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Synergistic induction of mitotic pyroptosis and tumor remission by inhibiting proteasome and WEE family kinases

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Signal Transduction and Targeted Therapy 2024年第8期9卷 3467-3482页

作者： Zhan-Li Chen Chen Xie Wei Zeng Rui-Qi Huang Jin-E Yang Jin-Yu Liu Ya-Jing Chen Shi-Mei Zhuang MOE Key laboratory of gene Function and regulation Guangdong Province Key Laboratory of Pharmaceutical Functional GenesSchool of Life SciencesState Key Laboratory of Oncology in Southern ChinaSun Yat-sen UniversityGuangzhouPR China Key laboratory of Liver Disease of Guangdong Province The Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510630PR China

Mitotic catastrophe(MC),which occurs under dysregulated mitosis,represents a fascinating tactic to specifically eradicate tumor *** pyroptosis can be a death form of MC remains ***-mediated protein degradation is crucial for ***(BTZ),which inhibits the 20S catalytic particle of proteasome,is approved to treat multiple myeloma and mantle cell lymphoma,but not solid tumors due to primary *** date,whether and how proteasome inhibitor affected the fates of cells in M-phase remains ***,we show that BTZ treatment,or silencing of PSMC5,a subunit of 19S regulatory particle of proteasome,causes G2-and M-phase arrest,multi-polar spindle formation,and consequent caspase-3/GSDME-mediated pyroptosis in M-phase(designated as mitotic pyroptosis).Further investigations reveal that inhibitor of WEE1/PKMYT1(PD0166285),but not inhibitor of ATR,CHK1 or CHK2,abrogates the BTZ-induced G2-phase arrest,thus exacerbates the BTZ-induced mitotic arrest and *** BTZ and PD0166285 treatment(named BP-Combo)selectively kills various types of solid tumor cells,and significantly lessens the IC50 of both BTZ and PD0166285 compared to BTZ or PD0166285 *** using various mouse models show that BP-Combo has much stronger inhibition on tumor growth and metastasis than BTZ or PD0166285 monotreatment,and no obvious toxicity is observed in BP-Combo-treated *** findings disclose the effect of proteasome inhibitors in inducing pyroptosis in M-phase,characterize pyroptosis as a new death form of mitotic catastrophe,and identify dual inhibition of proteasome and WEE family kinases as a promising anti-cancer strategy to selectively kill solid tumor cells.

关键词： proteasome inhibiting catastrophe

Current therapies for osteoarthritis and prospects of CRISPR-based genome,epigenome,and RNA editing in osteoarthritis treatment

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Journal of genetics and Genomics 2024年第2期51卷 159-183页

作者： Yuxi Chen Xiao Luo Rui Kang Kaixin Cui Jianping Ou Xiya Zhang Puping Liang MOE Key laboratory of gene Function and regulation State Key Laboratory of BiocontrolSchool of Life SciencesSun Yat-sen UniversityGuangzhouGuangdong 510275China Center for Reproductive Medicine The Third Affiliated Hospital of Sun Yat-sen UniversitySun Yat-sen UniversityGuangzhouGuangdong 510630China

Osteoarthritis(OA)is one of the most common degenerative joint diseases worldwide,causing pain,disability,and decreased quality of *** balance between regeneration and inflammation-induced degradation results in multiple etiologies and complex pathogenesis of ***,there is a lack of effective therapeutic strategies for OA *** the development of CRISPR-based genome,epigenome,and RNA editing tools,OA treatment has been improved by targeting genetic risk factors,activating chondrogenic elements,and modulating inflammatory *** by cell therapy and in vivo delivery vectors,genome,epigenome,and RNA editing tools may provide a promising approach for personalized OA *** review summarizes CRISPR-based genome,epigenome,and RNA editing tools that can be applied to the treatment of OA and provides insights into the development of CRISPR-based therapeutics for OA ***,in-depth evaluations of the efficacy and safety of these tools in human OA treatment are needed.

关键词： Osteoarthritis Genome editing Epigenone editing RNA editing

TaMYB72 directly activates the expression of TaFT to promote heading and enhance grain yield traits in wheat(Triticum aestivum L.)

