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N-phenylmaleimide induces bioenergetic switch and suppresses tumor growth in glioblastoma tumorspheres by inhibiting SLC25A11

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Cancer cell International 2025年第1期25卷 1-15页

作者： Cho, Hye Joung Yoo, Jihwan Choi, Ran Joo Lee, Jae-Seon Kim, Ryong Nam Park, Junseong Moon, Ju Hyung Kim, Eui Hyun Teo, Wan-Yee Chang, Jong Hee Kim, Soo-Youl Kang, Seok-Gu Department of Neurosurgery Brain Tumor Center Severance Hospital Yonsei University College of Medicine Seoul South Korea Brain Tumor Translational Research Laboratory Department of Biomedical Sciences Yonsei University College of Medicine Seoul South Korea Department of Neurosurgery Gangnam Severance Hospital Yonsei University College of Medicine Seoul South Korea Department of Medical Science Yonsei University Graduate School Seoul South Korea Department of Division of Cancer Biology National Cancer Center Goyang South Korea Department of College of Medicine The Catholic University of Korea Catholic Medical Center Seoul South Korea Cancer and Stem Cell Biology Program Duke-NUS Medical School Singapore Singapore Institute of Molecular and Cell Biology A*STAR Singapore Singapore Brain Research Institute Yonsei University College of Medicine Seoul 03722 South Korea

Background: Glioblastoma (GBM) is a highly resistant tumor, and targeting its bioenergetics could be a potential treatment strategy. GBM cells depend on cytosolic nicotinamide adenine dinucleotide (NADH), which is transported into the mitochondria via the malate-aspartate shuttle (MAS) for ATP production. N-phenylmaleimide (KN612) is a MAS inhibitor that targets SLC25A11, an antiporter protein of the MAS. Therefore, this study investigated the effects of KN612 in GBM treatment using in vitro and in vivo models. Methods: We examined the biological effects of KN612 in GBM tumorspheres (TSs), including its effects on cell viability, ATP level, cell cycle, stemness, invasive properties, energy metabolic pathways, and transcriptomes. Additionally, we investigated the in vivo efficacy of KN612 in a mouse orthotopic xenograft model. Results: Transcriptomic analysis showed that SLC25A11 mRNA expression was significantly higher in GBM TSs than in normal human astrocytes. Additionally, siRNA-mediated SLC25A11 knockdown and KN612-mediated MAS inhibition decreased the oxygen consumption rate, ATP levels, mitochondrial activity, and cell viability in GBM TSs and decreased the stemness and invasion ability of GBM cells. Moreover, gene ontology functional annotation indicated that KN612 treatment inhibited cell-cycle and mitotic processes. Furthermore, KN612 treatment reduced tumor size and prolonged survival in an orthotopic xenograft model. Conclusions: Targeting GBM bioenergetics using KN612 may represent a novel and effective approach for GBM treatment. © The Author(s) 2025.

关键词： Bioenergetics Glioblastoma KN612 Malate-aspartate shuttle SLC25A11

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Identification of druggable host dependency factors shared by multiple SARS-CoV-2 variants of concern

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Journal of Molecular cell Biology 2024年第3期16卷 9-23页

作者： Ilaria Frasson Linda Diamante Manuela Zangrossi Elena Carbognin Anna Dalla Pietà Alessandro Penna Antonio Rosato Ranieri Verin Filippo Torrigiani Cristiano Salata Marìa Paula Dizanzo Lorenzo Vaccaro Davide Cacchiarelli Sara N.Richter Marco Montagner Graziano Martello Department of Molecular Medicine University of PaduaPadua 35121Italy Department of Biology Armenise/Harvard Pluripotent Stem Cell Biology LaboratoryUniversity of PaduaPadua 35131Italy Department of Surgery Oncology and GastroenterologyUniversity of PaduaPadua 35128Italy Veneto Institute of Oncology IOV-IRCCS Padua 35128Italy Department of Comparative Biomedicine and Food Science University of PaduaPadua 35020Italy Telethon Institute of Genetics and Medicine(TIGEM) Armenise/Harvard Laboratory of Integrative GenomicsPozzuoli 80078Italy Department of Translational Medicine University of Naples Federico IINaples 80138Italy School for Advanced Studies Genomics and Experimental Medicine ProgramUniversity of Naples Federico IINaples 80138Italy Microbiology and Virology Unit Padua University HospitalPadua 35128Italy

