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Simultaneously targeting extracellular vesicle trafficking and TGF-β receptor kinase activity blocks signaling hyperactivation and metastasis

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Signal Transduction and Targeted Therapy 2024年第1期9卷 308-325页

作者： Adilson Fonseca Teixeira Yanhong Wang Josephine Iaria Peter ten Dijke Hong-Jian Zhu Department of Surgery(The Royal Melbourne Hospital) The University of MelbourneParkvilleVICAustralia Huagene Institute Kecheng Science and Technology ParkPukou DistrictNanjingJiangsuChina Department of cell and Chemical biology Oncode InstituteLeiden University Medical CenterLeidenThe Netherlands

Metastasis is the leading cause of cancer-related *** growth factor beta(TGF-β)signaling drives metastasis and is strongly enhanced during cancer ***,the use of on-target TGF-βsignaling inhibitors in the treatment of cancer patients remains unsuccessful,highlighting a gap in the understanding of TGF-βbiology that limits the establishment of efficient anti-metastatic ***,we show that TGF-βsignaling hyperactivation in breast cancer cells is required for metastasis and relies on increased small extracellular vesicle(sEV)*** sEV’s unique role,TGF-βsignaling levels induced by sEVs exceed the activity of matching concentrations of soluble ligand TGF-β.Further,genetic disruption of sEV secretion in highlymetastatic breast cancer cells impairs cancer cell aggressiveness by reducing TGF-βsignaling to nearly-normal ***,TGF-βsignaling activity in non-invasive breast cancer cells is inherently low,but can be amplified by sEVs,enabling invasion and metastasis of poorly-metastatic breast cancer *** the translational potential of inhibiting sEV trafficking in advanced breast cancers,treatment with dimethyl amiloride(DMA)decreases sEV secretion,TGF-βsignaling activity,and breast cancer progression in *** both the sEV trafficking and TGF-βsignaling by combining DMA and SB431542 at suboptimal doses potentiated this effect,normalizing the TGF-βsignaling in primary tumors to potently reduce circulating tumor cells,metastasis,and tumor ***,this study establishes sEVs as critical elements in TGF-βbiology,demonstrating the feasibility of inhibiting sEV trafficking as a new therapeutic approach to impair metastasis by normalizing TGF-βsignaling levels in breast cancer cells.

关键词： metastasis doses invasion

Inhalable metal–organic framework-mediated cuproptosis combined with PD-L1 checkpoint blockade for lung metastasis synergistic immunotherapy

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2281-2297页

作者： Chongzheng Yan Ying Liu Guozhi Zhao Huatian Yang Huaiyou Lv Genju Li Yuhan Li Yaqing Fu Fengqin Sun Yafei Feng Yizhe Li Zhongxi Zhao Department of Pharmaceutics Key Laboratory of Chemical Biology of Ministry of EducationSchool of Pharmaceutical SciencesCheelloo College of MedicineShandong UniversityJinan 250012China Key University laboratory of Pharmaceutics&Drug Delivery Systems of Shandong Province School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

Cuproptosis shows enormous application prospects in lung metastasis ***,the glycolysis,Cu^(+)efflux mechanisms,and insufficient lung drug accumulation severely restrict cuproptosis ***,an inhalable poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate)(OPDEA)-coated copper-based metal–organic framework encapsulating pyruvate dehydrogenase kinase 1 siRNA(siPDK)is constructed for mediating cuproptosis and subsequently promoting lung metastasis immunotherapy,namely *** inhalation,OMP shows highly efficient lung accumulation and long-term retention,ascribing to the OPDEA-mediated pulmonary mucosa *** tumor cells,OMP is degraded to release Cu2+under acidic condition,which will be reduced to toxic Cu^(+)to induce cuproptosis under glutathione(GSH)***,siPDK released from OMP inhibits intracellular glycolysis and adenosine-5ʹ-triphosphate(ATP)production,then blocking the Cu^(+)efflux protein ATP7B,thereby rendering tumor cells more sensitive to OMP-mediated ***,OMP-mediated cuproptosis triggers immunogenic cell death(ICD)to promote dendritic cells(DCs)maturation and CD8^(+)T cells ***,OMP-induced cuproptosis up-regulates membrane-associated programmed cell death-ligand 1(PD-L1)expression and induces soluble PD-L1 secretion,and thus synergizes with anti-PD-L1 antibodies(aPD-L1)to reprogram immunosuppressive tumor microenvironment,finally yielding improved immunotherapy ***,OMP may serve as an efficient inhalable nanoplatform and afford preferable efficacy against lung metastasis through inducing cuproptosis and combining with aPD-L1.

