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Seco-cyclic phorbol derivatives and their anti-HIV-1 activities

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Chinese Journal of Natural Medicines 2024年第4期22卷 365-374页

作者： HUANG Xiaolei HUANG Xusheng LI Qirun MA Mengdi CUI Yadong YANG Liumeng WANG Haibo LUO Ronghua CHEN Jinglei YANG Jingxuan LIN Jinrong LI Duxin ZHENG Yongtang ZHANG Jian College of Pharmaceutical Science Soochow UniversitySuzhou 215123China key laboratory of animal models and human disease mechanisms of the Chinese Academy of Sciences/key laboratory of Bioactive Peptides of yunnan province Kunming Institute of ZoologyChinese Academy of SciencesKunming 650223China Kunming College of Life Science University of Chinese Academy of SciencesKunming 650204China College of Traditional Chinese Medicine Yunnan University of Chinese MedicineKunming 650500China

Phorbol esters are recognized for their dual role as anti-HIV-1 agents and as activators of protein kinase C(PKC).The efficacy of phorbol esters in binding with PKC is attributed to the presence of oxygen groups at positions C20,C3/C4,and C9 of phorbol.Concurrently,the lipids located at positions C12/C13 are essential for both the anti-HIV-1 activity and the formation of the PKC-ligand complex.The influence of the cyclopropane ring at positions C13 and C14 in phorbol derivatives on their anti-HIV-1 activity requires further exploration.This research entailed the hydrolysis of phorbol,producing seco-cyclic phorbol derivatives.The anti-HIV-1 efficacy of these derivatives was assessed,and the affinity constant(Kd)for PKC-δprotein of selected seco-cyclic phorbol derivatives was determined through isothermal titration calorimetry.The findings suggest that the chemical modification of cyclopropanols could affect both the anti-HIV-1 activity and the PKC binding affinity.Remarkably,compound S11,with an EC_(50) of 0.27μmol·L^(−1) and a CC_(50) of 153.92μmol·L^(−1),demonstrated a potent inhibitory effect on the intermediate products of HIV-1 reverse transcription(ssDNA and 2LTR),likely acting at the viral entry stage,yet showed no affinity for the PKC-δprotein.These results position compound S11 as a potential candidate for further preclinical investigation and for studies aimed at elucidating the pharmacological mechanism underlying its anti-HIV-1 activity.

关键词： seco-Cyclic phorbol derivatives Hydrolysis reaction Cyclopropane ring Esterification Anti-HIV-1 agent

Long non-coding RNAs with essential roles in neurodegenerative disorders

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Neural Regeneration Research 2024年第6期19卷 1212-1220页

作者： Wandi Xiong Lin Lu Jiali Li key laboratory of animal models and human disease mechanisms of Chinese Academy of Sciences & yunnan province Kunming Institute of Zoology the Chinese Academy of Sciences Tsinghua-Peking Center for Life Sciences National Institute on Drug Dependence Peking University PKU/McGovern Institute for Brain Research Peking University Institute of Mental Health National Clinical Research Center for Mental Disorders Key Laboratory of Mental Health and Peking University Sixth Hospital Peking University

Recently, with the advent of high-resolution and high-throughput sequencing technologies, an increasing number of long non-coding RNAs(lncRNAs) have been found to be involved in the regulation of neuronal function in the central nervous system with specific spatiotemporal patterns, across different neurodegenerative diseases. However, the underlying mechanisms of lncRNAs during neurodegeneration remain poorly understood. This review provides an overview of the current knowledge of the biology of lncRNAs and focuses on introducing the latest identified roles, regulatory mechanisms, and research status of lncRNAs in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Finally, this review discusses the potential values of lncRNAs as diagnostic biomarkers and therapeutic targets for neurodegenerative diseases, hoping to provide broader implications for developing effective treatments.