The high mutation rate of SARS-CoV-2 leads to the emergence of multiple variants,some of which are resistant to vaccines and drugs targeting viral *** host dependency factors,*** proteins required for viral replication,would help prevent the development of ***,it remains unclear whether different SARS-CoV-2 variants induce conserved cellular responses and exploit the same core host *** this end,we compared three variants of concern and found that the host transcriptional response was conserved,differing only in kinetics and *** regularly interspaced short palindromic repeats screening identified host genes required for each variant during *** of the genes were shared by multiple *** validated our hits with small molecules and repurposed the US Food and Drug Administration-approved *** the drugs were highly active against all the tested variants,including new variants that emerged during the study(Delta and Omicron).Mechanistically,we identified reactive oxygen species production as a key step in early viral *** such as N-acetyl cysteine(NAC)were effective against all the variants in both human lung cells and a humanized mouse *** study supports the use of available antioxidant drugs,such as NAC,as a general and effective anti-COVID-19 approach.

关键词： SARS-CoV-2 variants of concern host dependency factors antivirals N-acetyl cysteine

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Human umbilical cord-derived mesenchymal stem cells treatment for refractory uveitis: a case series

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International Journal of Ophthalmology(English edition) 2021年第11期14卷 1784-1790页

作者： Jing Yang Xin-Jun Ren Xi-Teng Chen Yuan-Feng Jiang Zhi-Bo Han Zhong-Chao Han Xiao-Rong Li Xiao-Min Zhang Tianjin Key Laboratory of Retinal Functions and Diseases Tianjin Branch of National Clinical Research Center for Ocular DiseaseEye Institute and School of OptometryTianjin Medical University Eye HospitalTianjin 300384China National Engineering Research Center of Cell Products Tianjin 300457China Beijing Engineering Laboratory of Perinatal Stem Cells Beijing Institute of Health and Stem CellsBeijing 300457China

AIM:To evaluate therapeutic outcomes of human umbilical cord-derived mesenchymal stem cells(HUC-MSCs)treatment in patients with refractory ***:A retrospective and noncomparative review was performed on four patients with refractory uveitis from December 2013 to December ***-MSCs were administered intravenously at a dose of 1×106 cells/*** response,relapse rate,change of visual acuity,and other metrics were ***:All four patients presented with responses to HUC-MSCs treatment,with three males and one *** numbers of uveitis attacks per year after the HUCMSCs treatment(0,2,0,0 respectively)all decreased compared with the numbers before the treatment(3,6,4,4 respectively).The oral steroid and immunosuppressive agents were tapered in all patients without recrudescence of ocular inflammation,and three patients discontinued their oral medicine at the last *** best corrected visual acuity(BCVA)of 3 patients was improved to varying degrees,and the BCVA of 1 patient remained at 20/20(Snellen chart)from the first to the last ***:The study provides an effective therapy of HUC-MSCs in maintaining remission in patients affected by uveitis refractory to previous immunosuppressant treatments.

关键词： refractory uveitis human umbilical cord-derived mesenchymal stem cells therapeutics autoimmune disease

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Orphan nuclear receptors-induced ALT-associated PML bodies are targets for ALT inhibition

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Nucleic Acids Research 2024年第11期52卷 6472-6489页

作者： Marie Gaela, Venus Hsia, Hsuan-Yu Joseph, Nithila A. Tzeng, Wan-Yi Ting, Pin-Chao Shen, Yi-Ling Tsai, Chia-Tsen Boudier, Thomas Chen, Liuh-Yow Molecular and Cell Biology Taiwan International Graduate Program Academia Sinica Graduate Institute of Life Sciences National Defense Medical Center Taipei 11529 Taiwan Institute of Molecular Biology Academia Sinica Taipei 11529 Taiwan Insitute of Molecular and Cellular Biology National Taiwan University Taipei 106319 Taiwan Department and Graduate Institute of Microbiology and Immunology National Defense Medical Center Taipei 11490 Taiwan CENTURI multi-engineering platform Aix-Marseille Université Marseille 13288 France

