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ASF1A-dependent P300-mediated histone H3 lysine 18 lactylation promotes atherosclerosis by regulating EndMT

Acta Pharmaceutica Sinica B 2024年第7期14卷 3027-3048页

作者： Mengdie Dong Yunjia Zhang Minghong Chen Yongkang Tan Jiao Min Xian He Fuhao Liu Jiaming Gu Hong Jiang Longbin Zheng Jiajing Chen Quanwen Yin Xuesong Li Xiang Chen Yongfeng Shao Yong Ji Hongshan Chen Department of Cardiovascular Surgery the First Affiliated Hospital of Nanjing Medical Universityand Key Laboratory of Cardiovascular and Cerebrovascular MedicineSchool of PharmacyNational Vaccine Innovation PlatformNanjing Medical UniversityNanjing 211166China Key Laboratory of Cardiovascular and Cerebrovascular Medicine School of PharmacyNanjing Medical UniversityNanjing 211166China Department of Clinical Medicine Nanjing Medical University TIANYUAN Honors SchoolNanjing Medical UniversityNanjing 211166China Department of Anesthesiology Sir Run Run HospitalNanjing Medical UniversityNanjing 211166China Department of Cardiovascular Surgery the First Affiliated Hospital of Nanjing Medical UniversityNanjing 211166China Key Laboratory of Cardiovascular and Cerebrovascular Medicine Key Laboratory of Targeted Intervention of Cardiovascular DiseaseCollaborative Innovation Center for Cardiovascular Disease Translational MedicineState Key Laboratory of Reproductive MedicineSchool of Pharmacythe Affiliated Suzhou Hospital of Nanjing Medical UniversityGusu SchoolNanjing Medical UniversityNanjing 211166China National Key Laboratory of Frigid Zone Cardiovascular Diseases(NKLFZCD) Department of Pharmacology(State-Province Key Laboratories of Biomedicine-Pharmaceutics of China)College of PharmacyKey Laboratory of Cardiovascular Medicine Research and Key Laboratory of Myocardial IschemiaChinese Ministry of EducationNHC Key Laboratory of Cell Transplantationthe Central Laboratory of the First Affiliated HospitalHarbin Medical UniversityHarbin 150081China Key Laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Disease Translational MedicineNanjing Medical UniversityNanjing 211166China Department of Cardiology Huai’an First People’s Hospital Affiliated with Nanjing Medical UniversityHuai’an 223399China

Endothelial-to-mesenchymal transition(EndMT)is a key driver of *** glycolysis is increased in the endothelium of atheroprone areas,accompanied by elevated lactate *** lactylation,mediated by lactate,can regulate gene expression and participate in disease ***,whether histone lactylation is involved in atherosclerosis remains ***,we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactatedependent histone H3 lysine 18 lactylation(H3K18la)in vitro and in vivo,as well as in atherosclerotic patients’***,the histone chaperone ASF1A was first identified as a cofactor of P300,which precisely regulated the enrichment of H3K18la at the promoter of SNAI1,thereby activating SNAI1 transcription and promoting *** found that deletion of ASF1A inhibited EndMT and improved endothelial *** analysis based on Apoe^(KO)Asf1a^(ECKO) mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endotheliumspecific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis *** of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la,SNAI1 transcription,and EndMT-induced *** study illustrates precise crosstalk between metabolism and epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis,which provides emerging therapies for atherosclerosis.