关键词： Alzheimer’s disease amyotrophic lateral sclerosis biomarker Huntington’s disease long non-coding RNAs neurodegenerative diseases Parkinson’s disease therapy transcriptional regulation translational regulation

SARS-CoV-2 breakthrough infections following inactivated vaccine vaccination induce few neutralizing antibodies against the currently emerging Omicron XBB variants

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Virologica Sinica 2024年第1期39卷 173-176页

作者： Fan Shen Chun Liang Cui-Xian Yang Ying Lu An-Qi Li Ying Duan Mi Zhang c Ren-Rong Tian a Xing-Qi Dong Yong-Tang Zheng Wei Pang key laboratory of Bioactive Peptides of yunnan province/key laboratory of animal models and human disease mechanisms of the Chinese Academy of Sciences KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesKunming Institute of ZoologyChinese Academy of SciencesKunming650223China University of Chinese Academy of Sciences Beijing100049China yunnan Provincial Infectious disease Hospital Kunming650399China Department of Pathogen Biology and Immunology Faculty of Basic Medical ScienceKunming Medical UniversityKunming650500China

Dear Editor,COVID-19 inactivated vaccines have been extensively administered inChina.However,the majority of the Chinese population has experiencedbreakthrough infections from SARS-CoV-2 ancestral,Delta or Omicronvariants over the past three years,particularly during the wave of Omicron BA.5 and BA.7 variants at the end of 2022(Zhu et al.,2023).Subsequently,new Omicron variants,such as BQ.1,BQ.1.1,XBB,XBB.1/XBB.1.9,and XBB.1.5/XBB.1.9.1,are emerging in China(Yueetal.,2023;Zhu et al.,2023).Therefore,it is an urgentneed and a publichealth imperative to assess the extent of the immunoprotection established in this population.

关键词： breakthrough neutral Omi

Mast cell degranulation-triggered by SARS-CoV-2 induces tracheal-bronchial epithelial inflammation and injury

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Virologica Sinica 2024年第2期39卷 309-318页

作者： Jian-Bo Cao Shu-Tong Zhu Xiao-Shan Huang Xing-Yuan Wang Meng-Li Wu Xin Li Feng-Liang Liu Ling Chen Yong-Tang Zheng Jian-Hua Wang Guangzhou Institutes of Biomedicine and Health Chinese Academy of SciencesGuangzhou 510530China School of Life Sciences and Medicine University of Science and Technology of ChinaHefei 230026China key laboratory of Bioactive Peptides of yunnan province Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of SciencesKIZCUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesCenter for Biosafety Mega-ScienceKunming Institute of ZoologyChinese Academy of SciencesKunming 650223China University of Chinese Academy of Sciences Beijing 101408China

SARS-CoV-2 infection-induced hyper-inflammation is a key pathogenic factor of COVID-19.Our research,along with others',has demonstrated that mast cells(MCs)play a vital role in the initiation of hyper-inflammation caused by SARS-CoV-2.In previous study,we observed that SARS-CoV-2 infection induced the accumulation of MCs in the peri-bronchus and bronchioalveolar-duct junction in humanized mice.Additionally,we found that MC degranulation triggered by the spike protein resulted in inflammation in alveolar epithelial cells and capillary endothelial cells,leading to subsequent lung injury.The trachea and bronchus are the routes for SARS-CoV-2 transmission after virus inhalation,and inflammation in these regions could promote viral spread.MCs are widely distributed throughout the respiratory tract.Thus,in this study,we investigated the role of MCs and their degranulation in the development of inflammation in tracheal-bronchial epithelium.Histological analyses showed the accumulation and degranulation of MCs in the peri-trachea of humanized mice infected with SARS-CoV-2.MC degranulation caused lesions in trachea,and the formation of papillary hyperplasia was observed.Through transcriptome analysis in bronchial epithelial cells,we found that MC degranulation significantly altered multiple cellular signaling,particularly,leading to upregulated immune responses and inflammation.The administration of ebastine or loratadine effectively suppressed the induction of inflammatory factors in bronchial epithelial cells and alleviated tracheal injury in mice.Taken together,our findings confirm the essential role of MC degranulation in SARS-CoV-2-induced hyper-inflammation and the subsequent tissue lesions.Furthermore,our results support the use of ebastine or loratadine to inhibit SARS-CoV-2-triggered degranulation,thereby preventing tissue damage caused by hyper-inflammation.

