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

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 protection.Intranasal immunization can improvemucosal immunity,offer-ing protection against the infection and sustaining the spread of SARS-CoV-2.In 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 vaccine.After 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 receptors.Furthermore,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 spleen.Collectively,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

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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(www.***.int).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

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Structural disruption of melanin-like polymers with boosted UV protection

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Science China Chemistry 2024年第5期67卷 1653-1663页

作者： Zhen Yang Xianheng Wang Wanjie Bai Zikun Zou Haoxing Wu Yiwen Li Department of Radiology Huaxi MR Research CenterFunctional and Molecular Imaging Key Laboratory of Sichuan ProvinceNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China College of Polymer Science and Engineering State Key Laboratory of Polymer Materials EngineeringSichuan UniversityChengdu 610065China

Manipulating the energy structure of materials represents an efficient way to regulate their light absorption behaviors. For example, constructing donor-acceptor(D-A) structures to increase the polarizability and reduce the energy bandgap of local molecules has been widely used in the field of organic photovoltaics with ordered structures. Remarkably, even in disordered and chaotic systems such as melanin-like polydopamine(PDA), visible and near-infrared light absorption can be significantly improved using this strategy. However, there has been a noticeable dearth of research on the ultraviolet(UV) light absorption regulation of bioinspired polymers with disordered and chaotic architectures by tailoring the D-A microstructures. In this study, a series of benzoheterocyclic molecules with strong electron-donating features screened by molecular simulation calculations were involved in disrupting the D-A structures within PDA. The destruction of D-A structures promoted the increase of the energy band gap and finally boosted the UV absorption of PDA. The resulting PDA nanoparticles with enhanced UV absorption were further employed to fabricate UV shielding composite films to protect the growth of plants from harmful UV radiation. This research may open up new avenues for structural disruption of bioinspired polymers for enhanced photoprotection applications.

关键词： melanin-like polymers polydopamine D-A structure UV absorption photoprotection

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Engineering self-catabolic DNAzyme nanospheres for synergistic anticancer therapy

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Science China Chemistry 2024年第7期67卷 2412-2422页

作者： Yu Chen Yu Guo Jiaoli Wang Ruiting Liu Xiaohai Yang Kemin Wang Ying Pu Hui Shi Jin Huang key laboratory of Chemo/Biosensing and Chemometrics College of Chemistry and Chemical EngineeringKey Laboratory for Bio-Nanotechnology and Molecular Engineering of Hunan ProvinceHunan UniversityChangsha 410082China National Clinical Research Center for Geriatric Disorders Department of GeriatricsXiangya HospitalCentral South UniversityChangsha 410008China

DNAzyme-based gene therapy faces some challenges including cell penetration,activity limitation,and co-delivery functions.Self-assembled DNA nanomedicine has attracted widespread attention due to its many advantages.It is urgent to develop a universal DNA degradation strategy for precise programmable drug release.Herein,we reported a self-catabolic DNAzyme nanospheres(SCNS),which could simultaneously achieve cell penetration,activity enhancement,and co-delivery functions.The SCNS were assembled through Y-DNA stepwise hybridization with each other,which were then loaded with aptamer(Apt),doxorubicin(Dox),and zinc oxide nanoparticles(ZnO NPs).The acid-triggered dissociation of ZnO NPs leads to the generation of Zn^(2+)ions cofactors for immediately self-catabolic DNAzyme nanospheres.After the disassembly of the SCNS,three types of anticancer treatments would be activated,which include Zn^(2+)involved reactive oxygen species(ROS),Dox-induced chemotherapy,and DNAzyme-based gene therapy.The experimental results show that the nanoplatform(Apt-SCNS-Dox-ZnO)has a good tumor-killing effect and minimal side effects.As a smart self-driven drug delivery nanoplatform,it is anticipated to displace extraordinary potential in biomedicine and bioengineering.

关键词： DNAzyme nanosphere ZnO NPs ROS Dox anticancer therapy

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Colony-stimulating factor-1 receptor inhibition combined with paclitaxel exerts effective antitumor effects in the treatment of ovarian cancer

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Genes & Diseases 2024年第3期11卷 400-416页

作者： Meijia Yu Yiming Wu Qingfang Li Weiqi Hong Yang Yang Xiaoyi Hu Yanfei Yang Tianqi Lu Xia Zhao 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 Department of Gynecology and Obstetrics Development and Related Disease of Women and Children Key Laboratory of Sichuan ProvinceKey Laboratory of Birth Defects and Related Diseases of Women and ChildrenMinistry of EducationWest China Second HospitalSichuan UniversityChengduSichuan 610041China Department of Obstetrics and Gynecology The First Affiliated HospitalArmy Medical UniversityChongqing 400038China