关键词： Histone lactylation Atherosclerosis Endothelial-tomesenchymal transition ASF1A SNAI1 Endothelial dysfunction Lactate Epigenetic

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MFG-E8 Alleviates Cognitive Impairments Induced by Chronic Cerebral Hypoperfusion by Phagocytosing Myelin Debris and Promoting Remyelination

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Neuroscience Bulletin 2024年第4期40卷 483-499页

作者： Xiaohong Dong Zhi Zhang Xin Shu Zi Zhuang Pinyi Liu Renyuan Liu Shengnan Xia Xinyu Bao Yun Xu Yan Chen Department of Neurology Nanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjing210008China Department of Neurology Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjing210008China Department of Neurology Drum Tower Hospital of Nanjing Medical UniversityNanjing210008China Jiangsu Key Laboratory for Molecular Medicine Medical School of Nanjing UniversityNanjing210008China Jiangsu Provincial Key Discipline of Neurology Nanjing210008China

Chronic cerebral hypoperfusion is one of the pathophysiological mechanisms contributing to cognitive decline by causing white matter *** phagocytosing myelin debris in a timely manner can promote remyelination and contribute to the repair of white ***,milk fat globule-epidermal growth factor-factor 8(MFG-E8),a microglial phagocytosis-related protein,has not been well studied in hypoperfusion-related cognitive *** found that the expression of MFG-E8 was significantly decreased in the brain of mice after bilateral carotid artery stenosis(BCAS).MFG-E8 knockout mice demonstrated more severe BCAS-induced cognitive impairments in the behavioral *** addition,we discovered that the deletion of MFG-E8 aggravated white matter damage and the destruction of myelin microstructure through fluorescent staining and electron ***,MFG-E8 overexpression by AAV improved white matter injury and increased the number of mature oligodendrocytes after ***,in vitro and in vivo experiments showed that MFG-E8 could enhance the phagocytic function of microglia via theαVβ3/αVβ5/Rac1 pathway and IGF-1 production to promote the differentiation of oligodendrocyte progenitor cells into mature ***,we found that MFG-E8 was mainly derived from astrocytes,not *** findings suggest that MFG-E8 is a potential therapeutic target for cognitive impairments following cerebral hypoperfusion.

关键词： White matter injury Cognitive dysfunction MFG-E8 Remyelination Microglial phagocytosis

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Genetic variation of circHIBADH enhances prostate cancer risk through regulating HNRNPA1-related RNA splicing

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Journal of Biomedical Research 2024年第4期38卷 358-368页

作者： Yifei Cheng Rongjie Shi Shuai Ben Silu Chen Shuwei Li Junyi Xin Meilin Wang Gong Cheng Department of Environmental Genomics Jiangsu Key Laboratory of Cancer BiomarkersPrevention and TreatmentCollaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingJiangsu 211166China Department of Urology the First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu 210029China Department of Bioinformatics School of Biomedical Engineering and InformaticsNanjing Medical UniversityNanjingJiangsu 211166China Jiangsu Cancer hospital Jiangsu Institute of Cancer Researchthe Affiliated Cancer Hospital of Nanjing Medical UniversityNanjingJiangsu 210009China The Affiliated Suzhou hospital of nanjing medical university Suzhou Municipal HospitalGusu SchoolNanjing Medical UniversitySuzhouJiangsu 215002China

The current study aimed to investigate associations of circRNAs and related genetic variants with the risk of prostate cancer(PCa)as well as to elucidate biological mechanisms underlying the *** first compared expression levels of circRNAs between 25 paired PCa and adjacent normal tissues to identify riskassociated circRNAs by using the MiOncoCirc *** then used logistic regression models to evaluate associations between genetic variants in candidate circRNAs and PCa risk among 4662 prostate cancer patients and 3114 healthy controls,and identified circHIBADH rs11973492 T>C as a significant risk-associated variant(odds ratio=1.20,95%confidence interval:1.08-1.34,P=7.06×10^(-4))in a dominant genetic model,which altered the secondary structure of the corresponding RNA *** the in silico analysis,we found that circHIBADH sponged and silenced 21 RNA-binding proteins(RBPs)enriched in the RNA splicing pathway,among which HNRNPA1 was identified and validated as a hub RBP using an external RNA-sequencing data as well as the in-house(four tissue samples)and publicly available single-cell ***,we demonstrated that HNRNPA1 influenced hallmarks including MYC target,DNA repair,and E2F target signaling pathways,thereby promoting *** conclusion,genetic variants in circHIBADH may act as sponges and inhibitors of RNA splicing-associated RBPs including HNRNPA1,playing an oncogenic role in PCa.