关键词： Cuproptosis Immunogenic cell death PD-L1 checkpoint blockade Copper-based metal-organic framework Immunotherapy Tumor microenvironment Transmucosal deliveryLung metastasis

Role of immune cell interactions in alcohol-associated liver diseases

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Isoform-and cell-state-specific APOE homeostasis and function

肝脏研究（英文） 2024年第2期8卷 72-82页

作者： Xianda Wang Juan Wang Haodong Peng Li Zuo Hua Wang Innovation and Entrepreneurship laboratory for College Students Anhui Medical UniversityHefeiAnhuiChina Inflammation and Immune-Mediated Diseases laboratory of Anhui Province Anhui Medical UniversityHefeiAnhuiChina Department of Oncology The First Affiliated Hospital of Anhui Medical UniversityHefeiAnhuiChina Innovation and Entrepreneurship laboratory for College Students Anhui Medical UniversityHefeiAnhuiChina The First School of Clinical Medicine Anhui Medical UniversityHefeiAnhuiChina Innovation and Entrepreneurship laboratory for College Students Anhui Medical UniversityHefeiAnhuiChina laboratory of Molecular biology Department of BiochemistrySchool of Basic Medical SciencesAnhui Medical UniversityHefeiAnhuiChina

Research on inflammatory response,liver injury,and immune regulation has demonstrated that the intricate interactions among immune cells constitute a critical regulatory *** consumption alters the liver microenvironment,triggering inflammation and immune *** the inhibitory,cooperative,and synergistic effects among lymphocytes and myeloid cells may reveal the core mechanisms of alcohol-associated liver disease(ALD)pathogenesis and identify promising therapeutic *** review seeks to elucidate the intricate and multifaceted interactions among immune cells,encompassing both direct cellular interactions and the secretion of various effector *** is essential to underscore that these interactions have broader and more complex roles in ALD than the activities of individual immune cell *** interactions play a crucial role in mutually regulating one another,thereby preserving the homeostasis of the inflammatory and immune response in the liver *** these immune cell interactions is anticipated to offer a novel approach to the prevention and treatment of ALD.

关键词： Immune cell cell interactions Inflammation Alcohol-associated liver disease (ALD)

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Neural Regeneration Research 2024年第11期19卷 2456-2466页

作者： Karina Lindner Anne-Claude Gavin Department of cell Physiology and Metabolism Faculty of MedicineUniversity of GenevaGenevaSwitzerland Diabetes Center Faculty of MedicineUniversity of GenevaGenevaSwitzerland

Apolipoprotein E is the major lipid transporter in the brain and an important player in neuron-astrocyte metabolic *** ensures the survival of neurons under stressful conditions and hyperactivity by nourishing and detoxifying *** E polymorphism,combined with environmental stresses and/or age-related alterations,influences the risk of developing late-onset Alzheimer’s *** this review,we discuss our current knowledge of how apolipoprotein E homeostasis,*** synthesis,secretion,degradation,and lipidation,is affected in Alzheimer’s disease.

关键词： Alzheimer’s disease apolipoprotein E autophagy cholesterol lipid detoxification lipid transport lysosomal failure metabolic impairment triacylglycerol

CRISPR-based genetic screens advance cancer immunology

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Science China Life Sciences 2024年

作者： Yuanfang Cao Xueting Li Yumu Pan Huahe Wang Siyu Yang Lingjuan Hong Lupeng Ye Institute of Modern biology Nanjing University

CRISPR technologies have revolutionized research areas ranging from fundamental science to translational medicine. CRISPR-based genetic screens offer a powerful platform for unbiased screening in various fields, such as cancer immunology. Immune checkpoint blockade(ICB)therapy has been shown to strongly affect cancer treatment. However, the currently available ICBs are limited and do not work in all cancer patients. Pooled CRISPR screens enable the identification of previously unknown immune regulators that can regulate T-cell activation,cytotoxicity, persistence, infiltration into tumors, cytokine secretion, memory formation, T-cell metabolism, and CD4+T-cell *** novel targets can be developed as new immunotherapies or used with the current ICBs as new combination therapies that may yield synergistic efficacy. Here, we review the progress made in the development of CRISPR technologies, particularly technological advances in CRISPR screens and their application in novel target identification for immunotherapy.

