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Efficacy and safety of human umbilical cord-derived mesenchymal stem cells in the treatment of refractory immune thrombocytopenia:a prospective,single arm,phase I trial

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2250-2259页

作者： Yunfei Chen Yanmei Xu Ying Chi Ting Sun Yuchen Gao Xueqing Dou Zhibo Han Feng Xue Huiyuan Li Wei Liu Xiaofan Liu Huan Dong Rongfeng Fu Mankai Ju Xinyue Dai Wentian Wang Yueshen Ma Zhen Song Jundong Gu Wei Gong Renchi Yang Lei Zhang State key laboratory of Experimental Hematology National Clinical Research Centre for Blood DiseasesHaihe Laboratory of Cell EcosystemTianjin Key Laboratory of Gene Therapy for Blood DiseasesCAMS Key Laboratory of Gene Therapy for Blood DiseasesInstitute of Hematology&Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300020China Tianjin Institutes of Health Science Tianjin 301600China national Clinical Research Center for Hematologic Diseases Jiangsu Institute of HematologyThe First Affiliated Hospital of Soochow UniversitySuzhou 215006China national Engineering Research Centre of Cell Products Tianjin Key Laboratory of Engineering Technologies for Cell PharmaceuticalAmCellGene Engineering Co.LtdTianjin 300457China School of Population Medicine and Public Health Chinese Academy of Medical Sciences and Peking Union Medical College100730 BeijingChina

Patients with refractory immune thrombocytopenia(ITP)frequently encounter substantial bleeding risks and demonstrate limited responsiveness to existing *** cord-derived mesenchymal stem cells(UC-MSCs)present a promising alternative,capitalizing on their low immunogenicity and potent immunomodulatory effects for treating diverse autoimmune *** prospective phase I trial enrolled eighteen eligible patients to explore the safety and efficacy of UC-MSCs in treating refractory *** research design included administering UC-MSCs at escalating doses of 0.5×10^(6)cells/kg,1.0×10^(6)cells/kg,and 2.0×10^(6)cells/kg weekly for four consecutive weeks across three cohorts during the dose-escalation phase,followed by a dose of 2.0×10^(6)cells/kg weekly for the dose-expansion *** events,platelet counts,and changes in peripheral blood immunity were monitored and recorded throughout the administration and follow-up ***,12(with an addition of three patients in the 2.0×10^(6)cells/kg group due to dose-limiting toxicity)and six patients were enrolled in the dose-escalation and dose-expansion phase,*** patients(13/18,72.2%)experienced one or more treatment emergent adverse *** adverse events occurred in four patients(4/18,22.2%),including gastrointestinal hemorrhage(2/4),profuse menstruation(1/4),and acute myocardial infarction(1/4).The response rates were 41.7%in the dose-escalation phase(5/12,two received 1.0×10^(6)cells/kg per week,and three received 2.0×10^(6)cells/kg per week)and 50.0%(3/6)in the dose-expansion *** overall response rate was 44.4%(8/18)among all enrolled *** sum up,UC-MSCs are effective and well tolerated in treating refractory ITP(*** ID:NCT04014166).

关键词： doses immunity treatment

Expanding the horizons of targeted protein degradation:A non-small molecule perspective

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2402-2427页

作者： Xiaowei Huang Fengbo Wu Jing Ye Lian Wang Xiaoyun Wang Xiang Li Gu He Department of Pharmacy and Department of Dermatology&Venerology West China HospitalSichuan UniversityChengdu 610041China Department of Urology West China HospitalSichuan UniversityChengdu 610041China laboratory of Dermatology Clinical Institute of Inflammation and ImmunologyFrontiers Science Center for Disease-Related Molecular Network and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

Targeted protein degradation(TPD)represented by proteolysis targeting chimeras(PROTACs)marks a significant stride in drug discovery.A plethora of innovative technologies inspired by PROTAC have not only revolutionized the landscape of TPD but have the potential to unlock functionalities beyond ***-small-molecule-based approaches play an irreplaceable role in this field.A wide variety of agents spanning a broad chemical spectrum,including peptides,nucleic acids,antibodies,and even vaccines,which not only prove instrumental in overcoming the constraints of conventional small molecule entities but also provided rapidly renewing *** we summarize the burgeoning non-small molecule technological platforms inspired by PROTACs,including three major trajectories,to provide insights for the design strategies based on novel paradigms.

