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DNA framework signal amplification platform-based highthroughput systemic immune monitoring

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1115-1131页

作者： Ye Chen Xingyu Chen Bowen Zhang Yuxin Zhang Songhang Li Zhiqiang Liu Yang Gao Yuxuan Zhao Lin Yan Yi Li Taoran Tian Yunfeng Lin State Key laboratory of oral diseases National Center for StomatologyNational Clinical Research Center for Oral DiseasesWest China Hospital of StomatologySichuan UniversityChengdu 610041 SichuanPR China Department of Prosthodontics Tianjin Stomatological HospitalSchool of MedicineNankai UniversityTianjin 300041PR China Department of laboratory Medicine West China HospitalSichuan UniversityChengdu 610041 SichuanPR China Sichuan Provincial Engineering Research Center of oral Biomaterials Chengdu 610041 SichuanChina

systemic immune monitoring is a crucial clinical tool for disease early diagnosis,prognosis and treatment planning by quantitative analysis of immune cells.However,conventional immune monitoring using flow cytometry faces huge challenges in large-scale sample testing,especially in mass health screenings,because of time-consuming,technical-sensitive and high-cost features.However,the lack of high-performance detection platforms hinders the development of high-throughput immune monitoring technology.To address this bottleneck,we constructed a generally applicable DNA framework signal amplification platform(DSAP)based on post-systematic evolution of ligands by exponential enrichment and DNA tetrahedral framework-structured probe design to achieve high-sensitive detection for diverse immune cells,including CD4+,CD8+T-lymphocytes,and monocytes(down to 1/100μl).Based on this advanced detection platform,we present a novel high-throughput immune-cell phenotyping system,DSAP,achieving 30-min one-step immune-cell phenotyping without cell washing and subset analysis and showing comparable accuracy with flow cytometry while significantly reducing detection time and cost.As a proof-of-concept,DSAP demonstrates excellent diagnostic accuracy in immunodeficiency staging for 107 HIV patients(AUC>0.97)within 30 min,which can be applied in HIV infection monitoring and screening.Therefore,we initially introduced promising DSAP to achieve high-throughput immune monitoring and open robust routes for point-of-care device development.

关键词： diagnosis monitoring initially

Ultrasmall copper-based clusterzymes ameliorate Achilles tendinopathy by inhibiting acute oxidative stress

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Nano Research 2024年第6期17卷 5374-5389页

作者： Xuzhuo Chen Yi Du Yazi Huang Xianhao Zhou Xinru Xie Chang Li Chen Zhao Fengrong Dai Xijiao Yu Shanyong Zhang Department of oral Surgery Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineCollege of StomatologyShanghai Jiao Tong UniversityNational Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of StomatologyShanghai Research Institute of StomatologyShanghai 200011China Department of Endodontics Central LaboratoryJinan Stomatological HospitalJinan Key Laboratory of Oral Tissue RegenerationShandong Provincial Health Commission Key Laboratory of Oral Diseases and Tissue RegenerationJinan 250001China State Key laboratory of Structural Chemistry Fujian Institute of Research on the Structure of MatterChinese Academy of SciencesFuzhou 350002China Department of Chemistry College of Chemistry and EnvironmentGuangdong Ocean UniversityZhanjiang 524088China Department of Orthopedics Shanghai Key Laboratory of Orthopedic ImplantShanghai Ninth People's HospitalShanghai Jiao Tong University School of MedicineShanghai 200011China