关键词： SARS-CoV-2 Mast cell(MC) Bronchial epithelial cell Inflammation Tracheal injury

Cell reprogramming therapy for Parkinson’s disease

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Neural Regeneration Research 2024年第11期19卷 2444-2455页

作者： Wenjing Dong Shuyi Liu Shangang Li Zhengbo Wang State key laboratory of Primate Biomedical Research Institute of Primate Translational MedicineKunming University of Science and TechnologyKunmingYunnan ProvinceChina yunnan key laboratory of Primate Biomedical Research KunmingYunnan ProvinceChina

Parkinson’s disease is typically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta.Many studies have been performed based on the supplementation of lost dopaminergic neurons to treat Parkinson’s disease.The initial strategy for cell replacement therapy used human fetal ventral midbrain and human embryonic stem cells to treat Parkinson’s disease,which could substantially alleviate the symptoms of Parkinson’s disease in clinical practice.However,ethical issues and tumor formation were limitations of its clinical application.Induced pluripotent stem cells can be acquired without sacrificing human embryos,which eliminates the huge ethical barriers of human stem cell therapy.Another widely considered neuronal regeneration strategy is to directly reprogram fibroblasts and astrocytes into neurons,without the need for intermediate proliferation states,thus avoiding issues of immune rejection and tumor formation.Both induced pluripotent stem cells and direct reprogramming of lineage cells have shown promising results in the treatment of Parkinson’s disease.However,there are also ethical concerns and the risk of tumor formation that need to be addressed.This review highlights the current application status of cell reprogramming in the treatment of Parkinson’s disease,focusing on the use of induced pluripotent stem cells in cell replacement therapy,including preclinical animal models and progress in clinical research.The review also discusses the advancements in direct reprogramming of lineage cells in the treatment of Parkinson’s disease,as well as the controversy surrounding in vivo reprogramming.These findings suggest that cell reprogramming may hold great promise as a potential strategy for treating Parkinson’s disease.

关键词： animal models astrocytes autologous cell reprogramming cell therapy direct lineage reprogramming dopaminergic neurons induced pluripotent stem cells non-human primates Parkinson’s disease

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Semisynthesis of homogeneous spike RBD glycoforms from SARS-CoV-2 for profiling the correlations between glycan composition and function

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National Science Review 2024年第2期11卷 145-154页

作者： Farong Ye Cheng Li Feng-Liang Liu Xinliang Liu Peng Xu Rong-Hua Luo Wenping Song Yong-Tang Zheng Tianlei Ying Biao Yu Ping Wang Center for Chemical Glycobiology Frontiers Science Center for Transformative Molecules Zhangjiang Institute for Advanced Study School of Chemistry and Chemical Engineering Shanghai Jiao Tong University MOE/NHC/CAMS key laboratory of Medical Molecular Virology Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection Shanghai Institute of Infectious Disease and BiosecurityShanghai Engineering Research Center for Synthetic ImmunologySchool of Basic Medical Sciences Shanghai Medical College Fudan University key laboratory of animal models and human disease mechanisms of Chinese Academy of Sciences/key laboratory of Bioactive Peptides of yunnan province Center for Biosafety Mega-Science Kunming Institute of ZoologyChinese Academy of Sciences State key laboratory of Bioorganic and Natural Products Chemistry Center for Excellence in Molecular Synthesis Shanghai Institute of Organic Chemistry Chinese Academy of Sciences Shenzhen Research Institute of Shanghai Jiao Tong University

Vaccines have been the primary remedy in the global fight against coronavirus disease 2019（COVID-19）.The receptor-binding domain（RBD） of the spike protein, a critical viral immunogen, is affected by the heterogeneity of its glycan structures and relatively low immunogenicity. Here, we describe a scalable synthetic platform that enables the precise synthesis of homogeneously glycosylated RBD, facilitating the elucidation of carbohydrate structure–function relationships. Five homogeneously glycosylated RBDs bearing biantennary glycans were prepared, three of which were conjugated to T-helper epitope(Tpep) from tetanus toxoid to improve their weak immune response. Relative to natural HEK293-derived RBD, synthetic RBDs with biantennary N-glycan elicited a higher level of neutralising antibodies against SARS-CoV-2 in mice. Furthermore, RBDs containing Tpepelicited significant immune responses in transgenic mice expressing human angiotensin-converting enzyme 2. Our collective data suggest that trimming the N-glycans and Tpepconjugation of RBD could potentially serve as an effective strategy for developing subunit vaccines providing efficient protection.