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Myokines:metabolic regulation in obesity and type 2 diabetes

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Life Metabolism 2024年第3期3卷 21-45页

作者： Zhi-Tian Chen Zhi-Xuan Weng Jiandie D.Lin Zhuo-Xian Meng Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital School of MedicineZhejiang UniversityHangzhouZhejiang 310058China Key laboratory of Disease Proteomics of Zhejiang Province School of MedicineZhejiang UniversityHangzhouZhejiang 310058China Zhejiang University-University of Edinburgh Institute(ZJE) School of MedicineZhejiang UniversityHainingZhejiang 314400China Life Sciences Institute and Department of cell and Developmental biology University of MichiganAnn ArborMI 48109United States Department of Geriatrics Affiliated Hangzhou First People’s HospitalHangzhouZhejiang 310006China

Skeletal muscle plays a vital role in the regulation of systemic metabolism,partly through its secretion of endocrine factors which are collectively known as *** myokine levels are associated with metabolic diseases,such as type 2 diabetes(T2D).The significance of interorgan crosstalk,particularly through myokines,has emerged as a fundamental aspect of nutrient and energy ***,a comprehensive understanding of myokine biology in the setting of obesity and T2D remains a major chal*** this review,we discuss the regulation and biological functions of key myokines that have been extensively studied during the past two decades,namely interleukin 6(IL-6),irisin,myostatin(MSTN),growth differentiation factor 11(GDF11),fibroblast growth factor 21(FGF21),apelin,brain-derived neurotrophic factor(BDNF),meteorin-like(Metrnl),secreted protein acidic and rich in cysteine(SPARC),β-aminoisobutyric acid(BAIBA),Musclin,and Dickkopf 3(Dkk3).Related to these,we detail the role of exercise in myokine expression and secretion together with their contributions to metabolic physiology and *** significant advancements in myokine research,many myokines remain challenging to measure accurately and investigate ***,new research techniques and detection methods should be developed and rigorously ***,developing a comprehensive perspective on myokine biology is crucial,as this will likely offer new insights into the pathophysiological mechanisms underlying obesity and T2D and may reveal novel targets for therapeutic interventions.

关键词： myokines skeletal muscle obesity type 2 diabetes metabolism

Newcastle disease virus suppresses antigen presentation via inhibiting IL-12 expression in dendritic cells

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第3期25卷 254-270页

作者： Fulong NAN Wenlong NAN Xin YAN Hui WANG Shasha JIANG Shuyun ZHANG Zhongjie YU Xianjuan ZHANG Fengjun LIU Jun LI Xiaoqiong ZHOU Delei NIU Yiquan LI Wei WANG Ning SHI Ningyi JIN Changzhan XIE Xiaoni CUI He ZHANG Bin WANG Huijun LU Department of Special Medicine Department of Pathogenic BiologySchool of Basic MedicineQingdao UniversityQingdao 266071China China Animal Health and Epidemiology Center Qingdao 266032China Academician Workstation of Jilin Province Changchun University of Chinese MedicineChangchun 130117China Institute of Virology Wenzhou UniversityWenzhou 325035China College of Veterinary Medicine Jilin UniversityChangchun 130012China Changchun Veterinary Research Institute Chinese Academy of Agricultural SciencesChangchun 130122China Sino-cell Biomed Co. Ltd.Qingdao 266000China

As a potential vectored vaccine,Newcastle disease virus(NDV)has been subject to various studies for vaccine development,while relatively little research has outlined the immunomodulatory effect of the virus in antigen *** elucidate the key inhibitory factor in regulating the interaction of infected dendritic cells(DCs)and T cells,DCs were pretreated with the NDV vaccine strain LaSota as an inhibitor and stimulated with lipopolysaccharide(LPS)for further detection by enzyme-linked immunosorbent assay(ELISA),flow cytometry,immunoblotting,and quantitative real-time polymerase chain reaction(qRT-PCR).The results revealed that NDV infection resulted in the inhibition of interleukin(IL)-12p40 in DCs through a p38 mitogen-activated protein kinase(MAPK)-dependent manner,thus inhibiting the synthesis of IL-12p70,leading to the reduction in T cell proliferation and the secretion of interferon-(IFN-),tumor necrosis factor-α(TNF-α),and IL-6 induced by ***,downregulated cytokines accelerated the infection and viral transmission from DCs to T ***,several other strains of NDV also exhibited inhibitory *** current study reveals that NDV can modulate the intensity of the innate-adaptive immune cell crosstalk critically toward viral invasion improvement,highlighting a novel mechanism of virus-induced immunosuppression and providing new perspectives on the improvement of NDV-vectored vaccine.