Orphan nuclear receptors (NRs), such as COUP-TF1, COUP-TF2, EAR2, TR2 and TR4, are implicated in telomerase-negative cancers that maintain their telomeres through the alternative lengthening of telomeres (ALT) mechanism. However, how telomere association of orphan NRs is involved in ALT activation remains unclear. Here, we demonstrate that telomeric tethering of orphan NRs in human fibroblasts initiates formation of ALT-associated PML bodies (APBs) and features of ALT activity, including ALT telomere DNA synthesis, telomere sister chromatid exchange, and telomeric C-circle generation, suggesting de novo ALT induction. Overexpression of orphan NRs exacerbates ALT phenotypes in ALT cells, while their depletion limits ALT. Orphan NRs initiate ALT via the zinc finger protein 827, suggesting the involvement of chromatin structure alterations for ALT activation. Furthermore, we found that orphan NRs and deficiency of the ALT suppressor ATRX-DAXX complex operate in concert to promote ALT activation. Moreover, PML depletion by gene knockout or arsenic trioxide treatment inhibited ALT induction in fibroblasts and ALT cancer cells, suggesting that APB formation underlies the orphan NR-induced ALT activation. Importantly, arsenic trioxide administration abolished APB formation and features of ALT activity in ALT cancer cell line-derived mouse xenografts, suggesting its potential for further therapeutic development to treat ALT cancers. © The Author(s) 2024.

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In vitro and in vivo characterization of erythrosin B and derivatives against Zika virus

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1662-1670页

作者： Zhong Li Jimin Xu Yuekun Lang Xiangmeng Wu Saiyang Hu Subodh Kumar Samrat Anil M.Tharappel Lili Kuo David Butler Yongcheng Song Qing-Yu Zhang Jia Zhou Hongmin Li Department of Pharmacology and Toxicology College of PharmacyTucsonAZ 85721-0207USA Wadsworth Center New York State Department of HealthAlbanyNY 12208USA Chemical Biology Program Department of Pharmacology and ToxicologyUniversity of Texas Medical BranchGalvestonTX 77555USA The Neural Stem Cell Institute RensselaerNY 12144USA Department of Pharmacology and Chemical Biology Baylor College of MedicineHoustonTX 77030USA

Zika virus(ZIKV)causes significant human diseases without specific *** we found erythrosin B,an FDA-approved food additive,inhibited viral NS2B−NS3 interactions,leading to inhibition of ZIKV infection in cell *** this study,we performed pharmacokinetic and in vivo studies to demonstrate the efficacy of erythrosin B against ZIKV in 3D mini-brain organoid and mouse *** results showed that erythrosin B is very effective in abolishing ZIKV replication in the 3D organoid *** pharmacokinetics studies indicated that erythrosin B had a low absorption profile,mice challenged by a lethal dose of ZIKV showed a significantly improved survival rate upon oral administration of erythrosin B,compared to vehicle *** structure−activity relationship studies indicated that most analogs of erythrosin B with modifications on the xanthene ring led to loss or reduction of inhibitory activities towards viral NS2B−NS3 interactions,protease activity and antiviral *** contrast,introducing chlorine substitutions on the isobenzofuran ring led to slightly increased activities,suggesting that the isobenzofuran ring is well tolerated for *** studies indicated that all derivatives are nontoxic to human ***,our studies demonstrated erythrosin B is an effective antiviral against ZIKV both in vitro and in vivo.

关键词： Flavivirus Zika virus Dengue virus Antiviral Protease inhibitor Erythrosin B

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A CRISPR/Cas9-based kinome screen identifies ErbB signaling as a new regulator of human naïve pluripotency and totipotency

