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KCTD4 interacts with CLIC1 to disrupt calcium homeostasis and promote metastasis in esophageal cancer

Acta Pharmaceutica Sinica B 2023年第10期13卷 4217-4233页

作者： Cancan Zheng Xiaomei Yu Taoyang Xu Zhichao Liu Zhili Jiang Jiaojiao Xu Jing Yang Guogeng Zhang Yan He Han Yang Xingyuan Shi Zhigang Li Jinbao Liu Wen Wen Xu key laboratory of Biological targeting Diagnosis Therapy and Rehabilitation of Guangdong Higher Education Institutesthe Fifth Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510230China Department of Thoracic Surgery Shanghai Chest HospitalSchool of MedicineShanghai Jiao Tong University.Shanghai 200030China Department of Radiation Oncology the Fifth Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510230China Department of Thoracic Surgery Sun Yat-sen University Cancer CenterGuangzhou 510060China guangdong provincial key laboratory of Protein Modification and Degradation State Key Laboratory of Respiratory Diseaseand School of Basic Medical SciencesGuangzhou Medical UniversityGuangzhou 511495China

Increasing evidences suggest the important role of calcium homeostasis in hallmarks of cancer,but its function and regulatory network in metastasis remain unclear.A comprehensive investigation of key regulators in cancer metastasis is urgently *** sequencing(RNA-seq)of primary esophageal squamous cell carcinoma(ESCC)and matched metastatic tissues and a series of gain/loss-of-function experiments identified potassium channel tetramerization domain containing 4(KCTD4)as a driver of cancer ***4 expression was found upregulated in metastatic *** KCTD4 expression is associated with poor prognosis in patients with ESCC and contributes to cancer metastasis in vitro and in ***,KCTD4 binds to CLIC1 and disrupts its dimerization,thus increasing intracellular Ca^(2+)level to enhance NFATc1-dependent fibronectin ***4-induced fibronectin secretion activates fibroblasts in a paracrine manner,which in turn promotes cancer cell invasion via MMP24 signaling as positive ***,a lead compound K279-0738 significantly suppresses cancer metastasis by targeting the KCTD4-CLIC1 interaction,providing a potential therapeutic *** together,our study not only uncovers KCTD4 as a regulator of calcium homeostasis,but also reveals KCTD4/CLIC1-Ca^(2+)-NFATc1-fibronectin signaling as a novel mechanism of cancer *** findings validate KCTD4 as a potential prognostic biomarker and therapeutic target for ESCC.

关键词： Cancermetastasis Calcium homeostasis NFAT signaling Fibroblasts Esophageal cancer

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A simple and efficient in planta transformation method based on the active regeneration capacity of plants

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Plant Communications 2024年第4期5卷 166-176页

作者： Guoguo Mei Ao Chen Yaru Wang Shuquan Li Minyi Wu Yilong Hu Xu Liu Xingliang Hou guangdong provincial key laboratory of Applied Botany&State key laboratory of Plant Diversity and Specialty Crops South China Botanical GardenChinese Academy of SciencesGuangzhou 510650China University of Chinese Academy of Sciences Beijing 100049China These authors contributed equally to this article.

Plant genetic transformation strategies serve as essential tools for the genetic engineering and advanced molecular breeding of ***,the complicated operational protocols and low efficiency of cur-rent transformation strategies restrict the genetic modification of most plant *** paper de-scribes the development of the regenerative activity–dependent in planta injection delivery(RAPID)method based on the active regeneration capacity of *** this method,Agrobacterium tumefaciens is delivered to plant meristems via injection to induce transfected nascent *** transgenic plants can be obtained by subsequent vegetative propagation of the positive nascent *** method was successfully used for transformation of plants with strong regeneration capacity,including different genotypes of sweet potato(Ipomoea batatas),potato(Solanum tuberosum),and bayhops(Ipo-moea pes-caprae).Compared with traditional transformation methods,RAPID has a much higher trans-formation efficiency and shorter duration,and it does not require tissue culture *** RAPID method therefore overcomes the limitations of traditional methods to enable rapid in planta transformation and can be potentially applied to a wide range of plant species that are capable of active regeneration.