Ovarian cancer is the tumor with the highest mortality among gynecological malig-nancies.Studies have confirmed that paclitaxel chemoresistance is associated with increased infiltration of tumor-associated macrophages(TAMs)in the microenvironment.Colony-stimu-lating factor 1(CSF-1)receptor(CSF-1R)plays a key role in regulating the number and differ-entiation of macrophages in certain solid tumors.There are few reports on the effects of targeted inhibition of CSF-1R in combination with chemotherapy on ovarian cancer and the tu-mor microenvironment.Here,we explored the antitumor efficacy and possible mechanisms of the CSF-1R inhibitor pexidartinib(PLX3397)when combined with the first-line chemothera-peutic agent paclitaxel in the treatment of ovarian cancer.We found that CSF-1R is highly ex-pressed in ovarian cancer cells and correlates with poor prognosis.Treatment by PLX3397 in combination with paclitaxel significantly inhibited the growth of ovarian cancer both in vitro and in vivo.Blockade of CSF-1R altered the macrophage phenotype and reprogrammed the immunosuppressive cell population in the tumor microenvironment.

关键词： CSF-1R Ovariancancer Paclitaxel PLX3397 Targeted therapy Tumor-associated macrophages

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Ergothioneine and its congeners:anti-ageing mechanisms and pharmacophore

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Protein & Cell 2024年第3期15卷 191-206页

作者： Li Chen Liping Zhang Xujun Ye Zixin Deng Changming Zhao Department of geriatrics Zhongnan Hospital of Wuhan UniversityWuhan UniversityWuhan 430072China key laboratory of Combinatory Biosynthesis and Drug Discovery School of Pharmaceutical SciencesMinistry of EducationWuhan UniversityWuhan 430072China tThese authors contributed equally.

Ergothioneine,Ovothiol,and Selenoneine are sulfur/selenium-containing histidine-derived natural products widely distributed across different organisms.They exhibit significant antioxidant properties,making them as potential lead compounds for promoting health.Increasing evidence suggests that Ergothioneine is positively correlated with healthy ageing and longevity.The mechanisms underlying Ergothioneine's regulation of the ageing process at cellular and molecular levels are beginning to be understood.In this review,we provide an in-depth and extensive coverage of the anti-ageing studies on Ergothioneine and discuss its possible intracellular targeting pathways.In addition,we highlight the recent efforts in elucidating the biosynthetic details for Ergothioneine,Ovothiol,and Selenoneine,with a particular focus on the study of their pharmacophore-forming enzymology.

关键词： Ergothioneine antioxidant anti-ageing longevity biosynthesis enzymology

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Single-cell transcriptomics systematically discloses the immune-inflammatory responses of peripheral blood mononuclear cells for diabetic nephropathy

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Genes & Diseases 2024年第4期11卷 82-85页

作者： Jiangpeng wu Nan Hu Baochun Guo Hualin Ma Lulin Xie Yisha Huang Siyu Xia Yuke Jiang Zhije Li Jigang Wang Xinzhou Zhang Zhen Liang Department of Nephrology Shenzhen Key Laboratory of Kidney Diseasesand Shenzhen Clinical Research Centre for GeriatricsShenzhen People's Hospital(The Second Clinical Medical CollegeJinan UniversityThe First Affiliated HospitalSouthern University of Science and Technology)ShenzhenGuangdong 518020China Department of geriatrics and Shenzhen Clinical Research Centre for GeriatricsShenzhen People's Hospital(The Second Clinical Medical CollegeJinan UniversityThe First Affiliated HospitalSouthern University of Science and Technology)ShenzhenGuangdong 518020China State key laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs Artemisinin Research Centerand Institute of Chinese Materia MedicaChina Academy of Chinese Medical SciencesBeijing 100700China

Diabetic nephropathy(DN)has become the leading cause of end-stage renal disease with high morbidity and mortality among individuals with diabetes mellitus.Although functional alterations of renal infiltrating immune cells have been reported as part of the pathological mechanism of DN,the understanding of the immune response underlying peripheral blood mononuclear cells(PBMCs)in DN remains limited.Here,single-cell RNA sequencing(scRNA-seq)was used toprofile the transcriptomic signatures of PBMCs from DN patients.

关键词： nephropathy alterations mortality

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Pseudomonas aeruginosa regulator PvrA binds simultaneously to multiple pseudo-palindromic sites for efficient transcription activation

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Science China(Life Sciences) 2024年第5期67卷 900-912页

作者： Yibo Zhu Bingnan Luo Xingyu Mou Yingjie Song Yonghong Zhou Yongbo Luo Bo Sun Youfu Luo Hong Tang Zhaoming Su Rui Bao Center of Infectious Diseases Division of Infectious Diseases in State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China Department of geriatrics and National Clinical Research Center for geriatrics West China HospitalSichuan UniversityChengdu 610041China key laboratory of Biodiversity and Environment on the Qinghai-Tibetan Plateau Ministry of EducationSchool of Ecology and EnvironmentTibet UniversityLhasa 850000China Shanghai Advanced Research Institute Chinese Academy of SciencesShanghai 201210China College of Life Science Sichuan Normal UniversityChengdu 610101China Accurate Biotechnology(Hunan)Co. LtdChangsha 410006China