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Journal of Integrative Plant Biology 2024年第7期66卷 1266-1269页

作者： Lifen Wu Zhencheng Xie Danping Li Yaoyu Chen Chuan Xia Xiuying Kong Xu Liu Lichao Zhang State Key laboratory of Crop gene Resources and Breeding Institute of Crop Sciencesthe Chinese Academy of Agricultural SciencesBeijing 100081China State Key laboratory of North China Crop Improvement and regulation Hebei Sub‐Center for National Maize Improvement CenterCollege of AgronomyHebei Agricultural UniversityBaoding 071001China

Wheat(Triticum aestivum L.)is a staple food for approximately half the global *** the population continues to grow,the demand for high-yielding varieties is increasing(Zorb et al.,2018).Higher yields can be achieved by increasing the number and weight of grains produced and by optimizing heading dates to maximize production in local environments(Sakuma and Schnurbusch,2020).

关键词： heading Wheat yielding

ILF3 safeguards telomeres from aberrant homologous recombination as a telomeric R-loop reader

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Protein & Cell 2024年第7期15卷 493-511页

作者： Chuanle Wang Yan Huang Yue Yang Ruofei Li Yingying Li Hongxin Qiu Jiali Wu Guang Shi Wenbin Ma Zhou Songyang MOE Key laboratory of gene Function and regulation State Key Laboratory of Biocontrol and Guangzhou Key Laboratory of Healthy AgingSchool of LifesciencesSun Yat-sen UniversityGuangzhou 510275China Department of Oncology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510275China Department of Nephrology The First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China

Telomeres are specialized structures at the ends of linear chromosomes that protect genome *** telomeric repeat-containing RNA(TERRA)that is transcribed from subtelomeric regions can invade into double-stranded DNA regions and form RNA:DNA hybrid-containing structure called *** tumor cells,R-loop formation is closely linked to gene expression and the alternative lengthening of telomeres(ALT)*** R-loops can cause stalled replication forks and telomere ***,how R-loops are recognized and regulated,particularly at telomeres,is not well *** discovered that ILF3 selectively associates with telomeric R-loops and safeguards telomeres from abnormal homologous *** out ILF3 results in excessive R-loops at telomeres and triggers telomeric DNA damage *** addition,ILF3 deficiency disrupts telomere homeostasis and causes abnormalities in the ALT *** the proximity-dependent biotin identification(BioID)technology,we mapped the ILF3 interactome and discovered that ILF3 could interact with several DNA/RNA helicases,including ***,ILF3 may aid in the resolution of telomeric R-loops through its interaction with *** findings suggest that ILF3 may function as a reader of telomeric R-loops,helping to prevent abnormal homologous recombination and maintain telomere homeostasis.

关键词： ILF3 RNA:DNA hybrids telomeric R-loops homologous recombination telomeric DNA damage responses

Melatonin mitigates cold-induced damage to pepper seedlings by promoting redox homeostasis and regulating antioxidant profiling

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Horticultural Plant Journal 2024年第2期10卷 532-544页

作者： Muhammad Ahsan Altaf Yuanyuan Hao Huangying Shu Weiheng Jin Chuhao Chen Lin Li Yu Zhang Muhammad Ali Mumtaz Huizhen Fu Shanhan Cheng Guopeng Zhu Zhiwei Wang Key laboratory for Quality regulation of Tropical Horticultural Crops of Hainan Province Sanya Nanfan Research InstituteHainan UniversitySanyaHainan 572025China Key laboratory for Quality regulation of Tropical Horticultural Crops of Hainan Province School of HorticultureHainan UniversityHaikouHainan 570228China Hainan Yazhou Bay Seed laboratory SanyaHainan 572025China

