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Intranasal boosting with RBD-HR protein vaccine elicits robust mucosal and systemic immune responses

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Genes & Diseases 2024年第4期11卷 327-339页

作者： Li Chen Wenyan Ren Hong Lei Jiayu Wang Haiying Que Dandan Wan Aqu Alu Dandan Peng Minyang Fu Weiqi Hong Yuhe Huang Xiangrong Song Guangwen Lu Xiawei Wei Laboratory of Aging research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduSichuan 610041China

The emergence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)variants has decreased the efficacy of SARs-CoV-2 vaccines in containing coronavirus disease 2019(CoVID-19)over time,and booster vaccination strategies are urgently necessitated to achieve sufficient *** immunization can improvemucosal immunity,offer-ing protection against the infection and sustaining the spread of *** this study,an intranasal booster of the RBD-HR vaccine after two doses of the mRNA vaccine significantly increased the levels of specific binding antibodies in serum,nasal lavage fluid,and bronchoal-veolar lavage fluid compared with only two doses of mRNA *** intranasal boosting with the RBD-HR vaccine,the levels of serum neutralizing antibodies against prototype and variant strains of SARS-Cov-2 pseudoviruses weremarkedly higher than those in mice receiving mRNA vaccine alone,and intranasal boosting with the RBD-HR vaccine also inhibited the bind-ing of RBD to hACE2 ***,the heterologous intranasal immunization regimen promoted extensive memory T cell responses and activated CD103+dendritic cells in the respiratory mucosa,and potently enhanced the formation of T follicular helper cells and germinal center B cells in vital immune organs,including mediastinal lymph nodes,inguinal lymph nodes,and ***,these data infer that heterologous intranasal boosting with the RBD-HR vaccine elicited broad protective immunity against SARS-CoV-2 both locallyandsystemically.

关键词： Heterologous immunization Intranasal immunization mRNA vaccine SARS-CoV-2 Subunitprotein vaccine

Structural analysis of conformational changes in the mpox virus A7 protein

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Virologica Sinica 2024年第2期39卷 331-334页

作者： Xincheng Ni Kai Wang Yinze Han Jian Lei national clinical research center for geriatrics and State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu610041China

Dear Editor,The mpox(formerly known as monkeypox)disease caused by the mpox virus(MPXV)has infected more than 89,700 people and is linked to 157 deaths in 114 countries worldwide as of September 2023(***).Mpox is a zoonotic disease,the first human case of which was reported in 1970(Breman et al.,1980).Common symptoms in mpox-infected individuals include fever,myalgia,fatigue,headache,and a characteristic rash(Isidro et al.,2022).Current treatments for mpox remain limited,and an in-depth investigation of essential viral protein(s)will help to explore novel drug targets.

关键词： infected headache

Targeting RAS-RAF-MEK-ERK signaling pathway in human cancer:Current status in clinical trials

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Genes & Diseases 2023年第1期10卷 76-88页

作者： Yanlin Song Zhenfei Bi Yu Liu Furong Qin Yuquan Wei Xiawei Wei Laboratory of Aging research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduSichuan610041China

Molecular target inhibitors have been regularly approved by Food and Drug Administration(FDA)for tumor treatment,and most of them intervene in tumor cell proliferation and *** RAS-RAF-MEK-ERK pathway is a conserved signaling pathway that plays vital roles in cell proliferation,survival,and *** aberrant activation of the RAS-RAF-MEK-ERK signaling pathway induces *** 33%of tumors harbor RAS mutations,while 8%of tumors are driven by RAF *** efforts have been dedicated to targeting the signaling pathway for cancer treatment in the past *** this review,we summarized the development of inhibitors targeting the RAS-RAF-MEK-ERK pathway with an emphasis on those used in clinical ***,we discussed the potential combinations of inhibitors that target the RAS-RAF-MEK-ERK signaling pathway and other signaling *** inhibitors targeting the RAS-RAF-MEK-ERK pathway have essentially modified the therapeutic strategy against various cancers and deserve more attention in the current cancerresearchandtreatment.

关键词： clinical trials Molecular target therapy RAS-RAF-MEK-ERK signaling pathway

MicroRNAs of microglia： wrestling with central nervous system disease

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Neural Regeneration research 2018年第12期13卷 2067-2072页

作者： Xiao-Hua Wang Tian-Long Wang Department of Anesthesiology Xuanwu Hospital Capital Medical University Beijing China Institute of geriatrics Beijing China national clinical research center for Geriatric Disorders Beijing China

Microglia serve as brain-resident myeloid cells that affect cerebral development, ischemia, neurodegeneration, and neuro-viral infection. MicroRNAs play a key role in central nervous system disease through post-transcriptional regulation. Indeed, evidence shows that microRNAs are one of the most important regulators mediating microglial activation, polarization, and autophagy, and subsequently affecting neuroinflammation and the outcome of central nervous system disease. In this review, we provide insight into the function of microRNAs, which may be an attractive strategy and influential treatment for microglia-related central nervous system dysfunction. Moreover, we comprehensively describe how microglia fight against central nervous system disease via multiple functional microRNAs.

