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Coxsackievirus B3 HFMD animal models in Syrian hamster and rhesus monkey

Virologica Sinica 2024年第2期39卷 290-300页

作者： Suqin Duan Wei Zhang Yongjie Li Yanyan Li Yuan Zhao Weihua Jin Quan Liu Mingxue Li Wenting Sun Lixiong Chen Hongjie Xu Jie Tang Jinghan Hou Zijun Deng Fengmei Yang Shaohui Ma Zhanlong He Institute of medical Biology Chinese Academy of Medical Sciences Medical Primate Research Center Peking Union Medical CollegeYunnan Key Laboratory of Vaccine Research Development on Severe Infectious DiseaseKunming650118China

Coxsackievirus B3(CVB3)is the pathogen causing hand,foot and mouth disease(HFMD),which manifests across a spectrum of clinical severity from mild to ***,CVB3-infected mouse models mainly demonstrate viral myocarditis and pancreatitis,failing to replicate human HFMD *** several enteroviruses have been evaluated in Syrian hamsters and rhesus monkeys,there is no comprehensive data on *** this study,we have first tested the susceptibility of Syrian hamsters to CVB3 infection via different *** results showed that Syrian hamsters were successfully infected with CVB3 by intraperitoneal injection or nasal drip,leading to nasopharyngeal colonization,acute severe pathological injury,and typical HFMD ***,the nasal drip group exhibited a longer viral excretion cycle and more severe pathological *** the subsequent study,rhesus monkeys infected with CVB3 through nasal drips also presented signs of HFMD symptoms,viral excretion,serum antibody conversion,viral nucleic acids and antigens,and the specific organ damages,particularly in the ***,there were no significant differences in myocardial enzyme levels,and the clinical symptoms resembled those often associated with common,mild *** summary,the study successfully developed severe Syrian hamsters and mild rhesus monkey models for CVB3-induced *** models could serve as a basis for understanding the disease pathogenesis,conducting pre-trial prevention and evaluation,and implementing post-exposure intervention.

关键词： Coxsackievirus B3(CVB3) Hand foot and mouth disease(HFMD) Animal models Syrian hamster Rhesus monkey

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Magnetic resonance imaging of knees:a novel approach to predict recombinant human growth hormone therapy response in short-stature children in late puberty

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World Journal of Pediatrics 2024年第7期20卷 723-734页

作者： Xi Bai Zhi‑Bo Zhou Xiao‑Yuan Guo Yi‑Ling He Yue‑Lun Zhang Feng‑Dan Wang Feng Feng Hong‑Bo Yang Shi Chen Feng‑Ying Gong Hui‑Juan Zhu Hui Pan Department of Endocrinology Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanShandongChina Key laboratory of Endocrinology of National Health Commission Department of EndocrinologyState Key Laboratory of Complex Severe and Rare DiseasesPeking Union Medical College HospitalChinese Academy of Medical Science and Peking Union Medical CollegeBeijing 100730China medical research Center Peking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina Department of Radiology Peking Union Medical College HospitalChinese Academy of Medical Science and Peking Union Medical CollegeBeijingChina

Background There is no appropriate tool to predict recombinant human growth hormone(rhGH)response before therapy initiation in short-stature children in late *** current study aimed to explore the associations between magnetic resonance imaging(MRI)stages of the knee growth plates and rhGH response in short-stature children in late *** In this prospective cohort study,short-stature children in late puberty were treated with rhGH and followed up for 6 *** proposed a novel knee MRI staging system according to the growth plate states of distal femurs or proximal tibias and divided the participants into three groups:unclosed growth plate group,marginally closed growth plate group,and nearly closed growth plate *** primary outcomes were height gain and growth velocity(GV),which were assessed three months *** Fifty participants were enrolled,including 23 boys and 27 *** and height gain after 6 months of rhGH therapy decreased successively in the three groups with an increased degree of growth plate fusion,especially when grouped by proximal tibias(GV_(1-3 mon)from 9.38 to 6.08 to 4.56 cm/year,GV_(4-6 mon)from 6.75 to 4.92 to 3.25 cm/year,and height gain from 4.03 to 2.75 to 1.95 cm,all P<0.001).Moreover,the MRI stages of growth plates independently served as a significant variable for GV and height gain after therapy,especially when grouped by proximal tibias(all P<0.01).Conclusion The MRI staging method is expected to be an effective tool for predicting rhGH response before therapy initiation in short-stature children in late puberty.