关键词： peptide ligation glycosylation glycoprotein

A human-specific insertion promotes cell proliferation and migration by enhancing TBC1D8B expression

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Science China(Life Sciences) 2024年第4期67卷 765-777页

作者： Hui Zhao Lin-Lin Liu Jian Sun Lian Jin Hai-Bing Xie Jian-Bo Li Hui Xu Dong-Dong Wu Xiao-Lin Zhuang Min-Sheng Peng Ya-Jun Guo Wei-Zhu Qian Newton OOtecko Wei-Jie Sun Liang-Hu Qu Jie He Zhao-Li Chen Rong Liu Ce-Shi Chen Ya-Ping Zhang State key laboratory for Conservation and Utilization of Bio-resource School of Life SciencesSchool of Ecology and Environmental ScienceYunnan UniversityKunming 650091China School of Forensic Medicine Kunming Medical UniversityKunming 650500China Academy of Biomedical Engineering Kunming Medical UniversityKunming 650500China The Third Affiliated Hospital Kunming Medical UniversityKunming 650118China key laboratory of animal models and human disease mechanisms of the Chinese Academy of Sciences and yunnan province Kunming Institute of ZoologyChinese Academy of SciencesKunming 650201China State key laboratory of Genetic Resources and Evolution Yunnan Laboratory of Molecular Biology of Domestic AnimalsKunming Institute of ZoologyChinese Academy of SciencesKunming 650201China The key laboratory of Gene Engineering of the Ministry of Education State Key Laboratory for BiocontrolSun Yat-sen UniversityGuangzhou 510275China National Engineering Research Center for Antibody Medicine and Shanghai key laboratory of Cell Engineering and Antibody Shanghai 201203China Department of Thoracic Surgery Cancer Institute and HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100730China

human-specific insertions play important roles in human phenotypes and diseases.Here we reported a 446-bp insertion(Insert-446)in intron 11 of the TBC1D8B gene,located on chromosome X,and traced its origin to a portion of intron 6 of the EBF1 gene on chromosome 5.Interestingly,Insert-446 was present in the human Neanderthal and Denisovans genomes,and was fixed in humans after human-chimpanzee divergence.We have demonstrated that Insert-446 acts as an enhancer through binding transcript factors that promotes a higher expression of human TBC1D8B gene as compared with orthologs in macaques.In addition,over-expression TBC1D8B promoted cell proliferation and migration through“a dual finger”catalytic mechanism(Arg538 and Gln573)in the TBC domain in vitro and knockdown of TBC1D8B attenuated tumorigenesis in vivo.Knockout of Insert-446 prevented cell proliferation and migration in cancer and normal cells.Our results reveal that the human-specific Insert-446 promotes cell proliferation and migration by upregulating the expression of TBC1D8B gene.These findings provide a significant insight into the effects of human-specific insertions on evolution.

关键词： human-specific insertion enhancer gene expression cell proliferation and migration

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Transplantation of human placental chorionic plate-derived mesenchymal stem cells for repair of neurological damage in neonatal hypoxic-ischemic encephalopathy

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Neural Regeneration Research 2024年第9期19卷 2027-2035页

作者： Lulu Xue Ruolan Du Ning Bi Qiuxia Xiao Yifei Sun Ruize Niu Yaxin Tan Li Chen Jia Liu Tinghua Wang Liulin Xiong Transformation Research laboratory The Affiliated Hospital of Zunyi Medical UniversityZunyiGuizhou ProvinceChina State key laboratory of Biotherapy Sichuan UniversityChengduSichuan ProvinceChina Institute of Neurological disease Translational Neuroscience CenterWest China HospitalSichuan UniversityChengduSichuan ProvinceChina Department of animal Zoology Institute of NeuroscienceKunming Medical UniversityKunmingYunnan ProvinceChina Department of Anesthesiology The Affiliated Hospital of Zunyi Medical UniversityZunyiGuizhou ProvinceChina Department of Pediatrics the People’s Liberation Army Rocket Force Characteristic Medical CenterBeijingChina