关键词： plant genetic transformation RAPID active regeneration sweet potato potato bayhops

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Liquid crystal-based optical aptasensor for the sensitive and selective detection of Gram-negative bacteria

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Science China Chemistry 2022年第10期65卷 2023-2030页

作者： Mengjun Liu Minmin Zhang Jiamei Chen Ruizhi Yang Zhaofan Huang Zhenping Liu Na Li Lingling Shui guangdong provincial key laboratory of Nanophotonic Functional Materials and Devices School of Information and Optoelectronic Science and EngineeringSouth China Normal UniversityGuangzhou 510006China Joint laboratory of Optofluidic Technology and Systems National Center for International Research on Green OptoelectronicsSouth China Academy of Advanced OptoelectronicsSouth China Normal UniversityGuangzhou 510006China

The sensitive and differential detection of Gram-negative bacteria is essential in food processing,environmental monitoring,and the daily chemical ***,we propose and validate a liquid crystal(LC)-based aptasensor for the ultrasensitive detection of Escherichia coli(***),a model of Gram-negative *** nematic liquid crystal of 4-cyano-4’-pentylbiphenyl(5 CB) molecules can be orderly or disorderly arranged at the LC-aqueous interface via different stimuli,causing changes in optical texture due to *** schlieren texture is observed when a mixture solution of aptamer and hexadecyl trimethyl ammonium bromide(CTAB) is dripped onto the segmented LC films on a copper *** specific binding of aptamers with target bacteria biomarkers liberates the CTAB molecules,which then self-assemble at the LC-aqueous interface to induce the vertical alignment of *** optical transition from bright to dark is therefore achieved via the LC molecular orientation and serves as an *** the prominent affinity and specificity of the aptamer,the established sensitive and selective *** assay shows an ultralow detection limit of 27 cfu/*** prepared aptasensor can also be applied for the sensitive and selective determination of *** in fruit juice,soft drink,and cosmetic products,and shows great promise for the on-site detection of Gram-negative bacteria with high sensitivity and specificity for environmental monitoring,food safety assessment,and household chemical inspection.

关键词： liquid crystal molecular arrangement optical sensor aptamer Gram-negative bacteria

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Transcriptome analysis reveals therapeutic potential of NAMPT in protecting against abdominal aortic aneurysm in human and mouse

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Bioactive Materials 2024年第4期34卷 17-36页

作者： Yu Ouyang Yimei Hong Cong Mai Hangzhen Yang Zicong Wu Xiaoyan Gao Weiyue Zeng Xiaohui Deng Baojuan Liu Yuelin Zhang Qingling Fu Xiaojia Huang Juli Liu Xin Li Department of Emergency Medicine Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangdong510006China School of Medicine South China University of TechnologyGuangdong510006China Otorhinolaryngology Hospital The First Affiliated HospitalSun Yat-sen University58 Zhongshan Road IIGuangzhou510006China Extracellular Vesicle Research and Clinical Translational Center The First Affiliated HospitalSun Yat-sen UniversityGuangdong510006China Medical Research Institute Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhou510080China Department of Emergency Medicine The Key Laboratory of Advanced Interdisciplinary StudiesThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdong 510120China Global Health Research Center Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhou510080China

Abdominal Aortic Aneurysm(AAA)is a life-threatening vascular disease characterized by the weakening and ballooning of the abdominal aorta,which has no effective therapeutic approaches due to unclear molecular *** single-cell RNA sequencing,we analyzed the molecular profile of individual cells within control and AAA abdominal *** found cellular heterogeneity,with increased plasmacytoid dendritic cells and reduced endothelial cells and vascular smooth muscle cells(VSMCs)in ***-regulated genes in AAA were associated with muscle tissue development and *** controlling VSMCs aberrant switch from contractile to synthetic phenotype were significantly enriched in ***,VSMCs in AAA exhibited cell senescence and impaired oxidative *** observations were made in a mouse model of AAA induced by Angiotensin II,further affirming the relevance of our findings to human *** concurrence of gene expression changes between human and mouse highlighted the impairment of oxidative phosphorylation as a potential target for *** phosphoribosyltransferase(NAMPT,also named VISFATIN)signaling emerged as a signature event in *** was significantly downregulated in ***-extracellular vesicles(EVs)derived from mesenchymal stem cells restored NAMPT levels,and offered protection against ***,NAMPT-EVs not only repressed injuries,such as cell senescence and DNA damage,but also rescued impairments of oxidative phosphorylation in both mouse and human AAA models,suggesting NAMPT supplementation as a potential therapeutic approach for AAA *** findings shed light on the cellular heterogeneity and injuries in AAA,and offered promising therapeutic intervention for AAA treatment.

