cellular factors for successful replication. However, very few host factors have been revealed to be involved in the fusion of viral envelope and late endosomal membranes. In this study, we identified cation-dependent mannose-6-phosphate receptor(M6PR) as a crucial host factor for the replication of IAV. We found that siRNA knockdown of M6PR expression significantly reduced the growth titers of different subtypes of IAV, and that the inhibitory effect of M6PR siRNA treatment on IAV growth was overcome by the complement of exogenously expressed M6PR. When A549 cells were treated with siRNA targeting M6PR,the nuclear accumulation of viral nucleoprotein(NP) was dramatically inhibited at early timepoints post-infection, indicating that M6PR engages in the early stage of the IAV replication cycle. By investigating the role of M6PR in the individual entry and post-entry steps of IAV replication, we found that the downregulation of M6PR expression had no effect on attachment, internalization, early endosome trafficking,or late endosome acidification. However, we found that M6PR expression was critical for the fusion of viral envelope and late endosomal membranes. Of note, M6PR interacted with the hemagglutinin(HA) protein of IAV, and further studies showed that the lumenal domain of M6PR and the ectodomain of HA2 mediated the interaction and directly promoted the fusion of the viral and late endosomal membranes,thereby facilitating IAV replication. Together, our findings highlight the importance of the M6PR–HA interaction in the fusion of viral and late endosomal membranes during IAV replication.

关键词： influenza A virus M6PR HA membrane fusion late endosome

Genetically predicted waist circumference and risk of atrial fibrillation

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Chinese Medical Journal 2024年第1期137卷 82-86页

作者： Wenting Wang Jiang-shan Tan Jingyang Wang Wei Xu Liting Bai Yu Jin Peng Gao Peiyao Zhang Yixuan Li Yanmin Yang Jinping Liu Department of Cardiopulmonary Bypass State Key Laboratory of Cardiovascular DiseaseFuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100037China Department of Anaesthesiology Second Affiliated HospitalHainan Medical CollegeHaikouHainan 570311China State Key Laboratory of cardiovascular disease Fuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100037China

Introduction:Observational studies have revealed an association between waist circumference(WC)and atrial fibrillation(AF).However,it is difficult to infer a causal relationship from observational studies because the observed associations could be confounded by unknown risk factors.Therefore,the causal role of WC in AF is unclear.This study was designed to investigate the causal association between WC and AF using a two-sample Mendelian randomization(MR)analysis.Methods:In our two-sample MR analysis,the genetic variation used as an instrumental variable for MR was acquired from a genome-wide association study(GWAS)of WC(42 single nucleotide polymorphisms with a genetic significance of Pinstitute database,containing 55,114 AF cases and 482,295 controls)were used to assess the causal role of WC on AF.Three different approaches(inverse variance weighted[IVW],MR-Egger,and weighted median regression)were used to ensure that our results more reliable.Results:All three MR analyses provided evidence of a positive causal association between high WC and AF.High WC was suggested to increase the risk of AF based on the IVW method(odds ratio[OR]=1.43,95%confidence interval[CI],1.30-1.58,P=2.51×10^(-13)).The results of MR-Egger and weighted median regression exhibited similar trends(MR-Egger OR=1.40[95%CI,1.08-1.81],P=1.61×10^(-2);weighted median OR=1.39[95%CI,1.21-1.61],P=1.62×10^(-6)).MR-Egger intercepts and funnel plots showed no directional pleiotropic effects between high WC and AF.Conclusions:Our findings suggest that greater WC is associated with an increased risk of AF.Taking measures to reduce WC may help prevent the occurrence of AF.

关键词： Genetically predicted Waist circumference Atrial fibrillation Mendelian randomization

Taurine inhibits ischemia/reperfusion-induced compartment syndrome in rabbits

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Acta Pharmacologica Sinica 2005年第7期26卷 821-827页

作者： Ji-xian WANG~(2,3) Yan LI~2 Li-ke ZHANG~4 Jing ZHAO~5 Yong-zheng PANG~(2,3) Chao-shu TANG~(3,5) Jing ZHANG~(2,3,6) 1 institute of cardiovascular disease research,The First Hospital of Peking University,Beijing 100034,China 3 Key Laboratory of Molecular cardiovascular Science,Ministry of Education,Beijing 100083,China 4 Department of Pathophysiology,Capital institute of Medicine,Beijing 100054,China 5 Department of Physiology Health Center of Medical Sciences,Peking University,Beijing 100083,China institute of cardiovascular disease research The First Hospital of Peking University Beijing China Key Laboratory of Molecular cardiovascular Science Ministry of Education Beijing China Department of Pathophysiology Capital Institute of Medicine Beijing China Department of Physiology Health Center of Medical Sciences Peking University Beijing China