关键词： microglia neurodegeneration central nervous system disease microRNAs activation polarization autophagy neural regeneration

Genetic heterogeneity on sleep disorders in Parkinson’s disease: a systematic review and meta-analysis

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Translational Neurodegeneration 2022年第1期11卷 641-653页

作者： Jingxuan Huang Yangfan Cheng Chunyu Li Huifang Shang Laboratory of Neurodegenerative Disorders Department of NeurologyRare Diseases CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China

A growing amount of evidence has indicated contributions of variants in causative genes of Parkinson’s disease (PD) to the development of sleep disturbance in PD and prodromal PD stages. In this article, we aimed to investigate the role of genetics in sleep disorders in PD patients and asymptomatic carriers at prodromal stage of PD. A systematic review and meta-analysis of observational studies was conducted based on the MEDLINE, EMBASE and PsychINFO databases. A pooled effect size was calculated by odds ratio (OR) and standard mean difference (SMD). Forty studies were selected for quantitative analysis, including 17 studies on glucocerebrosidase (GBA), 25 studies on Leucine-rich repeat kinase 2 (LRRK2) and 7 on parkin (PRKN) genes, and 3 studies on alpha-synuclein gene (SNCA) were used for qualitative analysis. Patients with PD carrying GBA variants had a significantly higher risk for rapid-eye-movement behavior disorders (RBD) (OR, 1.82) and higher RBD Screening Questionnaire scores (SMD, 0.33). Asymptomatic carriers of GBA variants had higher severity of RBD during follow-up. Patients with PD carrying the LRRK2 G2019S variant had lower risk and severity of RBD compared with those without LRRK2 G2019S. Variants of GBA, LRRK2 and PRKN did not increase or decrease the risk and severity of excessive daytime sleepiness and restless legs syndrome in PD. Our findings suggest that the genetic heterogeneity plays a role in the development of sleep disorders, mainly RBD, in PD and the prodromal stage of PD.

关键词： Genetic variants Sleep disorder Rapid-eye-movement behavior disorders GBA LRRK2

gem-Difluorovinylation of alkynyl bromoarenes via dual nickel-/palladium-catalyzed crosselectrophile coupling

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Organic Chemistry Frontiers 2022年第2期9卷 305-310页

作者： Haotian Sun Baojian Xiong Yuan Yang Jiangjun Liu Xuemei Zhang Zhong Lian Department of Dermatology State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China Hospital and West China School of PharmacySichuan UniversityChengdu 610041China

A dual nickel-/palladium-catalyzed gem-difluorovinylation of alkynyl bromoarenes is *** method proceeds smoothly to afford various dihydrobenzofuran compounds containing gem-difluorovinyl fragments with excellent stere-oselectivities in moderate to excellent *** strategy also features good functional group *** studies reveal that the C-OTs bond and C-Br bond are selectively oxidative-added by nickel and palladium complexes respec-tively,and palladium is the center metal in the reductive elimination step.

关键词： palladium nickel vinyl

Role of circular RNA expression in the pathological progression after spinal cord injury

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Neural Regeneration research 2021年第10期16卷 2048-2055页

作者： Wen-Zhao Wang Jun Li Lei Liu Zheng-Dong Zhang Ming-Xin Li Qin Li Hui-Xu Ma Hai Yang Xiao-Ling Hou Department of Orthopedics National Clinical Research Center for GeriatricsWest China HospitalSichuan University/West China School of NursingSichuan UniversityChengduSichuan ProvinceChina