关键词： Growth hormone Growth velocity Late puberty Magnetic resonance imaging Short stature

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LncRNA CCRR maintains Ca^(2+)homeostasis against myocardial infarction through the FTO-SERCA2a pathway

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Science China(Life Sciences) 2024年第8期67卷 1601-1619页

作者： Hua Yang Lina Xuan Shengjie Wang Huishan Luo Xiaomeng Duan Jianjun Guo Shijia Cui Jieru Xin Junwei Hao Xiufang Li Jun Chen Feihan Sun Xiaolin Hu Siyun Li Ying Zhang Lei Jiao Baofeng Yang Lihua Sun Department of Pharmacology Harbin Medical University(State Key Laboratory of Frigid Zone Cardiovascular Diseasethe State-Province Key Laboratories of Biomedicine-Pharmaceutics of ChinaKey Laboratory of Cardiovascular ResearchMinistry of EducationJoint International Research Laboratory of Cardiovascular Medicine ResearchMinistry of EducationChina)College of PharmacyHarbin Medical UniversityHarbin 150081China

Cardiac conduction regulatory RNA(CCRR)has been documented as an antiarrhythmic lncRNA in our earlier *** study aimed to evaluate the effects of CCRR on SERCA2a and the associated Ca^(2+)homeostasis in myocardial infarction(MI).Overexpression of CCRR via AAV9-mediated delivery not only partially reversed ischemia-induced contractile dysfunction but also alleviated abnormal Ca^(2+)homeostasis and reduced the heightened methylation level of SERCA2a following *** effects were also observed in CCRR overexpressing transgenic mice.A conserved sequence domain of CCRR mimicked the protective function observed with the full ***,silencing CCRR in healthy mice led to intracellular Ca^(2+)overloading of *** increased SERCA2a protein stability by upregulating FTO *** direct interaction between CCRR and FTO protein was characterized by RNA-binding protein immunoprecipitation(RIP)analysis and RNA pulldown *** of NFATc3 was identified as an upstream mechanism responsible for CCRR downregulation in *** study demonstrates that CCRR is a protective lncRNA that acts by maintaining the function of FTO,thereby reducing the m^(6)A RNA methylation level of SERCA2a,ultimately preserving calcium homeostasis for myocardial contractile function in ***,CCRR may be considered a promising therapeutic strategy with a beneficial role in cardiac pathology.

关键词： CCRR calcium homeostasis FTO myocardial infarction SERCA2a

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pH-controlled reversible sol-gel inversion by cerous phosphate nanofibers for hemostasis

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Rare Metals 2024年第10期43卷 5141-5151页

作者： Tuo Su Jun-Chen Xu Wei Yu Dan Su Di-Er Shi Yi-Chao Pang Yao Ying Wang-Chang Li Juan Li Jing-Wu Zheng Liang Qiao Sheng-Lei Che Jing Yu research Center of Magnetic and Electronic Materials College of Materials Science and EngineeringZhejiang University of Technology State Key laboratory for Diagnosis and Treatment of Infectious Diseases Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang University Key laboratory of Drug Safety Evaluation and research of Zhejiang Province Department of Clinical MedicineHangzhou Medical College Department of Chemistry Zhejiang University Clinical medical college Yangzhou University