Aim:To investigate effects of taurine on ischemia/reperfusion(I/R)-induced com-partment syndrome in rabbit hind limbs.Methods:Rabbits underwent femoralartery occlusion after ligation of branches from terminal aorta to femoral artery.After a 7-h ischemia,reperfusion was established with the use of heparinizedpolyethylene shunts.Rabbits received taurine(1 g/kg)or normal saline(control)by iv infusion 10 min before shunt placement.During reperfusion,anterior com-partment pressure(ACP)was monitored continuously in the left lower extremity.Gastrocnemius muscle triphenyltetrazolium chloride(TTC)level,taurine contentand myeloperoxidase activity were assayed.Oxidative stress was induced in thein vitro gastrocnemius muscle slices by free radical generating systems(FRGS),and the malondialdehyde content was measured in presence or absence of taurine.Results:After 7 h of ischemia,none of the parameters that we measured weredifferent from those before ischemia,except that TTC reduction decreased by80%.In the control group,after 2 h of reperfusion,ACP increased 4.5-fold,andgastrocnemius muscle taurine content was reduced by 33%.In taurine-treatedanimals,at 2 h reperfusion,the mean arterial blood pressure and heart rate wereincreased,by 6% and 10%.ACP decreased by 39%,muscle edema decreased by16%,TTC reduction increased by 150%,and lactate dehydrogenase decreased by36% compared to control group.Plasma and muscle taurine content increased by70% and 88%,respectively.In the taurine-treated group,at 2 h repeffusion,plasmamalondialdehyde and conjugated diene content were decreased by 38% and 23%,respectively,and muscle malondialdehyde and conjugated diene content decreasedby 22% and 30%,respectively compared to the control group.At 2 h reperfusion,myeloperoxidase activity was increased 3.5-fold in control animals.In the in vitrostudy,taurine decreased malondialdehyde content in muscle slices incubatedwith hypochlorous acid in a dose-dependent manner,but there was no changewhen incubated with hydrogen peroxide and xanthine oxidase.Con

关键词： taurine compartment syndromes reperfu sion injury

Ciclopirox inhibits SARS-CoV-2 replication by promoting the degradation of the nucleocapsid protein

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2505-2519页

作者： Xiafei Wei Yuzheng Zhou Xiaotong Shen Lujie Fan Donglan Liu Xiang Gao Jian Zhou Yezi Wu Yunfei Li Wei Feng Zheng Zhang institute for Hepatology National Clinical Research Center for Infectious DiseaseShenzhen Third People's HospitalSouthern University of Science and TechnologyShenzhen 518112China Guangzhou Laboratory Guangzhou Medical UniversityGuangzhou 511495China State Key Laboratory of Respiratory disease National Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510120China

The nucleocapsid protein(NP)plays a crucial role in SARS-CoV-2 replication and is the most abundant structural protein with a long half-life.Despite its vital role in severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)assembly and host inflammatory response,it remains an unexplored target for drug development.In this study,we identified a small-molecule compound(ciclopirox)that promotes NP degradation using an FDA-approved library and a drug-screening cell model.Ciclopirox significantly inhibited SARS-CoV-2 replication both in vitro and in vivo by inducing NP degradation.Ciclopirox induced abnormal NP aggregation through indirect interaction,leading to the formation of condensates with higher viscosity and lower mobility.These condensates were subsequently degraded via the autophagy-lysosomal pathway,ultimately resulting in a shortened NP half-life and reduced NP expression.Our results suggest that NP is a potential drug target,and that ciclopirox holds substantial promise for further development to combat SARS-CoV-2 replication.

关键词： SARS-CoV-2 Nucleocapsid protein Viral replication Ciclopirox Abnormal aggregation Protein degradation Autophagy-lysosome Drug target

UniBind:a novel artificial intelligence-based prediction model for SARS-CoV-2 infectivity and variant evolution

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Signal Transduction and Targeted Therapy 2024年第1期9卷 14-15页

作者： Qihong Yan Jincun Zhao State Key Laboratory of Respiratory disease National Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina

In a recent study published in Nature Medicine,Wang et al.developed an excellent framework called UniBind based on artificial intelligence(AI),which enables accurately predicting infectivity of SARS-CoV-2 variants and evolutionary trends of future viral variants.1 This computational method holds the possibility to not only serve as a valuable early-warning tool for monitoring potential pathogenic SARS-CoV-2 variants but also facilitate fundamental research on protein-protein interactions(PPIs).

关键词： artificial Bind prediction