This study assessed the influence of exogenous ME in the mitigation of cold damage in pepper seedlings. Melatonin(ME) is a dynamic molecule that helps plants cope with stress in several ways. Cold stress(CS) is one of the most important environmental factors that restrict plant growth and yield. Pepper(Capsicum annuum L.) is a valuable commercial crop, highly sensitive to CS. Thus, identifying an efficient strategy to mitigate cold damage is critical for long-term pepper production. For this purpose, the roots of pepper seedlings were pretreated with ME(5 μmol · L^(-1)) and exposed to CS for 7 d. The results indicated that CS suppressed pepper growth, hampered photosynthetic capacity, and damaged root architecture in pepper plants. In contrast, the production of reactive oxygen species(ROS), malondialdehyde(MDA), electrolyte leakage(EL), proline, and soluble sugars were enhanced in plants under CS. ME(5 μmol · L^(-1)) pretreatment reduced the negative effects of CS by recovering plant growth, root traits, gas exchange elements, and pigment molecules compared to CS control treatment. Furthermore, ME application efficiently reduced oxidative stress markers [hydrogen peroxide(H_(2)O_(2)), superoxide ion(O_(2)^(·-)), EL, and MDA] while increasing proline and soluble sugar content in pepper leaves. ME application combined with CS further increased antioxidant enzymes and related gene expression. Collectively, our results confirmed the mitigating potential of ME supplementation for CS by maintaining pepper seedling growth,improving the photosynthesis apparatus, regulating pigments, and osmolyte content.

关键词： Pepper Melatonin Cold stress Antioxidant enzyme Root trait

The bHLH transcription factor CsPIF4 positively regulates high temperature-induced hypocotyl elongation in cucumber

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Horticultural Plant Journal 2024年第5期10卷 1187-1197页

作者： Jing Nie Yu Jiang Lijun Lv Yuzi Shi Peiyu Chen Qian Zhang Xiaolei Sui Beijing Key laboratory of Growth and Developmental regulation for Protected Vegetable Crops College of HorticultureChina Agricultural UniversityBeijing 100193China

High temperature-induced hypocotyl elongation is a typical thermomorphogenesis trait that may significantly affect early seedling growth and subsequent crop *** ambient temperature and endogenous auxin are two critical factors that regulate hypocotyl ***,the mechanism of temperature and auxin integration in horticultural plants remains poorly *** this study,the roles of the basic helix-loop-helix transcription factor CsPIF4 in regulating auxin biosynthesis genes and the auxin content in the hypocotyl of cucumber(Cucumis sativus L.)seedlings under high temperature were ***-PCR and in situ hybridization analysis revealed that expression of CsPIF4 was enhanced in the epidermis and vascular bundles in the hypocotyl of cucumber seedlings in response to high ***-PCR and HPLC analysis showed that CsPIF4 positively regulated transcription of the auxin biosynthesis gene CsYUC8 and the auxin content in the hypocotyl under high temperature(35℃).The CRISPR/Cas9-mediated knockout of CsPIF4 resulted in a shorter hypocotyl compared with that of the wild type,together with decreased expression of CsYUC8 and lower auxin content in response to high ***,biochemical assays showed that CsPIF4 could bind directly to the G-box motif of the CsYUC8 promoter and thereby activate CsYUC8 *** findings provide insight into the molecular mechanism of high temperature-mediated hypocotyl elongation in cucumber.

关键词： Cucumber Hypocotyl elongation High temperature CsPIF4 Auxin

Nanomedicine targeting ferroptosis to overcome anticancer therapeutic resistance

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Science China(Life Sciences) 2024年第1期67卷 19-40页

作者： Jing Cai Xiaoding Xu Phei Er Saw Guangdong Provincial Key laboratory of Malignant Tumor Epigenetics and gene regulation Guangdong-Hong Kong Joint Laboratory for RNA MedicineMedical Research CenterSun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Nanhai Translational Innovation Center of Precision Immunology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityFoshan 528200China

A potential reason for the failure of tumor therapies is treatment *** to chemotherapy,radiotherapy,and immunotherapy continues to be a major obstacle in clinic,resulting in tumor recurrence and *** major mechanisms of therapy resistance are inhibitions of cell deaths,like apoptosis and necrosis,through drug inactivation and excretion,repair of DNA damage,tumor heterogeneity,or changes in tumor microenvironment,*** studies have shown that ferroptosis play a major role in therapies resistance by inducing phospholipid peroxidation and iron-dependent cell *** ferroptosis inducers in combination with clinical treatment techniques have been used to enhance the effect in tumor ***,versatile ferroptosis nanoinducers exhibit an extensive range of functions in reversing therapy resistance,including directly triggering ferroptosis and feedback ***,we provide a detailed description of the design,mechanism,and therapeutic application of ferroptosis-mediated synergistic tumor *** also discuss the prospect and challenge of nanomedicine in tumor therapy resistance by regulating ferroptosis and combination therapy.