关键词： Abdominal aorta Vascular smooth muscle cells Senescence Oxidative phosphorylation Electron transport chain

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A homologous and molecular dual-targeted biomimetic nanocarrier for EGFR-related non-small cell lung cancer therapy

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Bioactive Materials 2023年第9期27卷 337-347页

作者： Bin Xu Fanjun Zeng Jialong Deng Lintong Yao Shengbo Liu Hengliang Hou Yucheng Huang Hongyuan Zhu Shaowei Wu Qiaxuan Li Weijie Zhan Hongrui Qiu Huili Wang Yundong Li Xianzhu Yang Ziyang Cao Yu Zhang Haiyu Zhou Department of Thoracic Surgery Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhou510080PR China Department of General Practice Guangdong Provincial Geriatrics InstituteGuangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhou510080PR China Department of Orthopedics Guangdong Provincial People’s Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhou510080GuangdongChina The Second School of Clinical Medicine Southern Medical UniversityGuangzhou510515PR China Shantou University Medical College Shantou515063PR China guangzhou University of Chinese Medicine Guangzhou510006PR China guangzhou First People’s Hospital South China University of TechnologyGuangzhou510006PR China School of Biology and Biological Engineering South China University of TechnologyGuangzhou510006PR China School of Medicine South China University of TechnologyGuangzhou510006PR China School of Biomedical Sciences and Engineering South China University of TechnologyGuangzhou International CampusGuangzhou511442PR China South China Sea Fisheries Research Institute Chinese Academy of Fishery SciencesKey Laboratory of South China Sea Fishery Resources Exploitation and UtilizationMinistry of Agriculture and Rural AffairsGuangzhou510300China

The abnormal activation of epidermal growth factor receptor(EGFR)drives the development of non-small cell lung cancer(NSCLC).The EGFR-targeting tyrosine kinase inhibitor osimertinib is frequently used to clinically treat NSCLC and exhibits marked efficacy in patients with NSCLC who have an EGFR ***,free osimertinib administration exhibits an inadequate response in vivo,with only~3%patients demonstrating a complete clinical ***,we designed a biomimetic nanoparticle(CMNP^(@Osi))comprising a polymeric nanoparticle core and tumor cell-derived membrane-coated shell that combines membrane-mediated homologous and molecular targeting for targeted drug delivery,thereby supporting a dual-target strategy for enhancing osimertinib *** intravenous injection,CMNP^(@Osi)accumulates at tumor sites and displays enhanced uptake into cancer cells based on homologous *** is subsequently released into the cytoplasm,where it suppresses the phosphorylation of upstream EGFR and the downstream AKT signaling pathway and inhibits the proliferation of NSCLC ***,this dual-targeting strategy using a biomimetic nanocarrier can enhance molecular-targeted drug delivery and improve clinical efficacy.

关键词： Biomimetic nanoparticles Membrane targeting EGFR mutation Tyrosine kinase inhibitor Intracellular drug delivery Clinical efficacy Non-small cell lung cancer

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Research progress on natural products against hepatocellular carcinoma

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BIOCELL 2024年第6期48卷 905-922页

作者： LINGLI ZHANG YAN LI JINGXIN MAO Chongqing key laboratory of High Active Traditional Chinese Drug Delivery System Chongqing Medical and Pharmaceutical CollegeChongqing400030China provincial key laboratory of Pharmaceutical Bioactive Substances School of Life Sciences and BiopharmaceuticalsGuangdong Pharmaceutical UniversityGuangzhou510006China

Hepatocellular carcinoma(HCC)remains a prevalent and challenging malignancy globally,characterized by its numerous causal factors and generally unfavorable *** the relentless pursuit of effective treatment modalities,natural products have emerged as a promising and relatively non-toxic alternative,garnering signiﬁcant *** integration of natural products with contemporary medical research has yielded encouraging therapeutic outcomes in the management of *** review offers a comprehensive overview of the causal factors underlying HCC,and the diverse treatment options available,and highlights the advancements made by natural products in anti-HCC ***,we provide an outline of the various types of natural products,their corresponding nomenclature,target molecules,and mechanisms of action that exhibit anti-HCC *** products are anticipated to play a pivotal role in future comprehensive treatment plans for liver cancer,potentially offering patients improved survival rates and an enhanced quality of life.