Tetracycline repressor(TetR)family regulators(TFRs)are the largest group of DNA-binding transcription factors and are widely distributed in bacteria and archaea.TFRs play vital roles in controlling the expression of various genes and regulating diverse physiological processes.Recently,a TFR protein Pseudomonas virulence regulator A(PvrA),was identified from Pseudomonas aeruginosa as the transcriptional activator of genes involved in fatty acid utilization and bacterial virulence.Here,we show that PvrA can simultaneously bind to multiple pseudo-palindromic sites and upregulate the expression levels of target genes.Cryo-electron microscopy(cryo-EM)analysis indicates the simultaneous DNA recognition mechanism of PvrA and suggests that the bound DNA fragments consist of a distorted B-DNA double helix.The crystal structure and functional analysis of PvrA reveal a hinge region that secures the correct domain motion for recognition of the promiscuous promoter.Additionally,our results showed that mutations disrupting the regulatory hinge region have differential effects on biofilm formation and pyocyanin biosynthesis,resulting in attenuated bacterial virulence.Collectively,these findings will improve the understanding of the relationship between the structure and function of the TetR family and provide new insights into the mechanism of regulation of P.aeruginosa virulence.

关键词： Pseudomonas aeruginosa transcription regulator TetR protein-structure virulence

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Decoding aging: examining the non-evolutionary event from an evolutionary perspective

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Science China Life Sciences 2024年

作者： Yannan Guo Kang Xu Jianping Cai Zhao Wang Beijing Institute of geriatrics Beijing Hospital Protein Science key laboratory of the Ministry of Education School of Pharmaceutical Sciences Tsinghua University

In an era marked by increased longevity,a deeper understanding of the older population is vital. By introducing an overlooked evolutionary perspective on aging, this article challenges traditional biogerontology, which primarily focuses on biological and clinical aspects. It articulately differentiates between chronological and physiological aging, suggesting that aging is an evolutionary byproduct rather than a direct evolutionary event.

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Immunoglobulin G-mediated food intolerance and metabolic syndrome influence the occurrence of reflux esophagitis in Helicobacter pylori-infected patients

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World Journal of Gastroenterology 2024年第8期30卷 855-862页

作者： Li-Hui Wang Bin-Bin Su Sheng-Shu Wang Guan-Chao Sun Kun-Ming Lv Yi Li Hui Shi Qian-Qian Chen College Chinese PLA General HospitalBeijing 100853China Department of Gastroenterology Second Medical Center of Chinese PLA General HospitalBeijing 100853China Institute of geriatrics The 2nd Medical CenterBeijing Key Laboratory of Aging and GeriatricsNational Clinical Research Center for Geriatrics DiseasesSecond Medical Center of Chinese PLA General HospitalBeijing 100853China Department of Gastroenterology First Medical Center of Chinese PLA General HospitalBeijing 100853China

BACKGROUND Reflux esophagitis has an increasing prevalence and complex and diverse symptoms.Identifying its risk factors is crucial to understanding the etiology,prevention,and management of the disease.The occurrence of reflux esophagitis may be associated with food reactions,Helicobacter pylori(H.pylori)infection,and metabolic syndromes.AIM To investigate the risk factors for reflux esophagitis and analyze the effects of immunoglobulin(Ig)G-mediated food intolerance,H.pylori infection,and metabolic syndrome on reflux esophagitis.METHODS Outpatients attending the Second Medical Center of the PLA General Hospital between 2017 and 2021 were retrospectively enrolled.The patients’basic information,test results,gastroscopy results,H.pylori test results,and IgG-mediated food intolerance results were collected.Multivariate logistic regression analysis was used to analyze risk factors for reflux esophagitis.Statistical mediation analysis was used to evaluate the effects of IgG-mediated food intolerance and metabolic syndrome on H.pylori infection affecting reflux esophagitis.RESULTS A total of 7954 outpatients were included;the prevalence of reflux esophagitis,IgG-mediated food intolerance,H.pylori infection,and metabolic syndrome were 20.84%,61.77%,35.91%,and 60.15%,respectively.Multivariate analysis showed that the independent risk factors for reflux esophagitis included IgG-mediated food intolerance(OR=1.688,95%CI:1.497-1.903,P<0.00001)and metabolic syndrome(OR=1.165,95%CI:1.030-1.317,P=0.01484),and the independent protective factor for reflux esophagitis was H.pylori infection(OR=0.400,95%CI:0.351-0.456,P<0.00001).IgG-mediated food intolerance had a partially positive mediating effect on H.pylori infection as it was associated with reduced occurrence of reflux esophagitis(P=0.0200).Metabolic syndrome had a partially negative mediating effect on H.pylori infection and reduced the occurrence of reflux esophagitis(P=0.0220).CONCLUSION Patients with IgG-mediated food intolerance and metabolic syndrome were at higher ris

关键词： Gastroesophageal reflux Esophagitis Food intolerance Metabolic syndrome Helicobacter pylori Chemokines

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