Differential expression of non-coding RNA after traumatic spinal cord injury(TSCI)is closely related to the pathophysiological *** purposes of this study were to systematically profile and characterize expression of circular RNA(circRNA)in the lesion epicenter of spinal tissues after TSCI,and predict the structure and potential function of the regulatory circRNA/miRNA ***-eight C57BL/6 mice were randomly and equally assigned to two groups:one subjected to TSCI at T8–10 with an Allen’s drop impactor,and a second subjected to laminectomy without *** cord samples were stained with hematoxylin and eosin,sequenced,and ***-Seq,Gene Ontology analysis,Kyoto Encyclopedia of Genes and Genomes analysis,and network analyses(Targetscan and miRanda)were used to predict and annotate the circRNA/miRNA/mRNA *** reporter,quantitative reverse transcription polymerase chain reaction,and western blot assays were used to profile expression and regulation patterns of the network in mouse models of ***-eosin staining revealed severe damage to the blood-spinal cord barrier after *** expressed circRNA and miRNA profiles were obtained after TSCI;differentially expressed circRNAs,which were abundant in the cytoplasm,were involved in positive regulation of transcription and protein ***-135b-5p was the most significantly downregulated miRNA after TSCI;circRNAAbca1 and KLF4 were predicted to be its target circRNA and mRNA,***,the circAbca1/miR-135b-5P/KLF4 regulatory axis was predicted and constructed,and its targeted binding was *** inhibiting circAbca1,GAP43 expression was *** expression of circRNAs might play an important role after ***1 plays a neuroinhibitory role by targeted binding of the miR-135b-5P/KLF4 *** identified circRNA/miRNA/mRNA network could provide the basis for understanding pathophysiological mechanisms underlying

关键词： bioinformatics circRNA/miRNA/mRNA network circular RNA gene KLF4 miR-135b-5p spinal cord injury trauma

Tripterin liposome relieves severe acute respiratory syndrome as a potent COVID-19 treatment

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Signal Transduction and Targeted Therapy 2023年第1期8卷 288-301页

作者： Haiying Que Weiqi Hong Tianxia Lan Hao Zeng Li Chen Dandan Wan Zhenfei Bi Wenyan Ren Min Luo Jingyun Yang Cai He Ailing Zhong Xiawei Wei Laboratory of Aging research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduSichuanPeople’s Republic of China

For coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),15–30%of patients are likely to develop COVID-19-related acute respiratory distress syndrome(ARDS).There are still few effective and well-understood therapies *** variants and short-lasting immunity are posing challenges to vaccine efficacy,so finding antiviral and antiinflammatory treatments remains ***,tripterin(TP),a traditional Chinese medicine,was encapsulated into liposome(TP lipo)to investigate its antiviral and antiinflammatory effects in severe *** using two severe COVID-19 models in human ACE2-transgenic(hACE2)mice,an analysis of TP lipo’s effects on pulmonary immune responses was *** pathological alterations and viral burden were reduced by TP lipo *** lipo inhibits SARS-CoV-2 replication and hyperinflammation in infected cells and mice,two crucial events in severe COVID-19 pathophysiology,it is a promising drug candidate to treat SARS-CoV-2-induced ARDS.

关键词： immunity alterations distress

FFAR4 improves the senescence of tubular epithelial cells by AMPK/SirT3 signaling in acute kidney injury

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Signal Transduction and Targeted Therapy 2022年第12期7卷 4435-4449页

作者： Letian Yang Bo Wang Fan Guo Rongshuang Huang Yan Liang Lingzhi Li Sibei Tao Ting Yin Ping Fu Liang Ma Kidney research Institute National Clinical Research Center for Geriatrics and Division of NephrologyWest China Hospital of Sichuan UniversityChengdu610041China research Core Facility of West China Hospital Chengdu610041China

Acute kidney injury(AKI)is a serious clinical complication with high morbidity and mortality *** substantial progress in understanding the mechanism of AKI,no effective therapy is available for treatment or *** previously found that G protein-coupled receptor(GPCR)family member free fatty acid receptor 4(FFAR4)agonist TUG891 alleviated kidney dysfunction and tubular injury in AKI ***,the versatile role of FFAR4 in kidney has not been well *** the study,the expression of FFAR4 was abnormally decreased in tubular epithelial cells(TECs)of cisplatin,cecal ligation/perforation and ischemia/reperfusion injury-induced AKI mice,*** and conditional TEC-specific knockout of FFAR4 aggravated renal function and pathological damage,whereas FFAR4 activation by TUG-891 alleviated the severity of disease in cisplatin-induced AKI ***,FFAR4,as a key determinant,was firstly explored to regulate cellular senescence both in injured kidneys of AKI mice and TECs,which was indicated by senescence-associatedβ-galactosidase(SA-β-gal)activity,marker protein p53,p21,Lamin B1,phospho-histone H2A.X,phospho-Rb expression,and secretory phenotype IL-6 ***,pharmacological activation and overexpression of FFAR4 reversed the decrease of aging-related SirT3 protein,where FFAR4 regulated SirT3 expression to exhibit anti-senescent effect via Gq subunit-mediated CaMKKβ/AMPK signaling in cisplatin-induced mice and *** findings highlight the original role of tubular FFAR4 in cellular senescence via AMPK/SirT3 signaling and identify FFAR4 as a potential drug target against AKI.

关键词： kidney injury Acute