关键词： Hepatocellular carcinoma Natural products targets Research progress Drug

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Fargeted elimination of mutant mitochondria DNA in MELAS-iPSCs by mitoTALENs

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Protein & Cell 2018年第3期9卷 283-297页

作者： Yi Yang Han Wu Xiangjin Kang Yanhui Liang Ting Lan Tianjie Li Tao Tan Jiangyun Peng Quanjun Zhang Geng An Yali Liu Qian Yu Zhenglai Ma Ying Lian Boon Seng Soh Qingfeng Chen Ping Liu Yaoyong Chen Xiaofang Sun Rong Li Xiumei Zhen Yang Yu Xiaoping Li Yong Fan key laboratory for Major Obstetric Diseases of guangdong Province Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes The Third Affiliated Hospital of Guangzhou Medical University Guangzhou 510150 China key laboratory of Regenerative Biology of the Chinese Academy of Sciences and guangdong provincial key laboratory of Stem Cells and Regenerative Medicine South China Institute for Stem Cell Biology and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou 510530 China Center of Reproductive Medicine Department of Obstetrics and Gynecology Peking University Third Hospital Beijing 100191 China Yunnan key laboratory of Primate Biomedical Research Institute of Primate Translational Medicine Kunming University of Science and Technology Kunming 650500 China Disease Modeling and Therapeutics laboratory A'STAR Institute of Molecular and Cell Biology 61 Biopolis Drive Proteos Singapore 138673 Singapore Department of Biological Sciences National University of Singapore Singapore 117543 Singapore

Mitochondrial diseases are maternally inherited hetero- geneous disorders that are primarily caused by mitochondrial DNA （mtDNA） mutations. Depending on the ratio of mutant to wild-type mtDNA, known as heteroplasmy, mitochondrial defects can result in a wide spectrum of clinical manifestations. Mitochondria-targeted endonucleases provide an alternative avenue for treating mitochondrial disorders via targeted destruc- tion of the mutant mtDNA and induction of heteroplasmic shifting. Here, we generated mitochondrial disease patient-specific induced pluripotent stem cells （MiPSCs） that harbored a high proportion of m.3243A〉G mtDNA mutations and caused mitochondrial encephalomyopathy and stroke-like episodes （MELAS）. We engineered mitochondrial-targeted transcription activator-like effector nucleases （mitoTALENs） and successfully eliminated the m.3243A〉G mutation in MiPSCs. Off-target mutagenesis was not detected in the targeted MiPSC clones. Utilizing a dual fluorescence iPSC reporter cell line expressing a 3243G mutant mtDNA sequence in the nuclear genome, mitoTALENs displayed a significantly limited ability to target the nuclear genome compared with nuclear-localized TALENs. Moreover, genetically rescued MiPSCs displayed normal mitochondrial respiration and energy production. Moreover, neuronal progenitor cells differentiated from the rescued MiPSCs also demonstrated normal metabolic profiles. Further- more, we successfully achieved reduction in the human m.3243A〉G mtDNA mutation in porcine oocytes via injection of mitoTALEN mRNA. Our study shows the great potential for using mitoTALENs for specific targeting of mutant mtDNA both in iPSCs and mammalian oocytes, which not only provides a new avenue for studying mitochondrial biology and disease but also suggests a potential therapeutic approach for the treatment of mitochondrial disease, as well as the prevention of germline transmission of mutant mtDNA.

关键词： mitochondria iPSCs TALEN MELAS

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mTORC1 induces plasma membrane depolarization and promotes preosteoblast senescence by regulating the sodium channel Scn1a

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Bone Research 2022年第2期10卷 394-408页

作者： Ajuan Chen Jian Jin Shasha Cheng Zezheng Liu Cheng Yang Qingjing Chen Wenquan Liang Kai Li Dawei Kang Zhicong Ouyang Chenfeng Yao Xiaochun Bai Qingchu Li Dadi Jin Bin Huang Academy of Orthopedics Guangdong ProvinceGuangdong Provincial Key Laboratory of Bone and Joint Degeneration DiseasesDepartment of Spine SurgeryThe Third Affiliated Hospital of Southern Medical UniversityGuangzhouChina Department of Spine Surgery Nanfang HospitalSouthern Medical UniversityGuangzhouChina Department of Clinical laboratory The Third Affiliated Hospital of Southern Medical UniversityGuangzhouChina Department of Cell Biology School of Basic Medical ScienceSouthern Medical UniversityGuangzhouChina

Senescence impairs preosteoblast expansion and differentiation into functional osteoblasts,blunts their responses to bone formation-stimulating factors and stimulates their secretion of osteoclast-activating *** to these adverse effects,preosteoblast senescence is a crucial target for the treatment of age-related bone loss;however,the underlying mechanism remains *** found that mTORC1 accelerated preosteoblast senescence in vitro and in a mouse ***,mTORC1 induced a change in the membrane potential from polarization to depolarization,thus promoting cell senescence by increasing Ca^(2+)influx and activating downstream NFAT/ATF3/p53 *** further identified the sodium channel Scn1a as a mediator of membrane depolarization in senescent ***1a expression was found to be positively regulated by mTORC1 upstream of C/EBPα,whereas its permeability to Na^(+)was found to be gated by protein kinase A(PKA)-induced *** stresses increased the permeability of Scn1a to Na^(+)by suppressing PKA activity and induced depolarization in ***,our findings identify a novel pathway involving mTORC1,Scn1a expression and gating,plasma membrane depolarization,increased Ca^(2+)influx and NFAT/ATF3/p53 signaling in the regulation of preosteoblast *** studies of the related pathways and agents might lead to novel potential treatments for agerelated bone loss.