Tendinopathy is a prevalent musculoskeletal disorder,accounting for over 30%of musculoskeletal lesions.However,current therapeutic strategies for tendinopathy are limited and often yield unsatisfactory clinical outcomes.Therefore,there is a critical need to explore novel therapeutic approaches with minimal side effects for tendinopathy and its early lesions.In this study,we successfully designed and synthesized a copper(I)-based nanocluster,named Cu_(11),which possesses remarkable enzyme-like and ROS-scavenging activities.This unique combination of properties qualifies Cu_(11)as an attractive anti-inflammatory and anti-ROS agent.The Cu_(11)clusterzymes specifically target mitochondria,effectively scavenging excessive reactive oxygen species(ROS)and reducing oxidative stress.Furthermore,Cu_(11)clusterzymes inhibit the activation of key signaling pathways involved in inflammation,namely tumor necrosis factor(TNF),mitogen-activated protein kinase(MAPK),and nuclear factor(NF)-κB,leading to a decrease in the release of proinflammatory cytokines.Excitingly,our in vivo experiments using a collagenase-induced acute Achilles tendinopathy model demonstrated that Cu_(11)clusterzymes effectively alleviate inflammation and oxidative stress,without causing systemic toxicity.This study highlights the potential of copper-based clusterzymes as therapeutic agents for the treatment of Achilles tendinopathy and other inflammatory diseases.The unique enzyme-like and ROS-scavenging activities of Cu_(11)make it a promising candidate for further development and clinical translation.

关键词： nanoclusters clusterzymes oxidative stress tendinopathy reactive oxygen species(ROS)

Does young feces make the elderly live better? Application of fecal microbiota transplantation in healthy aging

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BIOCELL 2024年第6期48卷 873-887页

作者： YUANYUAN LIAO XINSI LI QIAN LI YIZHONG WANG XIUJUN TAN TING GONG Department of Endodontics Stomatological Hospital of Chongqing Medical UniversityChongqingChina Chongqing Key laboratory of oral diseases and Biomedical Sciences ChongqingChina Chongqing Municipal Key laboratory of oral Biomedical Engineering of Higher Education ChongqingChina Department of Research&Development Zhejiang Charioteer Pharmaceutical Co.Ltd.TaizhouChina Department of Implantology Stomatological Hospital of Chongqing Medical UniversityChongqingChina

As we are facing an aging society,anti-aging strategies have been pursued to reduce the negative impacts of aging and increase the health span of human beings.Gut microbiota has become a key factor in the anti-aging process.Modulation of gut microbiota by fecal microbiota transplantation(FMT)to prevent frailty and unhealthy aging has been a hot topic of research.This narrative review summarizes the beneﬁts of FMT for health span and lifespan,brains,eyes,productive systems,bones,and others.The mechanisms of FMT in improving healthy aging are discussed.The increased beneﬁcial bacteria and decreased pathological bacteria decreased gut permeability and systemic inﬂammation,increased short-chain fatty acid(SCFA)and SCFA-producing bacteria,and other factors are listed as mechanisms of FMT to improve healthy aging.The points that need to be considered to ensure the optimal outcomes of FMT are also discussed,such as recipients’age,sex,genetic background,and gut microbiota after FMT.Although thisﬁeld is still in its infancy,it has shown that FMT has great potential to improve healthy aging.

关键词： Gut microbiota Healthy aging Lifespan Fecal microbiota transplantation Co-housing Short-chain fatty acid Inﬂammaging

Advances in oral mesenchymal stem cell-derived extracellular vesicles in health and disease

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Genes & diseases 2024年第1期11卷 346-357页

作者： Huanyu Luo Anahid Ahmadi Birjandi Feilong Ren Tianmeng Sun Paul T.Sharpe Hongchen Sun Zhengwen An Department of oral Biology Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingSchool and Hospital of StomatologyJilin UniversityChangchunJilin 130021China Faculty of Dentistry Oral&Craniofacial SciencesCentre for Craniofacial and Regenerative BiologyKing's College LondonLondonSE19RTUK Department of oral Pathology Jilin Provincial Key Laboratory of Tooth Development and Bone RemodelingSchool and Hospital of StomatologyJilin UniversityChangchunJilin 130021China