关键词： genetic variants prostate cancer circRNA RNA-binding protein RNA splicing sing-cell RNA sequencing

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The diagnostic value of tenascin-C in acute aortic syndrome

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Journal of Geriatric Cardiology 2024年第3期21卷 359-368页

作者： Ming MA Wei CHEN Hai-Long CAO Jun PAN Qing ZHOU Xin-Long TANG Dong-Jin WANG Department of Thoracic and Cardiovascular Surgery Nanjing Drum Tower Hospital Clinical College of Nanjing Medical UniversityNanjingChina Department of Thoracic and Cardiovascular Surgery Nanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjingChina Department of Thoracic surgery Kunshan Hospital of Traditional Chinese MedicineJiangsuChina

OBJECTIVES Misdiagnosis of acute aortic syndrome(AAS)significantly increases ***-C(TN-C)is an extracellular matrix glycoprotein related to cardiovascular *** elevation of TN-C in AAS and whether it can discriminate suddenonset of acute chest pain in Chinese remains *** We measured the plasma concentration of TN-C by ELISA in a cohort of 376 patients with chest or back *** to discriminate AAS from acute coronary syndrome(ACS)were compared and *** From October 2016 to September 2021,376 undiagnosed patients with chest or back pain were enrolled.166 of them were finally diagnosed as AAS,100 were ACS and 110 without cardiovascular diseases(NCV).TN-C was significantly elevated in AAS at 18.18 ng/mL(IQR:13.10–27.68)compared with 7.51 ng/mL(IQR:5.67–11.38)in ACS(P<0.001)and 3.68 ng/mL(IQR:2.50–5.29)in NCV(P<0.001).There was no significant difference in TN-C level among the subtypes of *** the 166 AAS patients,the peaked level of TN-C was at acute stage(P=0.012),then a slight of decrease was observed at subacute *** area under receiver operating characteristic curve for AAS patients versus NCV was 0.979(95%CI:0.964-0.994)for *** a cutoff level of 11.474 ng/mL,TN-C has a sensitivity of 76.0%,specificity of 85.5%,accuracy of 82.0%,positive predictive value(PPV)of 76.0%,negative predictive value(NPV)of 85.5%.Diagnostic performance of TN-C was superior to D-dimer and *** The concentration of serum TN-C in AAS patients was significantly higher than that in ACS patients and ***-C could be a new biomarker to distinguish AAS patients in the early stage after symptoms onset from other pain diseases.

关键词： acute cardiovascular elevated

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Machine learning and human‐machine trust in healthcare:A systematic survey

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CAAI Transactions on Intelligence Technology 2024年第2期9卷 286-302页

作者： Han Lin Jiatong Han Pingping Wu Jiangyan Wang Juan Tu Hao Tang Liuning Zhu Jiangsu Key Laboratory of Public Project Audit School of Engineering AuditNanjing Audit UniversityNanjingChina School of Information Engineering Nanjing Audit UniversityNanjingChina School of Statistics and Data Science Nanjing Audit UniversityNanjingChina Key Laboratory of Modern Acoustics(MOE) School of PhysicsNanjing UniversityNanjingChina Department of Information Technology and Electrical Engineering ETH ZurichZurichSwitzerland The first Affiliated hospital with nanjing medical university Jiangsu Province HospitalNanjingChina

As human‐machine interaction(HMI)in healthcare continues to evolve,the issue of trust in HMI in healthcare has been raised and *** is critical for the development and safety of healthcare that humans have proper trust in medical *** machines that have applied machine learning(ML)technologies continue to penetrate deeper into the medical environment,which also places higher demands on intelligent *** order to make machines play a role in HMI in healthcare more effectively and make human‐machine cooperation more harmonious,the authors need to build good humanmachine trust(HMT)in *** article provides a systematic overview of the prominent research on ML and HMT in *** addition,this study explores and analyses ML and three important factors that influence HMT in healthcare,and then proposes a HMT model in ***,general trends are summarised and issues to consider addressing in future research on HMT in healthcare are identified.