Life Medicine

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Life Medicine 2023年第4期2卷 6页

作者： Jiayu Li Xiwen Lin Liangfu Xie Jingru Zhao Chunsheng Han Hongkui Deng Jun Xu Department of Cell Biology School of Basic Medical Sciences Peking University Stem Cell Research Center Peking University Health Science Center Peking University Beijing 100191 China State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences Beijing 100101 China Institute for Stem Cell and Regeneration Chinese Academy of Sciences Beijing 100101 China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101 China MOE Engineering Research Center of Regenerative Medicine School of Basic Medical Sciences State Key Laboratory of Natural and Biomimetic Drugs Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation College of Life Sciences Peking-Tsinghua Center for Life Sciences Peking University Beijing 100191 China State Key Laboratory of Stem Cell and Reproductive Biology Institute of Zoology Chinese Academy of Sciences Beijing 100101 China Institute for Stem Cell and Regeneration Chinese Academy of Sciences Beijing 100101 China Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101 China Savaid Medical School University of Chinese Academy of Sciences Beijing 101408 China

Regulation of totipotency and na?ve pluripotency is crucial for early human embryo development. However, the mechanisms of na?ve pluripotency and totipotency regulation in humans, especially the signaling pathways involved in these processes, remain largely unknown. Here, using the conversion of human extended pluripotent stem cells (hEPSCs) to na?ve pluripotent stem cells as a model, we performed a CRISPR/Cas9-based kinome knockout screen to analyze the effect of disrupting 763 kinases in regulating human na?ve pluripotency. Further validation using small molecules revealed that the inhibition of ErbB family kinases promoted the transition of hEPSCs to human na?ve pluripotent stem cells. More importantly, chemical inhibition of the ErbB family also promoted induction of totipotent signatures in human pluripotent cells under different culture conditions. Our findings provide new mechanistic insights into the regulation of na?ve pluripotency and totipotency in humans.

关键词： totipotency na?ve pluripotency hEPSCs CRISPR screens kinome

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Me 2 SO -free preservation of iPS cells and iPS-derived sensory neurons

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Cryobiology 2022年 109卷 40-41页

作者： Allison Hubel Rui Li James Dutton Department of Mechanical Engineering University of Minnesota United States Department of Biomedical Engineering University of Minnesota United States Stem Cell Institute University of Minnesota United States

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An Asymmetric Natural Nanofiber with Rapid Temperature Responsive Detachability Inspired by Andrias davidianus for Full‑Thickness Skin Wound Healing

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Advanced Fiber Materials 2024年第2期6卷 473-488页

作者： Zhe Huang Heng An Haitao Guo Shen Ji Qi Gu Zhen Gu Yongqiang Wen School of Chemistry and Biological Engineering University of Science and Technology BeijingHaidian DistrictBeijing 100083China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesChaoyang DistrictBeijing 100101China Beijing Institute for Stem Cell and Regenerative Medicine Chaoyang DistrictBeijing 100101China University of Chinese Academy of Sciences Huairou DistrictBeijing 100049China

Wound dressing management is critical in healthcare,and frequent dressing changes for full-thickness skin wounds can hinder *** dressings that resemble the extracellular matrix,have gained popularity in wound repair,however,it is challenging to explore how to frequently change it without affecting healing processing and avoiding secondary ***,we developed a self-adhesive and detachable nanofiber dressing inspired by Andrias *** asymmetric nanofiber dressing exhibits strong adhesion(26 kPa),to the wound at high temperature(approximately 25°C)to the wound surface and can be easily detached(4 kPa)at low temperature(below 8°C),enabling painless dressing changes that minimize secondary *** dressing comprises an outer layer of polylactic acid which provides mechanical property,support,and pollution resistance,with an inner layer of nanofibrous membrane,composed of gelatin and Andrias davidianus skin secretions,which promotes cellular migration,enhances wound healing and possesses inherent antimicrobial ***,the all-natural nanofiber dressings can be prepared on a large scale and offer favorable biocompatibility to meet the basic requirements of wound *** findings demonstrate the potential applicability of our multilayer nanofiber dressing for advancing wound healing practices.