Extracellular vesicles(EVs)are nano-size vesicles secreted naturally by all cells into the extracellular space and have been recognized as important cell-cell mediators in multicel-lular organisms.EVs contain nucleic acids,proteins,lipids,and other cellular components,regulating many basic biological processes and playing an important role in regenerative med-icine and diseases.EVs can be traced to their cells of origin and exhibit a similar function.Moreover,EVs demonstrate low immunogenicity,good biocompatibility,and fewer side ef-fects,compared to their parent cells.Mesenchymal stem cells(MsCs)are one of the most important resource cells for EVs,with a great capacity for self-renewal and multipotent differ-entiation,and play an essential role in stem cell therapy.The mechanism of MsC therapy was thought to be attributed to the differentiation of MsCs after targeted migration,as previously noted.However,emerging evidence shows the previously unknown role of MsC-derived para-crine factors in stem cell therapy.Especially EVs derived from oral tissue MSCs(OMSC-EVs),show more advantages than those of all other MsCs in tissue repair and regeneration,due to their lower invasiveness and easier accessibility for sample collection.Here,we systematically review the biogenesis and biological characteristics of OMSC-EVs,as well as the role of OMsC-EVs in intercellular communication.Furthermore,we discuss the potential therapeutic roles of OMSC-EVs in oral and systemic diseases.We highlight the current challenges and future directions of OMSC-EVs to focus more attention on clinical translation.We aim to provide valuable insights for the explorative clinical application of OMSC-EVs.

关键词： Disease Extracellular vesicles oral tissue MSC Therapeutic application Tissue regeneration

systemic antibiotics increase microbiota pathogenicity and oral bone loss

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International Journal of oral Science 2023年第1期15卷 99-112页

作者： Xulei Yuan Fuyuan Zhou He Wang Xinxin Xu Shihan Xu Chuangwei Zhang Yanan Zhang Miao Lu Yang Zhang Mengjiao Zhou Han Li Ximu Zhang Tingwei Zhang Jinlin Song Chongqing Key laboratory for oral diseases and Biomedical Sciences Chongqing Municipal Key Laboratory for Oral Biomedical Engineering of Higher EducationStomatological Hospital of Chongqing Medical UniversityChongqingChina

Periodontitis is the most widespread oral disease and is closely related to the oral microbiota.The oral microbiota is adversely affected by some pharmacologic treatments.systemic antibiotics are widely used for infectious diseases but can lead to gut dysbiosis,causing negative effects on the human body.Whether systemic antibiotic-induced gut dysbiosis can affect the oral microbiota or even periodontitis has not yet been addressed.In this research,mice were exposed to drinking water containing a cocktail of four antibiotics to explore how systemic antibiotics affect microbiota pathogenicity and oral bone loss.The results demonstrated,for the first time,that gut dysbiosis caused by long-term use of antibiotics can disturb the oral microbiota and aggravate periodontitis.Moreover,the expression of cytokines related to Th17 was increased while transcription factors and cytokines related to Treg were decreased in the periodontal tissue.Fecal microbiota transplantation with normal mice feces restored the gut microbiota and barrier,decreased the pathogenicity of the oral microbiota,reversed the Th17/Treg imbalance in periodontal tissue,and alleviated alveolar bone loss.This study highlights the potential adverse effects of long-term systemic antibiotics-induced gut dysbiosis on the oral microbiota and periodontitis.A Th17/Treg imbalance might be related to this relationship.Importantly,these results reveal that the periodontal condition of patients should be assessed regularly when using systemic antibiotics in clinical practice.

关键词： Th17/Treg diseases reversed

Human dental pulp stem/stromal cells in clinical practice

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World Journal of Stem Cells 2024年第2期16卷 54-57页

作者： Mohammed E Grawish Department of oral Biology Faculty of DentistryMansoura UniversityMansoura 35561Egypt Department of oral Biology Faculty of Oral and Dental MedicineDelta University for Science and TechnologyMansoura 11152Egypt