Neonatal hypoxic-ischemic encephalopathy is often associated with permanent cerebral palsy,neurosensory impairments,and cognitive deficits,and there is no effective treatment for complications related to hypoxic-ischemic encephalopathy.The therapeutic potential of human placental chorionic plate-derived mesenchymal stem cells for various diseases has been explored.However,the potential use of human placental chorionic plate-derived mesenchymal stem cells for the treatment of neonatal hypoxic-ischemic encephalopathy has not yet been investigated.In this study,we injected human placental chorionic plate-derived mesenchymal stem cells into the lateral ventricle of a neonatal hypoxic-ischemic encephalopathy rat model and observed significant improvements in both cognitive and motor function.Protein chip analysis showed that interleukin-3 expression was significantly elevated in neonatal hypoxic-ischemic encephalopathy model rats.Following transplantation of human placental chorionic plate-derived mesenchymal stem cells,interleukin-3 expression was downregulated.To further investigate the role of interleukin-3 in neonatal hypoxic-ischemic encephalopathy,we established an in vitro SH-SY5Y cell model of hypoxic-ischemic injury through oxygen-glucose deprivation and silenced interleukin-3 expression using small interfering RNA.We found that the activity and proliferation of SH-SY5Y cells subjected to oxygen-glucose deprivation were further suppressed by interleukin-3 knockdown.Furthermore,interleukin-3 knockout exacerbated neuronal damage and cognitive and motor function impairment in rat models of hypoxic-ischemic encephalopathy.The findings suggest that transplantation of hpcMSCs ameliorated behavioral impairments in a rat model of hypoxic-ischemic encephalopathy,and this effect was mediated by interleukin-3-dependent neurological function.

关键词： behavioral evaluations gene knockout human neuroblastoma cells(SH-SY5Y) human placental chorionic derived mesenchymal stem cells interleukin-3 neonatal hypoxic-ischemic encephalopathy nerve injury oxygen-glucose deprivation protein chip small interfering RNA

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Identification of novel mammalian viruses in tree shrews(Tupaia belangeri chinensis)

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Zoological Research 2024年第2期45卷 429-438页

作者： Hong Zhou Ren-Rong Tian Xiu-Rong Wang Jin-Xuan Yang Yun-Xiao Wang Ming-Liang Zhao Xu-Dong Zhang Yu-Hua Ma Long-Bao Lv Edward CHolmes Yong-Tang Zheng Wei-Feng Shi School of Clinical and Basic Medical Sciences Shandong First Medical University&Shandong Academy of Medical SciencesJi’nanShandong 250117China key laboratory of Emerging Infectious diseases in Universities of Shandong Shandong First Medical University and Shandong Academy of Medical SciencesTaianShandong 271000China key laboratory of animal models and human disease mechanisms of the Chinese Academy of Sciences/key laboratory of Bioactive Peptides of yunnan province KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesCenter for Biosafety Mega-ScienceKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650223China School of Public Health Shandong First Medical University&Shandong Academy of Medical SciencesJi’nanShandong 250117China National Resource Center for Non-human Primates Kunming Primate Research CenterKunming Institute of ZoologyChinese Academy of SciencesKunmingYunnan 650107China Sydney Institute for Infectious diseases School of Medical SciencesThe University of SydneySydneyNew South Wales 2006Australia Department of Infectious diseases Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai Institute of Virology Shanghai Jiao Tong University School of MedicineShanghai 200025China

The Chinese tree shrew(Tupaia belangeri chinensis),a member of the mammalian order Scandentia,exhibits considerable similarities with primates,including humans,in aspects of its nervous,immune,and metabolic systems.These similarities have established the tree shrew as a promising experimental model for biomedical research on cancer,infectious diseases,metabolic disorders,and mental health conditions.Herein,we used metatranscriptomic sequencing to analyze plasma,as well as oral and anal swab samples,from 105 healthy asymptomatic tree shrews to identify the presence of potential zoonotic viruses.In total,eight mammalian viruses with complete genomes were identified,belonging to six viral families,including Flaviviridae,Hepeviridae,Parvovirinae,Picornaviridae,Sedoreoviridae,and Spinareoviridae.Notably,the presence of rotavirus was recorded in tree shrews for the first time.Three viruses-hepacivirus 1,parvovirus,and picornavirus-exhibited low genetic similarity(94%)to known viral strains.Phylogenetic analyses also revealed that the rotavirus and mammalian orthoreovirus identified in this study may be novel reassortants.These findings provide insights into the diverse viral spectrum present in captive Chinese tree shrews,highlighting the necessity for further research into their potential for crossspecies transmission.

关键词： Tree shrew(Tupaia belangeri chinensis) Meta-transcriptomic sequencing Mammalian viruses Genomic analysis

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