关键词： depolarization mTORC1 treatment

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Challenges and strategies for next-generation bispecific antibody-based antitumor therapeutics

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Cellular & molecular Immunology 2020年第5期17卷 451-461页

作者： Heliang Li Phei Er Saw Erwei Song guangdong provincial key laboratory of Malignant Tumor Epigenetics and Gene Regulation Medical Research CenterSun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhou 510120China Breast Tumor Center Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhou 510120China Zhongshan School of Medicine Sun Yatsen University74 Zhongshan Road IIGuangzhou 510080China guangzhou Regenerative Medicine and Health guangdong laboratory Guangzhou 510005China

Bispecific antibodies(bsAbs)refer to a large family of molecules that recognize two different epitopes or *** a series of challenges,especially immunogenicity and chain mispairing issues,once hindered the development of bsAbs,they have been gradually overcome with the help of rapidly developing technologies in the past 5 *** the meantime,an increasing number of bsAb platforms have been designed to satisfy different clinical ***,numerous preclinical and clinical trials are underway,portraying a promising future for bsAb-based cancer ***,bsAb drugs still face enormous challenges in their application as cancer therapeutics,including tumor heterogeneity and mutational burden,intractable tumor microenvironment(TME),insufficient costimulatory signals to activate T cells,the necessity for continuous injection,fatal systemic side effects,and off-target toxicities to adjacent normal ***,we provide several strategies as solutions to these issues,which comprise generating multispecific bsAbs,discovering neoantigens,combining bsAbs with other anticancer therapies,exploiting natural killer(NK)-cell-based bsAbs and producing bsAbs in *** this review,we mainly discuss previous and current challenges in bsAb development and underscore corresponding strategies,with a brief introduction of several typical bsAb formats.

关键词： Bispecific antibodies(bsAbs) Tumor microenvironment(TME) Tumor immunotherapy Monoclonal antibodies(mAbs)

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Nuclear TIGAR mediates an epigenetic and metabolic autoregulatory loop via NRF2 in cancer therapeutic resistance

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1871-1884页

作者： Hong Wang Qianqian Wang Guodi Cai Zhijian Duan Zoann Nugent Jie Huang Jianwei Zheng Alexander D.Borowsky Jian Jian Li Peiqing Liu Hsing-Jien Kung Leigh Murphy Hong-Wu Chen Junjian Wang School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China Department of Biochemistry and molecular Medicine University of CaliforniaDavisSacramentoCA 95817USA Research Institute in Oncology and Hematology University of Manitoba and CancerCare ManitobaWinnipeg R3E 0V9Canada guangdong Lung Cancer Institute Guangdong Provincial Key Laboratory of Translational Medicine in Lung CancerGuangdong Provincial People’s Hospital and Guangdong Academy of Medical SciencesGuangzhou 510080China Department of Pathology and laboratory Medicine University of CaliforniaDavisSacramentoCA 95817USA Department of Radiation Oncology University of CaliforniaDavisSacramentoCA 95817USA National-Local Joint Engineering laboratory of Druggability and New Drugs Evaluation Guangdong Provincial Key Laboratory of New Drug Design and EvaluationSun Yat-sen UniversityGuangzhou 510006China UC Davis Comprehensive Cancer Center School of MedicineUniversity of CaliforniaDavisSacramentoCA 95817USA

Metabolic and epigenetic reprogramming play important roles in cancer therapeutic ***,their interplays are poorly *** report here that elevated TIGAR(TP53-induced glycolysis and apoptosis regulator),an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2(nuclear receptor binding SET domain protein 2),is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 ***,TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2,H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new(NSD2)and established(NQO1/2,PRDX1 and GSTM4)targets of NRF2,independent of its enzymatic *** TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox *** addition,nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor *** findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.

关键词： TIGAR NSD2 NRF2 Metabolism Oxidative stress Epigenetic reprogramming Therapeutic resistance Redox homeostasis

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