关键词： human-machine interaction machine learning trust

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GM-CSF Promotes the Development of Dysfunctional Vascular Networks in Moyamoya Disease

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Neuroscience Bulletin 2024年第4期40卷 451-465页

作者： Huiqin Li Xiang Cao Xinya Gu Mengqi Dong Lili Huang Chenglu Mao Shengnan Xia Haiyan Yang Xinyu Bao Yongbo Yang Yun Xu Department of Neurology and Neurosurgery Nanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjing210008China Department of Neurology and Neurosurgery Nanjing Drum Tower HospitalState Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical DiseasesNanjing UniversityNanjing210008China Department of Neurology and Neurosurgery Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical UniversityNanjing210008China Department of Neurology and Neurosurgery Nanjing Drum Tower Hospital Clinical College of Nanjing Medical UniversityNanjing210008China Jiangsu Key Laboratory for Molecular Medicine Medical School of Nanjing UniversityNanjing210008China Jiangsu Provincial Key Discipline of Neurology Nanjing210008China nanjing Neurology medical Center Nanjing210008China

Moyamoya disease(MMD)is a chronic occlusive cerebrovascular disease with the development of a network of abnormal *** inflammation is associated with the occurrence and development of ***,the mechanisms underlying the formation of the abnormal vascular network remain ***-eight patients with MMD,26 ischemic stroke patients,and 26 unrelated healthy volunteers were enrolled in this study The data showed that the levels of granulocyte-macrophage colony-stimulating factor(GM-CSF)were higher in MMD patients than in healthy controls(Pfirst time the important involvement of GM-CSF in MMD and that GM-CSF is an important factor in the formation of abnormal vascular networks in MMD.

关键词： Moyamoya disease Vascular endothelial cells GM-CSF VEGF

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Promotion effect of FOXCUT as a microRNA sponge for miR-24-3p on progression in triple-negative breast cancer through the p38 MAPK signaling pathway

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Chinese medical Journal 2024年第1期137卷 105-114页

作者： Xiafei Yu Fangze Qian Xiaoqiang Zhang Yanhui Zhu Gao He Junzhe Yang Xian Wu Yi Zhou Li Shen Xiaoyue Shi Hongfei Zhang Xiao’an Liu Department of Breast Surgery The First Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu 210029China

Background:Triple-negative breast cancer(TNBC)is a type of highly invasive breast cancer with a poor *** to new research,long noncoding RNAs(lncRNAs)play a significant role in the progression of *** the role of lncRNAs in breast cancer has been well reported,few studies have focused on *** study aimed to explore the biological function and clinical significance of forkhead box C1 promoter upstream transcript(FOXCUT)in triple-negative breast ***:Based on a bioinformatic analysis of the cancer genome atlas(TCGA)database,we detected that the lncRNA FOXCUT was overexpressed in TNBC tissues,which was further validated in an external cohort of tissues from the General Surgery Department of the first Affiliated hospital of nanjing medical *** functions of FOXCUT in proliferation,migration,and invasion were detected in vitro or in *** assays and RNA immunoprecipitation(RIP)were performed to reveal that FOXCUT acted as a competitive endogenous RNA(ceRNA)for the microRNA miR-24-3p and consequently inhibited the degradation of ***:lncRNA FOXCUT was markedly highly expressed in breast cancer,which was associated with poor prognosis in some *** of FOXCUT significantly inhibited cancer growth and metastasis in vitro or in ***,FOXCUT competitively bounded to miR-24-3p to prevent the degradation of p38,which might act as an oncogene in breast ***:Collectively,this research revealed a novel FOXCUT/miR-24-3p/p38 axis that affected breast cancer progression and suggested that the lncRNA FOXCUT could be a diagnostic marker and therapeutic target for breast cancer.