关键词： Targeted protein degradation Proteolysis targeting chimera Endocytosis Autophagy Proximity-inducing modality Post-translational modification

Alternative splicing and related RNA binding proteins in human health and disease

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Signal Transduction and Targeted Therapy 2024年第3期9卷 839-871页

作者： Yining Tao Qi Zhang Haoyu Wang Xiyu Yang Haoran Mu Department of Orthopedics Shanghai General HospitalShanghai Jiao Tong University School of Medicine200000 ShanghaiChina Shanghai Bone Tumor Institution 200000 ShanghaiChina Department of Biochemistry and Molecular Cell Biology Shanghai Key Laboratory for Tumor Microenvironment and InflammationShanghai Jiao Tong University School of Medicine200000 ShanghaiChina

Alternative splicing(AS)serves as a pivotal mechanism in transcriptional regulation,engendering transcript diversity,and modifications in protein structure and *** varying tissues,developmental stages,or under specific conditions,AS gives rise to distinct splice *** implies that these isoforms possess unique temporal and spatial roles,thereby associating AS with standard biological activities and *** these,AS-related RNA-binding proteins(RBPs)play an instrumental role in regulating alternative splicing *** physiological conditions,the diversity of proteins mediated by AS influences the structure,function,interaction,and localization of proteins,thereby participating in the differentiation and development of an array of tissues and *** pathological conditions,alterations in AS are linked with various diseases,particularly *** changes can lead to modifications in gene splicing patterns,culminating in changes or loss of protein *** instance,in cancer,abnormalities in AS and RBPs may result in aberrant expression of cancer-associated genes,thereby promoting the onset and progression of *** and RBPs are also associated with numerous neurodegenerative diseases and autoimmune ***,the study of AS across different tissues holds significant *** review provides a detailed account of the recent advancements in the study of alternative splicing and AS-related RNA-binding proteins in tissue development and diseases,which aids in deepening the understanding of gene expression complexity and offers new insights and methodologies for precision medicine.

关键词： organs alterations thereby

Advanced nano-based strategies for mRNA tumor vaccine

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Acta Pharmaceutica Sinica B 2024年第1期14卷 170-189页

作者： Yangqi Qu Jingjing Xu Tong Zhang Qinjun Chen Tao Sun Chen Jiang key laboratory of Smart Drug Delivery(Ministry of Education) Minhang HospitalState Key Laboratory of Medical NeurobiologyDepartment of PharmaceuticsSchool of PharmacyFudan UniversityShanghai 201203China

Tumor vaccine is a promising strategy for cancer immunotherapy by introducing tumor antigens into the body to activate specific anti-tumor immune *** with the technological breakthroughs in genetic engineering and delivery systems,messenger ribonucleic acid(mRNA)technology has achieved unprecedented development and application over the last few years,especially the emergency use authorizations of two mRNA vaccines during the COVID-19 pandemic,which has saved countless lives and makes the world witness the powerful efficacy of mRNA technology in ***,unlike infectious disease vaccines,which mainly induce humoral immunity,tumor vaccines also need to activate potent cellular immunity to control tumor growth,which creates a higher demand for mRNA delivery to the lymphatic organs and antigen-presenting cells(APCs).Here we review the existing bottlenecks of mRNA tumor vaccines and advanced nano-based strategies to overcome those challenges,as well as future considerations of mRNA tumor vaccines and their delivery systems.

关键词： mRNA vaccine Nanoparticle Tumor vaccine Delivery system Stability Targeting Transfection Immunogenicity

TREM-2 Drives Development of Multiple Sclerosis by Promoting Pathogenic Th17 Polarization

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Neuroscience Bulletin 2024年第1期40卷 17-34页

作者： Siying Qu Shengfeng Hu Huiting Xu Yongjian Wu Siqi Ming Xiaoxia Zhan Cheng Wang Xi Huang Center for Infection and immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging The Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhai 519000China The State key laboratory of Respiratory Disease Guangdong Provincial Key Laboratory of Allergy and Clinical ImmunologyThe Second Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510260China Department of laboratory Medicine The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510080China Division of Nephrology Department of Medicinethe Fifth Affliated Hospital of Sun Yat-sen UniversityZhuhai 519000China