关键词： ferroptosis cancer therapy therapy resistance nanoinducers

Correction of a CADASIL point mutation using adenine base editors in hiPsCsandbloodvessel organoids

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Journal of genetics and Genomics 2024年第2期51卷 197-207页

作者： Jingwen Wang Lei Zhang Guanglan Wu Jinni Wu Xinyao Zhou Xiaolin Chen Yongxia Niu Yiren Jiao Qianyi Liu Puping Liang Guang Shi Xueqing Wu Junjiu Huang MOE Key laboratory of gene Function and regulation State Key Laboratory of BiocontrolSchool of Life SciencesSun Yat-sen UniversityGuangzhouGuangdong 510275China Key laboratory of Reproductive Medicine of Guangdong Province The First Affiliated Hospital and School of Life SciencesSun Yat-sen UniversityGuangzhouGuangdong 510275China Center of Reproductive Medicine Children's Hospital of Shanxi and Women Health Center of ShanxiTaiyuanShanxi 030013China

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic small vessel disease caused by mutations in the NOTCH3 gene. However, the pathogenesis of CADASIL remains unclear, and patients have limited treatment options. Here, we use human induced pluripotent stem cells (hiPSCs) generated from the peripheral blood mononuclear cells of a patient with CADASIL carrying a heterozygous NOTCH3 mutation (c.1261C>T, p.R421C) to develop a disease model. The correction efficiency of different adenine base editors (ABEs) is tested using the HEK293T-NOTCH3 reporter cell line. ABEmax is selected based on its higher efficiency and minimization of predicted off-target effects. Vascular smooth muscle cells (VSMCs) differentiated from CADASIL hiPSCs show NOTCH3 deposition and abnormal actin cytoskeleton structure, and the abnormalities are recovered in corrected hiPSC-derived VSMCs. Furthermore, CADASIL blood vessel organoids generated for in vivo modeling show altered expression of genes related to disease phenotypes, including the downregulation of cell adhesion, extracellular matrix organization, and vessel development. The dual adeno-associated virus (AAV) split-ABEmax system is applied to the genome editing of vascular organoids with an average editing efficiency of 8.82%. Collectively, we present potential genetic therapeutic strategies for patients with CADASIL using blood vessel organoids and the dual AAV split-ABEmax system.

关键词： CADASIL Induced pluripotent stem cells Adenine base editors AAV Blood vessel Organoid

Overexpression of the peroxidase gene ZmPRX1 increases maize seedling drought tolerance by promoting root development and lignification

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The Crop Journal 2024年第3期12卷 753-765页

作者： Xiuzhen Zhai Xiaocui Yan Tinashe Zenda Nan Wang Anyi Dong Qian Yang Yuan Zhong Yue Xing Huijun Duan State Key laboratory of North China Crop Improvement and regulation Key laboratory of Crop Germplasm Resources in North China Ministry of EducationCollege of AgronomyHebei Agricultural UniversityBaoding 071001HebeiChina

Drought is a main abiotic stress factor hindering plant growth,development,and crop ***,it is crucial to understand the mechanisms by which plants cope with drought ***,the function of the maize peroxidase gene ZmPRX1 in drought stress tolerance was investigated by measurement of its expression in response to drought treatment both in a ZmPRX1 overexpression line and a mutant *** higher root lignin accumulation and seedling survival rate of the overexpression line than that of the wild type or mutant support a role for ZmPRX1 in maize drought tolerance by regulating root development and ***,yeast one-hybrid,Dule luciferase and ChIP-qPCR assays showed that ZmPRX1 is negatively regulated by a nuclear-localized ZmWRKY86 transcription *** gene could potentially be used for breeding of drought-tolerant cultivars.

关键词： Drought tolerance Maize ZmPRX1 Root development Lignin biosynthesis