关键词： Natural Rapid Temperature Responsive Detachability Asymmetric Nanofibers Bionic Wound Healing

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Piezoelectric wearable atrial fibrillation prediction wristband enabled by machine learning and hydrogel affinity

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Nano Research 2023年第9期16卷 11674-11681页

作者： Yuan Xi Sijing Cheng Shengyu Chao Yiran Hu Minsi Cai Yang Zou Zhuo Liu Wei Hua Puchuan Tan Yubo Fan Zhou Li Beijing Advanced Innovation Centre for Biomedical Engineering Key Laboratory for Biomechanics and Mechanobiology of Ministry of EducationSchool of Biological Science and Medical EngineeringSchool of Engineering MedicineBeihang UniversityBeijing 100191China CAS Center for Excellence in Nanoscience Beijing Key Laboratory of Micro-nano Energy and Sensor Beijing Institute of Nanoenergy and NanosystemsChinese Academy of SciencesBeijing 101400China The Cardiac Arrhythmia Center State Key Laboratory of Cardiovascular DiseaseNational Clinical Research Center of Cardiovascular DiseasesFuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100037China School of Life Science Institute of Engineering MedicineBeijing Institute of TechnologyBeijing 100081China School of Nanoscience and Technology University of Chinese Academy of SciencesBeijing 100049China Center on Nanoenergy Research School of Physical Science and TechnologyGuangxi UniversityNanning 530004China Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijing 100101China

Atrial fibrillation(AF)is a common and serious *** diagnosis usually requires 12-lead electrocardiogram,which is heavy and *** the same time,the venue for diagnosis is also limited to the *** the development of the concept of intelligent medical,a wearable,portable,and reliable diagnostic method is needed to improve the patient’s comfort and alleviate the patient’s ***,we reported a wearable atrial fibrillation prediction wristband(AFPW)which can provide longterm monitoring and AF *** uses polyvinylidene fluoride piezoelectric film as sensing material and hydrogel as skin bonding material,of which the structure and design have been optimized and *** hydrogel skin bonding layer has good stability and skin affinity,which can greatly improve the user *** has enhanced signal,strong signal-tonoise ratio,and wireless transmission *** a sample library of 385 normal people/patients is analyzed and tested by linear discriminant analysis,the diagnostic success rate of atrial fibrillation is 91%.All these excellent performances demonstrate the great application potential of AFPW in wearable device diagnosis and intelligent medical treatment.

关键词： piezoelectricity atrial fibrillation prediction machine learning wristband

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Therapeutic prospects of mesenchymal stem/stromal cells in COVID-19 associated pulmonary diseases:From bench to bedside

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World Journal of stem cells 2021年第8期13卷 1058-1071页

作者： Lei-Sheng Zhang Yi Yu Hao Yu Zhong-Chao Han Qianfoshan Hospital&The First Affiliated Hospital Shandong First Medical UniversityJinan 250014Shandong ProvinceChina State Key Laboratory of Experimental Hematology&National Clinical Research Center for Blood Disease Institute of Hematology&Blood Diseases HospitalChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300020China School of Medicine Nankai UniversityTianjin 300071China Precision Medicine Division Health-Biotech(Tianjin)Stem Cell Research Institute Co.Ltd.Tianjin 301700China The First Affiliated Hospital Zhejiang UniversityHangzhou 310003Zhejiang ProvinceChina Cell Products of National Engineering Center&National Stem Cell Engineering Research Center Tianjin IMCELL Stem Cell and Gene Technology Co.Ltd.Tianjin 300457China

The ongoing outbreak of coronavirus disease 2019(COVID-19)caused by the novel severe acute respiratory syndrome coronavirus 2 has become a sudden public emergency of international concern and seriously threatens millions of people’s life *** current studies have indicated a favorable role for mesenchymal stem/stromal cells(MSCs)in clinical remission of COVID-19 associated pulmonary diseases,yet the systematical elaboration of the therapeutics and underlying mechanism is far from *** the present review,we summarize the therapeutic potential of MSCs in COVID-19 associated pulmonary diseases such as pneumonia induced acute lung injury,acute respiratory distress syndrome,and pulmonary ***,we review the underlying mechanism of MSCs including direct-and trans-differentiation,autocrine and paracrine anti-inflammatory effects,homing,and neovascularization,as well as constitutive ***,we discuss the prospects and supervision of MSC-based cytotherapy for COVID-19 management before large-scale application in clinical ***,this review supplies overwhelming new references for understanding the landscapes of MSCs in the remission of COVID-19 associated pulmonary diseases.

关键词： Mesenchymal stem/stromal cells COVID-19 Acute lung injury Acute respiratory distress syndrome Pulmonary fibrosis Molecular mechanism

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