Multiple sclerosis(MS)is a neuroinflammatory demyelinating disease,mediated by pathogenic T helper 17(Th17)***,the therapeutic effect is accompa-nied by the fluctuation of the proportion and function of Th17 cells,which prompted us to find the key regulator of Th17 differentiation in ***,we demonstrated that the triggering receptor expressed on myeloid cells 2(TREM-2),a modulator of pattern recognition receptors on innate immune cells,was highly expressed on pathogenic CD4-positive T lymphocyte(CD4^(+)T)cells in both patients with MS and experimental autoimmune encephalomyelitis(EAE)mouse *** knockout of Trem-2 in CD4^(+)T cells significantly alleviated the disease activity and reduced Th17 cell infiltration,activation,differentiation,and inflammatory cytokine production and secretion in EAE ***,with Trem-2 knockout in vivo experiments and in vitro inhibitor assays,the TREM-2/zeta-chain associated protein kinase 70(ZAP70)/signal transducer and activator of transcription 3(STAT3)signal axis was essential for Th17 activation and differentiation in EAE *** conclusion,TREM-2 is a key regulator of pathogenic Th17 in EAE mice,and this sheds new light on the potential of this therapeutic target for MS.

关键词： Multiple sclerosis Experimental autoimmune encephalomyelitis T helper 17 Triggering receptor expressed on myeloid cells 2

Single-cell transcriptomic landscape of peripheral blood cells provides insights into adaptation of red-eared sliders(Trachemys scripta elegans)

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Integrative Zoology 2024年第3期19卷 468-479页

作者： Rui GUO Guangwei MA Xiaofei ZHAI Haitao SHI Jichao WANG Ministry of Education key laboratory for Ecology of Tropical Islands Key Laboratory of Tropical Animal and Plant Ecology of Hainan ProvinceCollege of Life SciencesHainan Normal UniversityHaikouChina

Red-eared sliders(Trachemys scripta elegans),as one of the 100 most threatening aliens,have stronger immunity than the native species in response to environmental *** cells are an important component of immunity in the ***,the blood cell researches of turtle are still in the traditional blood cell classification and morphological structure ***,turtle granulocytes cannot be accurately identified using traditional ***-cell RNA sequencing techniques have been successfully implemented to study cells based on the mRNA expression patterns of each *** present study profiled the transcriptomes of peripheral blood cells in red-eared sliders to construct a single-cell transcriptional landscape of the different cell types and explored environmental adaptation mechanism from the perspective of *** 14 transcriptionally distinct clusters(platelets,erythrocytes1,erythrocytes2,CSF1R monocytes,POF1B monocytes,neutrophils,GATA2high basophils,GATA2low basophils,CD4 T cells,CD7 T cells,B cells,ACKR4 cells,serotriflin cells,and ficolin cells)were identified in the peripheral blood cells of the red-eared *** particular,a subtype of erythrocytes(erythrocytes1)that expressed immune signals was *** blood cells were grouped into three lineages:platelet,erythroid/lymphoid,and myeloid cell ***,based on differentiation trajectory and up-regulated gene expression,ACKR4 cells were newly identified as lymphocytes,and serotriflin and ficolin cells as *** single-cell transcriptional atlas of the peripheral blood cells in red-eared sliders provided in the present study will offer a comprehensive transcriptome reference for the exploration of physiological and pathological hematology in this species.

关键词： blood cells single-cell RNA-seq Trachemys scripta elegans

Major royal-jelly proteins intake modulates immune functions and gut microbiota in mice

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Food Science and Human Wellness 2024年第1期13卷 444-453页

作者： Hang Wu Shican Zhou Wenjuan Ning Xiao Wu Xiaoxiao Xu Zejin Liu Wenhua Liu Kun Liu Lirong Shen Junpeng Wang Infection and immunity Institute and Translational Medical Center of Huaihe Hospital Henan UniversityKaifeng 475000China College of Biology Science and Engineering Hebei University of Economics and BusinessShijiazhuang 050061China College of Biosystems Engineering and Food Science Zhejiang Key Laboratory for Agro-Food ProcessingZhejiang UniversityHangzhou 310058China

In this study,we investigated the effects of major royal jelly proteins(MRJPs)on the estrogen,gut microbiota,and immunological responses in *** given 250 or 500 mg/kg,not 125 mg/kg of MRJPs,enhanced the proliferation of splenocytes in response to *** splenocytes and mesenteric lymphocytes activated by T-cell mitogens(Con A and anti-CD3/CD28 antibodies)released high levels of IL-2 but low levels of IFN-γand *** release of IL-4 was unaffected by ***,splenocytes and mesenteric lymphocytes activated by LPS were prevented by MRJPs at the same dose as that required for producing IL-1βand IL-6,two pro-inflammatory *** production of IL-1β,IL-6,and IFN-γwas negatively associated with estrogen levels,which were higher in the MRJP-treated animals than in the control *** of the gut microbiota revealed that feeding mice 250 mg/kg of MRJPs maintained the stability of the natural intestinal microflora of ***,the LEf Se analysis identified biomarkers in the MRJP-treated mice,including Prevotella,Bacillales,Enterobacteriales,Gammaproteobacteria,Candidatus_Arthromitus,and *** results showed that MRJPs are important components of royal jelly that modulate host immunity and hormone levels and help maintain gut microbiota stability.