关键词： Triple negative breast neoplasms RNA,long noncoding FOXCUT miR-24-3p p38 MAPK signaling pathway Disease progression

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Huangqin Decoction Delays Progress of Colitis-Associated Carcinogenesis by Regulating Nrf2/HO-1 Antioxidant Signal Pathwayin Mice

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Chinese Journal of Integrative Medicine 2024年第2期30卷 135-142页

作者： GU Li-mei LI He-zhong GAO Lei LI Hui WEI Lan-fu PAN Cheng-yu WU Ke-xuan TIAN Yao-zhou Department of Gastrointestinal Endoscopy Affiliated Hospital of Nanjing University of Chinese MedicineNanjing(210029)China Department of Gastroenterology Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjing(210028)China School of Integrated Chinese and Western Medicine Nanjing University of Chinese MedicineNanjing(210023)China

Objective:To investigate the effect of Huangqin Decoction(HQD)on nuclear factor erythroid 2 related-factor 2(Nrf2)/heme oxygenase(HO-1)signaling pathway by inducing the colitis-associated carcinogenesis(CAC)model mice with azoxymethane(AOM)/dextran sodium sulfate(DSS).Methods:The chemical components of HQD were analyzed by liquid chromatography-quadrupole-time-of-flight mass spectrometry(LC-Q-TOF-MS/MS)to determine the molecular constituents of *** 48 C57BL/6J mice were randomly divided into 6 groups by a random number table,including control,model(AOM/DSS),mesalazine(MS),low-,medium-,and high-dose HQD(HQD-L,HQD-M,and HQD-H)groups,8 mice in each *** for the control group,the mice in the other groups were intraperitoneally injected with AOM(10 mg/kg)and administrated with 2.5%DSS orally for 1 week every two weeks(totally 3 rounds of DSS)to construct a colitis-associated carcinogenesis mouse *** mice in the HQD-L,HQD-M and HQD-H groups were given HQD by gavage at doses of 2.925,5.85,and 11.7 g/kg,respectively;the mice in the MS group was given a suspension of MS at a dose of 0.043 g/kg(totally 11 weeks).The serum levels of malondialdehyde(MDA)and superoxide dismutase(SOD)were measured by enzyme-linked immunosorbent *** mRNA and protein expression levels of Nrf2,HO-1,and inhibitory KELCH like ECH-related protein 1(Keap1)in colon tissue were detected by quantitative real-time PCR,immunohistochemistry,and Westem blot,***:LC-Q-TOF-MS/MS analysis revealed that the chemical constituents of HQD include baicalin,paeoniflorin,and glycyrrhizic *** to the control group,significantly higher MDA levels and lower SOD levels were observed in the model group(P<0.05),whereas the expressions of Nrf2 and HO-1 were significantly decreased,and the expression of Keap1 increased(P<0.01).Compared with the model group,serum MDA level was decreased and SOD level was increased in the HQD-M,HQD-H and MS groups(P<0.05).Higher expressions of

关键词： Huangqin Decoction colitis-associated carcinogenesis nuclear factor erythroid 2 related-factor 2/heme oxygenase signaling pathway oxidative stress Chinese medicine

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Protective and Adverse Roles of DDX3X in Different Cell Types in Nonalcoholic Steatohepatitis Progression

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Research 2024年第3期6卷 561-574页

作者： Suzhen Yang Lin Zhou Tianming Zhao Hanlong Zhu Tingting Luo Kang Jiang Xiaoxiao Shi Chunyan Chen Han Zhang Si Zhao Xiaoping Zou Yuzheng Zhuge Fangyu Wang Lei Wang Mingzuo Jiang Bing Xu Department of Gastroenterology the Affiliated Drum Tower Hospital of Nanjing University Medical SchoolJiangsuNanjing210002China. Department of Gastroenterology and Hepatology the Affiliated Jinling Hospital of Nanjing University Medical SchoolJiangsuNanjing210002China School of Medicine Northwest UniversityShaanxiXi’an710069China. Department of Gastroenterology Nanjing Drum Tower HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeJiangsuNanjing210008China.