Dental pulp stem/stromal cells(DPSCs)are fibroblast-like,neural crest-derived,and multipotent cells that can differentiate into several lineages.They are relatively easy to isolate from healthy and inflamed pulps,with little ethical concerns and can be successfully cryopreserved and thawed.The therapeutic effects of DPSCs derived from animal or human sources have been extensively studied through in-vitro and in-vivo animal experiments and the findings indicated that DPSCs are effective not only for dental diseases but also for systemic diseases.Understanding that translational research is a critical step through which the fundamental scientific discoveries could be translated into applicable diagnostics and therapeutics that directly benefit humans,several clinical studies were carried out to generate evidence for the efficacy and safety of autogenous or allogeneic human DPSCs(hDPSCs)as a treatment modality for use in cell-based therapy,regenerative medicine/dentistry and tissue engineering.In clinical medicine,hDPSCs were effective for treating acute ischemic stroke and human exfoliated deciduous teeth-conditioned medium(SHED-CM)repaired vascular damage of the corpus cavernous,which is the main cause of erectile dysfunction.Whereas in clinical dentistry,autologous SHED was able to rege-nerate necrotic dental pulp after implantation into injured teeth,and micrografts enriched with autologous hDPSCs and collagen sponge were considered a treatment option for human intrabony defects.In contrast,hDPSCs did not add a significant regenerative effect when they were used for the treatment of post-extraction sockets.Large-scale clinical studies across diverse populations are still lacking to provide robust evidence on the safety and efficacy of hDPSCs as a new treatment option for various human diseases including dental-related problems.

关键词： Dental pulp stem/stromal cells Human clinical studies Regenerative medicine Regenerative dentistry Cell-based therapy

Clinical utility of PDX cohorts to reveal biomarkers of intrinsic resistance and clonal architecture changes underlying acquired resistance to cetuximab in HNSCC

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Signal Transduction and Targeted Therapy 2022年第4期7卷 1202-1218页

作者： Yanli Yao Yujue Wang Lan Chen Zhen Tian Guizhu Yang Rui Wang Chong Wang Qi Wu Yaping Wu Jiamin Gao Xindan Kang Shengzhong Duan Zhiyuan Zhang Shuyang Sun Department of oral and Maxillofacial-Head Neck Oncology Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghaiChina College of Stomatology Shanghai Jiao Tong UniversityNational Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of StomatologyShanghaiChina Department of oral Pathology Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghaiChina laboratory of oral microbiota and systemic diseases Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghaiChina

Cetuximab is a widely used drug for treating head and neck squamous cell carcinomas(HNSCCs);however,it provides restricted clinical benefits,and its response duration is limited by drug resistance.Here,we conducted randomized“Phase II-like clinical trials”of 49 HNSCC PDX models and reveal multiple informative biomarkers for intrinsic resistance to cetuximab(e.g.,amplification of ANKH,up-regulation of PARP3).After validating these intrinsic resistance biomarkers in another HNSCC PDX cohort(61 PDX models),we generated acquired cetuximab resistance PDX models and analyzed them to uncover resistance mechanisms.Whole exome sequencing and transcriptome sequencing revealed diverse patterns of clonal selection in acquired resistant PDXs,including the emergence of subclones with strongly activated RAS/MAPK.Extending these insights,we show that a combination of a RAC1/RAC3 dual-target inhibitor and cetuximab could overcome acquired cetuximab resistance in vitro and in vivo.Beyond revealing intrinsic resistance biomarkers,our PDX-based study shows how clonal architecture changes underlying acquired resistance can be targeted to expand the therapeutic utility of this important drug to more HNSCC patients.

关键词： resistance PDX intrinsic

Nitrate reduction capacity of the oral microbiota is impaired in periodontitis:potential implications for systemic nitric oxide availability

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International Journal of oral Science 2024年第1期16卷 52-61页

作者： Bob T.Rosier William Johnston Miguel Carda-Diéguez Annabel Simpson Elena Cabello-Yeves Krystyna Piela Robert Reilly Alejandro Artacho Chris Easton Mia Burleigh Shauna Culshaw Alex Mira Department of Genomics and Health FISABIO FoundationCenter for Advanced Research in Public HealthValenciaSpain Department of Biological and Biomedical Sciences Glasgow Caledonian UniversityGlasgowUK oral Sciences University of Glasgow Dental SchoolSchool of MedicineDentistry and NursingCollege of MedicalVeterinary and Life SciencesUniversity of GlasgowGlasgowUK Sport and Physical Activity Research Institute University of the West of ScotlandBlantyreScotland Instituto de Biomedicina de Valencia Consejo Superior de Investigaciones Científicas(IBV-CSIC)ValenciaSpain CIBER Center for Epidemiology and Public Health MadridSpain