Developing biomimetic soft materials that display stimuli responsiveness using solely inorganic materials has been regarded as a challenge owing to that such materials?properties typically vary from those of living ***,biomimetic soft materials have been developed using organic materials or inorganic materials modified with organic small *** this study,we prepared cerium phosphate nanofibers （CePO4NFs） by using inorganic agents only without further *** CePO4NFs demonstrate sol-ge switching properties in response to pH value,allowing them to form a gel under high hydroxide ion （OH-） concentrations and turn back into sol under low *** formation of gel could be ascribed to the physical cross-linking of the nanofibers induced by the attractive electrostatic force of OH-and surface Ce3+.As a result,CePO4NFs are able to form a gel when in contac with blood of high pH value for *** specific clotting mechanism makes them better candidates for hemostasis of heavy bleeding.

关键词： Cerium phosphate nanofibers Hemostasis pH-responsive Reversible Sol-gel switching

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Carrimycin inhibits coronavirus replication by decreasing the efficiency of programmed–1 ribosomal frameshifting through directly binding to the RNA pseudoknot of viral frameshift-stimulatory element

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2567-2580页

作者： Hongying Li Jianrui Li Jiayu Li Hu Li Xuekai Wang Jing Jiang Lei Lei Han Sun Mei Tang Biao Dong Weiqing He Shuyi Si Bin Hong Yinghong Li Danqing Song Zonggen Peng Yongsheng Che Jian-Dong Jiang CAMS Key laboratory of Antiviral Drug research Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Beijing Key laboratory of Antimicrobial Agents Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Key laboratory of Biotechnology of Antibiotics the National Health and Family Planning Commission(NHFPC)Institute of Medicinal BiotechnologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China

The pandemic of SARS-CoV-2 worldwide with successive emerging variants urgently calls for small-molecule oral drugs with broad-spectrum antiviral ***,we show that carrimycin,a new macrolide antibiotic in the clinic and an antiviral candidate for SARS-CoV-2 in phase III trials,decreases the efficiency of programmed–1 ribosomal frameshifting of coronaviruses and thus impedes viral replication in a broad-spectrum *** binds directly to the coronaviral frameshift-stimulatory element(FSE)RNA pseudoknot,interrupting the viral protein translation switch from ORF1a to ORF1b and thereby reducing the level of the core components of the viral replication and transcription *** carrimycin with known viral replicase inhibitors yielded a synergistic inhibitory effect on *** the FSE mechanism is essential in all coronaviruses,carrimycin could be a new broad-spectrum antiviral drug for human coronaviruses by directly targeting the conserved coronaviral FSE *** finding may open a new direction in antiviral drug discovery for coronavirus variants.

关键词： Carrimycin Coronavirus Broad-spectrum antiviral activity Programmed-1 ribosomal frameshifting RNA pseudoknot Antiviral agent RNA target Synergistic inhibitory effect

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Epigenetics and environmental health

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Frontiers of Medicine 2024年第4期18卷 571-596页

作者： Min Zhang Ting Hu Tianyu Ma Wei Huang Yan Wang Key laboratory of Cancer and Microbiome State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100021China Beijing Key laboratory of Cancer Invasion and Metastasis research Department of Biochemistry and Molecular BiologySchool of Basic Medical SciencesCapital Medical UniversityBeijing100069China

Epigenetic modifications including DNA methylation,histone modifications,chromatin remodeling,and RNA modifications complicate gene regulation and heredity and profoundly impact various physiological and pathological *** recent years,accumulating evidence indicates that epigenetics is vulnerable to environmental changes and regulates the growth,development,and diseases of individuals by affecting chromatin activity and regulating gene *** exposure or induced epigenetic changes can regulate the state of development and lead to developmental disorders,aging,cardiovascular disease,Alzheimer's disease,cancers,and so ***,epigenetic modifications are *** use of specific epigenetic inhibitors targeting epigenetic changes in response to environmental exposure is useful in disease ***,we provide an overview of the role of epigenetics in various ***,we summarize the mechanism of epigenetic alterations induced by different environmental exposures,the influence of different environmental exposures,and the crosstalk between environmental variation epigenetics,and genes that are implicated in the body's ***,the interaction of multiple factors and epigenetics in regulating the initiation and progression of various diseases complicates clinical *** discuss some commonly used epigenetic drugs targeting epigenetic modifications and methods to prevent or relieve various diseases regulated by environmental exposure and epigenetics through diet.