Persistent hepatic cellular metabolic stress and liver inflammatory stimuli are key signatures of nonalcoholic steatohepatitis(NASH).DDX3X is a vital molecule involved in cell fate decisions in both pro-survival stress granule(SG)and pro-death NOD-like receptor family pyrin domain containing 3(NLRP3)inflammasome assembly in response to stress ***,the role of DDX3X in NASH remains *** characterized the cell type-specific roles of DDX3X in *** liver tissues from NASH patients and normal control subjects were collected to assess DDX3X expression and *** steatohepatitis models were constructed by feeding macrophage-specific DDX3X knockout(DDX3^(XΔMφ)),hepatocyte-specific DDX3X knockout(DDX3X^(Δhep)),and wild-type control(DDX3X^(fl/fl))mice a high-fat and high-cholesterol(HFHC)diet,a methionine-and choline-deficient(MCD)diet,and a high-fat/high-iron/high-fructose/high-cholesterol,low-methionine,and choline-deficient(HFHIHFHC-MCD)*** study demonstrated that DDX3X was predominantly expressed in macrophages and hepatocytes in control liver tissues,and its expression was down-regulated in patients or mice with *** to DDX3X^(fl/fl) littermates,DDX3^(XΔMφ)mice showed improved liver histology in nutritional steatohepatitis *** of macrophage DDX3X inhibited NLRP3 inflammasome-mediated pyroptosis,causing anti-inflammatory M2 polarization and alleviating hepatocyte steatohepatitic ***3X^(Δhep) mice developed marked steatohepatitis in multiple nutritional steatohepatitis models compared to DDX3X^(fl/fl) ***3X-deleted hepatocytes showed impaired SG assembly,leading to increased sensitivity and intolerance to metabolic stimulation and resultant *** conclusion,DDX3X plays opposite roles in different cell types during the progression of NASH.A better understanding of the cell-specific differences in the crosstalk between SG formation and NLRP3 activation is crucial for developing pr

关键词： NLRP3 impaired inhibited

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Mechanism of Endogenous Peptide PDYBX1 and Precursor Protein YBX1 in Hirschsprung’s Disease

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Neuroscience Bulletin 2024年第6期40卷 695-706页

作者： Qiaochu Sun Zhengke Zhi Chenglong Wang Chunxia Du Jie Tang Hongxing Li Weibing Tang Department of Pediatric Surgery Children’s Hospital of Nanjing Medical UniversityNanjing210008China

Endogenous peptides,bioactive agents with a small molecular weight and outstanding absorbability,regulate various cellular processes and ***,their role in the occurrence of Hirschsprung’s disease(HSCR)remains ***,we found that the expression of an endogenous peptide derived from YBX1(termed PDYBX1 in this study)was upregulated in the aganglionic colonic tissue of HSCR patients,whereas its precursor protein YBX1 was *** shown by Transwell and cytoskeleton staining assays,silencing YBX1 inhibited the migration of enteric neural cells,and this effect was partially reversed after treatment with ***,immunoprecipitation and immunofluorescence revealed that ERK2 bound to YBX1 and *** of YBX1 blocked the ERK1/2 pathway,but upregulation of PDYBX1 counteracted this effect by binding to ERK2,thereby promoting cell migration and *** together,the endogenous peptide PDYBX1 may partially alleviate the inhibition of the ERK1/2 pathway caused by the downregulation of its precursor protein YBX1 to antagonize the impairment of enteric neural ***1 may be exploited to design a novel potential therapeutic agent for HSCR.

关键词： Hirschsprung’s disease YBX1 Endogenous peptide PDYBX1 Enteric neural cell

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