The reduction of nitrate to nitrite by the oral microbiota has been proposed to be important for oral health and results in nitric oxide formation that can improve cardiometabolic conditions. Studies of bacterial composition in subgingival plaque suggest that nitrate-reducing bacteria are associated with periodontal health, but the impact of periodontitis on nitrate-reducing capacity(NRC)and, therefore, nitric oxide availability has not been evaluated. The current study aimed to evaluate how periodontitis affects the NRC of the oral microbiota. First, 16S rRNA sequencing data from five different countries were analyzed, revealing that nitratereducing bacteria were significantly lower in subgingival plaque of periodontitis patients compared with healthy individuals(P oral NRC was determined in vitro by incubating saliva with 8 mmol/L nitrate(a concentration found in saliva after nitrate-rich vegetable intake) and compared with the NRC of 15healthy individuals. Salivary NRC was found to be diminished in periodontal patients before treatment(P systemic health should be explored in future studies.

关键词： impaired intake nitrate

Local administration of liposomal-based Plekhf1 gene therapy attenuates pulmonary fibrosis by modulating macrophage polarization

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Science China(Life Sciences) 2023年第11期66卷 2571-2586页

作者： Lifeng Yan Chenchen Hou Juan Liu Yi Wang Chenxi Zeng Jun Yu Tianyu Zhou Qing Zhou Shengzhong Duan Weining Xiong Department of Respiratory and Critical Care Medicine Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200011China Department of Pulmonary and Critical Care Medicine The Center for Biomedical ResearchTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Thoracic Surgery Tongji HospitalTongji Medical CollegeHuazhong University of Sciences and TechnologyWuhan 430030China Shanghai Key laboratory of Tissue Engineering Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of MedicineShanghai 200011China laboratory of oral microbiota and systemic diseases Shanghai Ninth People’s HospitalCollege of StomatologyShanghai Jiao Tong University School of MedicineShanghai 200011China National Center for Stomatology National Clinical Research Center for Oral DiseasesShanghai Key Laboratory of StomatologyShanghai 200011China

Idiopathic pulmonary fibrosis(IPF)is a fatal interstitial lung disease with limited therapeutic options.Macrophages,particularly alternatively activated macrophages(M2),have been recognized to contribute to the pathogenesis of pulmonary fibrosis.Therefore,targeting macrophages might be a viable therapeutic strategy for IPF.Herein,we report a potential nanomedicinebased gene therapy for IPF by modulating macrophage M2 activation.In this study,we illustrated that the levels of pleckstrin homology and FYVE domain containing 1(Plekhf1)were increased in the lungs originating from IPF patients and PF mice.Further functionality studies identified the pivotal role of Plekhf1 in macrophage M2 activation.Mechanistically,Plekhf1 was upregulated by IL-4/IL-13 stimulation,after which Plekhf1 enhanced PI3K/Akt signaling to promote the macrophage M2 program and exacerbate pulmonary fibrosis.Therefore,intratracheal administration of Plekhf1 siRNA-loaded liposomes could effectively suppress the expression of Plekhf1 in the lungs and notably protect mice against BLM-induced lung injury and fibrosis,concomitant with a significant reduction in M2 macrophage accumulation in the lungs.In conclusion,Plekhf1 may play a crucial role in the pathogenesis of pulmonary fibrosis,and Plekhf1 siRNA-loaded liposomes might be a promising therapeutic approach against pulmonary fibrosis.

关键词： idiopathic pulmonary fibrosis macrophages alternatively activated macrophages Plekhf1 liposomes