关键词： epigenetics environmental exposure health prevention and therapy

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Meiotic nuclear divisions 1 suppresses the proliferation and invasion of pancreatic cancer cells via regulating H2A.X variant histone

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BIOCELL 2024年第1期48卷 111-122页

作者： DONGQIN WANG YAN SHI ZHIQIANG WANG JING ZHANG LUYAO WANG HONGYU MA SHUHUA SHI XIAOFU LIAN HUA HUANG XIAOJING WANG CHAOQUN LIAN Anhui Province Key laboratory of Clinical and Preclinical research in Respiratory Disease Molecular Diagnosis CenterThe Department of Pulmonary Critical Care MedicineFirst Affiliated Hospital of Bengbu Medical CollegeBengbu233030China Department of Genetics School of Life SciencesBengbu Medical CollegeBengbu233000China Department of Clinical Medicine Bengbu Medical CollegeBengbu233030China research Center of Clinical laboratory Science Bengbu Medical CollegeBengbu233030China

Introduction:Among all malignant tumors of the digestive system,pancreatic carcinoma exhibits the highest mortality ***,prevention and effective treatment are urgent issues that need to be ***:The study focused on meiotic nuclear divisions 1(MND1),integrating data from the Gene Expression Profiling Interactive Analysis(GEPIA)database with prognostic survival ***,experiments at cellular level were employed to demonstrate the effect of MND1 on the proliferation and migration of *** small-molecule inhibitor of MND1 was used to suppress the migration of PC cells by knocking down MND1 using small interfering RNA(siRNA)in Patu-8988 and Panc1 cell ***:The results of Cell Counting Kit-8 indicated that the suppression of MND1 resulted in a decrease in cell *** healing and Transwell assays revealed that MND1 knockdown reduced cell migration and *** cytometry revealed that inhibiting MND1 hindered the cell ***,MND1 could stimulate the proliferation,migration,and invasion of Patu-8988 and Panc1 cells by increasing the expression of ***,MND1 had a positive effect on H2AFX expression in PC *** MND1 expression suggests the low overall survival rate of individuals diagnosed with ***:These findings suggest that MND1 has the potential to be a gene with the ability to accurately diagnose and treat PC.

关键词： Pancreatic carcinoma MND1 H2AFX Cell cycle

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Docking protein 6 (DOK6) selectively docks the neurotrophic signaling transduction to restrain peripheral neuropathy

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1147-1164页

作者： Yan Guo Pan Xiang Xiaojiao Sun Wei Liu Jiafeng Zhou Bin Yin Lin Hou Boqin Qiang Huiliang Li Pengcheng Shu Xiaozhong Peng Department of Molecular Biology and Biochemistry Institute of Basic Medical SciencesMedical Primate Research CenterNeuroscience CenterChinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijingChina State Key laboratory of Common Mechanism research for Major Diseases Beijing 100005China Wolfson Institute for Biomedical research University College LondonGower StreetLondon WC1E 6BTUK Chinese Institute for Brain research Beijing 102206China State Key laboratory of Respiratory Health and Multimorbidity Beijing 100005China Institute of laboratory Animal Science Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100021China