关键词： Major royal-jelly proteins immunity Estrogen Gut microbiota Cytokines

Reynosin protects neuronal cells from microglial neuroinflammation by suppressing NLRP3 inflammasome activation mediated by NADPH oxidase

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Chinese Journal of Natural Medicines 2024年第6期22卷 486-500页

作者： YANG Yanqiu CHE Yue FANG Mingxia YAO Xiaohu ZHOU Di WANG Feng CHEN Gang LIANG Dong LI Ning HOU Yue key laboratory of Bioresource Research and Development of Liaoning Province College of Life and Health SciencesNorth-eastern UniversityShenyang 110000China national Frontiers Science Center for Industrial Intelligence and Systems Optimization Key Laboratory of Data Analytics and Optimization for Smart IndustryMinistry of EducationNortheastern UniversityShenyang 110000China School of Traditional Chinese Materia Medica Key Laboratory of Innovative Traditional Chinese Medicine for Major Chronic Diseases of Liaoning provinceKey Laboratory for TCM Material Basis Study and Innovative Drug Development of Shenyang CityShenyang Pharmaceutical UniversityShenyang 110000China State key laboratory for Chemistry and Molecular Engineering of Medicinal Resources School of Chemistry and Pharmaceutical SciencesGuangxi Normal UniversityGuilin 541000China

Neuroinflammation,mediated by the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing-3(NLRP3)inflammasome,is a significant contributor to the pathogenesis of neurodegenerative diseases(NDDs).Reynos-in,a natural sesquiterpene lactone(SL),exhibits a broad spectrum of pharmacological effects,suggesting its potential therapeutic ***,the effects and mechanism of reynosin on neuroinflammation remain *** current study explores the effects and mechanisms of reynosin on neuroinflammation using mice and BV-2 microglial cells treated with lipopolysaccharide(LPS).Our findings reveal that reynosin effectively reduces microglial inflammation in vitro,as demonstrated by decreased CD11b expression and lowered interleukin-1 beta(IL-1β)and interleukin-18(IL-18)mRNA and protein ***,in vivo,results showed a re-duction in the number of Iba-1 positive cells and alleviation of morphological alterations,alongside decreased expressions of IL-1βand *** analysis indicates that reynosin inhibits NLRP3 inflammasome activation,evidenced by reduced transcription of NLRP3 and caspase-1,diminished NLRP3 protein expression,inhibited apoptosis-associated speck-like protein containing a CARD(ASC)oli-gomerization,and decreased caspase-1 ***,reynosin curtailed the activation of nicotinamide adenine dinuc-leotide phosphate(NADPH)oxidase,demonstrated by reduced NADP^(+)and NADPH levels,downregulation of gp91^(phox) mRNA,pro-tein expression,suppression of p47^(phox) expression and translocation to the ***,reynosin exhibited a neuroprotective effect against microglial inflammation in vivo and in *** collective findings underscore reynosin’s capacity to mitigate mi-croglial inflammation by inhibiting the NLRP3 inflammasome,thus highlighting its potential as a therapeutic agent for managing neuroinflammation.

关键词： Microglia NLRP3 inflammasome Reactive oxygen species NADPH oxidase Neuron Reynosin

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 ***,current therapeutic strategies for tendinopathy are limited and often yield unsatisfactory clinical ***,there is a critical need to explore novel therapeutic approaches with minimal side effects for tendinopathy and its early *** this study,we successfully designed and synthesized a copper(I)-based nanocluster,named Cu_(11),which possesses remarkable enzyme-like and ROS-scavenging *** unique combination of properties qualifies Cu_(11)as an attractive anti-inflammatory and anti-ROS *** Cu_(11)clusterzymes specifically target mitochondria,effectively scavenging excessive reactive oxygen species(ROS)and reducing oxidative ***,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 ***,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 *** study highlights the potential of copper-based clusterzymes as therapeutic agents for the treatment of Achilles tendinopathy and other inflammatory *** 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)