关键词： Newcastle disease virus Dendritic cells Interleukin-12(IL-12) T cells Immunosuppression

Sorafenib inhibits ossification of the posterior longitudinal ligament by blocking LOXL2-mediated vascularization

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Bone Research 2024年第2期12卷 372-389页

作者： Longqing Wang Wenhao Jiang Siyuan Zhao Dong Xie Qing Chen Qi Zhao Hao Wu Jian Luo Lili Yang Spine Center Department of OrthopaedicsShanghai Changzheng HospitalSecond Affiliated Hospital of Naval Medical UniversityShanghai 200003PR China Yangzhi Rehabilitation Hospital(Shanghai Sunshine Rehabilitation Center) Tongji University School of MedicineShanghaiPR China Shanghai Key laboratory of Regulatory biology Institute of Biomedical Sciences and School of Life SciencesEast China Normal UniversityShanghaiPR China Department of Orthopaedics No.905 Hospital of PLA NavyShanghaiPR China

Ossification of the Posterior Longitudinal Ligament(OPLL)is a degenerative hyperostosis disease characterized by the transformation of the soft and elastic vertebral ligament into bone,resulting in limited spinal mobility and nerve *** both bulk and single-cell RNA sequencing,we elucidate the molecular characteristics,cellular components,and their evolution during the OPLL process at a single-cell resolution,and validate these findings in clinical *** study also uncovers the capability of ligament stem cells to exhibit endothelial cell-like phenotypes in vitro and in ***,our study identifies LOXL2 as a key regulator in this *** gain-and loss-of-function studies,we elucidate the role of LOXL2 in the endothelial-like differentiation of ligament *** acts via the HIF1A pathway,promoting the secretion of downstream VEGFA and *** function is not related to the enzymatic activity of ***,we identify sorafenib,a broad-spectrum tyrosine kinase inhibitor,as an effective suppressor of LOXL2-mediated vascular *** disrupting the coupling between vascularization and osteogenesis,sorafenib demonstrates significant inhibition of OPLL progression in both BMP-induced and enpp1 deficiency-induced animal models while having no discernible effect on normal bone *** findings underscore the potential of sorafenib as a therapeutic intervention for OPLL.

关键词： LOXL2 ligament finding

Bionic immunoactivator copresenting autophagy promoting and costimulatory molecules for synergistic cancer immunotherapy

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Nano Research 2024年第3期17卷 1710-1724页

作者： Yiwei Peng Yiliang Yang Zhenzhen Yang Datong Gao Jiajia Li Qi Sun Yitian Du Meng Lin Xianrong Qi Beijing Key laboratory of Molecular Pharmaceutics and New Drug Delivery System School of Pharmaceutical SciencesPeking UniversityBeijing 100191China

Immunotherapy has great promise in improving malignant tumor ***,the efficacy of existing strategies is often limited by the immunosuppressive ***,we demonstrate an in situ bionic immunoactivator,PLT-Bec1/DTA-1,with possessed natural advantages of platelets for tumor recruitment and activation,on which DTA-1(CD357 monoclonal antibody)and Bec1 were tethered as combined immune ***-Bec1/DTA-1,as a self-triggered release repository,can deliver the pre-tethered Bec1 and DTA-1 deeply through the secretion of platelet microparticles(PMPs),thereby cooperate tacitly and exhibit superiority in immune activation of dendritic cells(DCs)and T cells via autophagy inducibility,coupled with glucocorticoid-induced tumor necrosis factor receptor(GITR)-triggered T_(Reg) suppression,remodeled the immunosuppressive network of tumor ***-Bec1/DTA-1 promoted antigen presentation and T cell proliferation,and alleviated the low activity state of bone marrow-derived dendritic cells(BMDCs)in tumor suppressive ***-Bec1/DTA-1 inhibited tumor recurrence(5-and 13-fold lower of control group in tumor volume)and CD8^(+)T/T_(Reg) ratio(6.3-and 8.8-fold *** group)in mouse tumor model after intravenous or subcutaneous ***,PLT-Bec1/DTA-1 prevented tumor colonization in lung through in situ immune activation,and was slightly superior to the combined of Bec1 and *** findings highlight the promise of delivering immunostimulatory payloads via bionic carriers,eliciting automatic in situ activation of effector immune cells in tumor microenvironment for tumor *** these results provide promising prospects into the application of immunoactivator in improving cancer synergistic immunotherapy to overcome the bottlenecks in clinic.

关键词： in situ bionic immunoactivator autophagy glucocorticoid-induced tumor necrosis factor receptor(GITR)agonist platelets and platelet microparticles cancer immunotherapy