The appropriate and specific response of nerve cells to various external cues is essential for the establishment and maintenance of neural circuits,and this process requires the proper recruitment of adaptor molecules to selectively activate downstream ***,we identified that DOK6,a member of the Dok(downstream of tyrosine kinases)family,is required for the maintenance of peripheral axons,and that loss of Dok6 can cause typical peripheral neuropathy symptoms in mice,manifested as impaired sensory,abnormal posture,paw deformities,blocked nerve conduction,and ***,Dok6 is highly expressed in peripheral neurons but not in Schwann cells,and genetic deletion of Dok6 in peripheral neurons led to typical peripheral myelin outfolding,axon destruction,and hindered retrograde axonal ***,DOK6 acts as an adaptor protein for selectivitymediated neurotrophic signal transduction and retrograde transport for TrkC and Ret but not for TrkA and ***6 interacts with certain proteins in the trafficking machinery and controls their phosphorylation,including MAP1B,Tau and Dynein for axonal transport,and specifically activates the downstream ERK1/2 kinase pathway to maintain axonal survival and *** finding provides new clues to potential insights into the pathogenesis and treatment of hereditary peripheral neuropathies and other degenerative diseases.

关键词： impaired restrain peripheral

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Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

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Acta Pharmaceutica Sinica B 2024年第2期14卷 533-578页

作者： Xiaopeng Peng Zhihao Hu Limei Zeng Meizhu Zhang Congcong Xu Benyan Lu Chengpeng Tao Weiming Chen Wen Hou Kui Cheng Huichang Bi Wanyi Pan Jianjun Chen college of Pharmacy Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of EducationGannan Medical UniversityGanzhou 314000China college of Basic Medicine Gannan Medical UniversityGanzhou 314000China Guangdong Provincial Key laboratory of New Drug Screening NMPA Key Laboratory for Research and Evaluation of Drug MetabolismSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators(e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges,including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result,the design of new epigenetic modulators(e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging(Hy T) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review,we aim to provide an in-depth illustration of new degrading strategies(2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

关键词： Epigenetic Degrader PROTAC Molecularglue Hydrophobic tagging

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PDK1 promotes breast cancer progression by enhancing the stability and transcriptional activity of HIF-1α

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Genes & Diseases 2024年第4期11卷 353-367页

作者： Yu Wei Dian Zhang He Shi Husun Qian Hongling Chen Qian Zeng Fangfang Jin Yan Ye Zuli Ou Minkang Guo Bianqin Guo Tingmei Chen Key laboratory of Clinical laboratory Diagnostics(Ministry of Education) College of Laboratory MedicineChongqing Medical UniversityChongqing 400016China Chongqing Key laboratory of Translational research for Cancer Metastasis and Individualized Treatment Chongqing University Cancer HospitalChongqing 400030China

Pyruvate dehydrogenase kinase 1(PDK1)phosphorylates the pyruvate dehydroge-nase complex,which inhibits its *** pyruvate dehydrogenase complex inhibits the tricarboxylic acid cycle and the reprogramming of tumor cell metabolism to glycolysis,which plays an important role in tumor *** study aims to elucidate how PDK1 pro-motes breast cancer *** found that PDK1 was highly expressed in breast cancer tissues,and PDK1 knockdown reduced the proliferation,migration,and tumorigenicity of breast cancer cells and inhibited the HIF-1α(hypoxia-inducible factor 1α)*** investigation showed that PDK1 promoted the protein stability of HIF-1αby reducing the level of ubiquitination of HIF-1α.The HIF-1αprotein levels were dependent on PDK1 kinase ***,HIF-1αphosphorylation at serine 451 was detected in wild-type breast cancer cells but not in PDK1 knockout breast cancer *** phosphorylation of HIF-1αat Ser 451 stabilized its protein levels by inhibiting the interaction of HIF-1αwith von Hippel-Lindau and prolyl hydroxylase *** also found that PDK1 enhanced HIF-1αtranscriptional *** summary,PDK1 enhances HIF-1αprotein stability by phosphorylating HIF-1αat Ser451 and promotes HIF-1αtranscriptional activity by enhancing the binding of HIF-1αto ***1 and HIF-1αform a positive feedback loop to promote breast cancer progression.

关键词： Breast cancer HIF-1α PDK1 Protein phosphorylation Transcriptional activity

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