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Disruption of PABPN1 phase separation by SNRPD2 drives colorectal cancer cell proliferation and migration through promoting alternative polyadenylation of CTNNBIP1

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science china(life sciences) 2024年第6期67卷 1212-1225页

作者： Zhijie Hu Mengxia Li Yufeng chen Liutao chen Yuting Han chengyong chen Xin Lu Nan You Yawen Lou Yingye Huang Zhanfeng Huo Chao Liu cheng Liang Susu Liu Ke Deng Liangfu chen Shangwu chen Guohui Wan Xiaojian Wu Yonggui Fu Anlong Xu state key laboratory of Biocontrol Guangdong Province Key Laboratory of Pharmaceutical Functional GenesDepartment of BiochemistrySchool of Life SciencesSun Yat-sen UniversityGuangzhou 510275China Department of General Surgery(Colorectal Surgery)&Guangdong Provincial key laboratory of Colorectal and Pelvic Floor Diseases&Biomedical Innovation Center The Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhou 510655China National-Local Joint Engineering laboratory of Druggability and New Drug Evaluation National Engineering Research Center for New Drug and Druggability(cultivation)Guangdong Province Key Laboratory of New Drug Design and EvaluationSchool of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China School of life sciences Beijing University of Chinese MedicineBeijing 100029China

Generally shortened 3′UTR due to alternative polyadenylation(APA)is widely observed in cancer,but its regulation mechanisms for cancer are not well ***,with profiling of APA in colorectal cancer tissues and poly(A)signal editing,we firstly identified that the shortened 3′UTR of CTNNIBP1 in colorectal cancer promotes cell proliferation and *** found that liquid-liquid phase separation(LLPS)of PABPN1 is reduced albeit with higher expression in cancer,and the reduction of LLPS leads to the shortened 3′UTR of CTNNBIP1and promotes cell proliferation and ***,the splicing factor SNRPD2 upregulated in colorectal cancer,can interact with glutamic-proline(EP)domain of PABPN1,and then disrupt LLPS of PABPN1,which attenuates the repression effect of PABPN1 on the proximal poly(A)*** results firstly reveal a new regulation mechanism of APA by disruption of LLPS of PABPN1,suggesting that regulation of APA by interfering LLPS of 3′end processing factor may have the potential as a new way for the treatment of cancer.

关键词： alternative polyadenylation colorectal cancer CTNNBIP1 PABPN1 liquid-liquid phase separation SNRPD2

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Phosphatidic acid-enabled MKL1 contributes to liver regeneration:Translational implication in liver failure

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Acta Pharmaceutica Sinica B 2024年第1期14卷 256-272页

作者： Jiawen Zhou Xinyue Sun Xuelian chen Huimin Liu Xiulian Miao Yan Guo Zhiwen Fan jie Li Yong Xu Zilong Li state key laboratory of Natural Medicines Department of PharmacologyChina Pharmaceutical UniversityNanjing 211198China Institute of Biomedical Research Liaocheng UniversityLiaocheng 252200China Department of Pathology Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210008China Department of Infectious Diseases Nanjing Drum Tower Hospital Affiliated with Nanjing University Medical SchoolNanjing 210008China Institute of Viruses and Infectious Diseases Nanjing UniversityNanjing 210008China

Liver regeneration following injury aids the restoration of liver mass and the recovery of liver *** the present study we investigated the contribution of megakaryocytic leukemia 1(MKL1),a transcriptional modulator,to liver *** report that both MKL1 expression and its nuclear translocation correlated with hepatocyte proliferation in cell and animal models of liver regeneration and in liver failure *** with MKL1 deletion exhibited defective regenerative response in the *** analysis revealed that MKL1 interacted with E2F1 to program pro-regenerative ***2 mediated phosphorylation primed MKL1 for its interaction with *** interest,phospholipase d2 promoted MKL1 nuclear accumulation and liver regeneration by catalyzing production of phosphatidic acid(PA).PA administration stimulated hepatocyte proliferation and enhanced survival in a MKL1-dependent manner in a pre-clinical model of liver ***,PA levels was detected to be positively correlated with expression of pro-regenerative genes and inversely correlated with liver injury in liver failure *** conclusion,our data reveal a novel mechanism whereby MKL1 contributes to liver *** for small-molecule compounds boosting MKL1 activity may be considered as a reasonable approach to treat acute liver failure.

关键词： Liver failure Liver regeneration Transcription regulation Transcription factor Hepatocytes Phosphatidic acid Phospholipase d2 Translational medicine

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Targeting STING oligomerization with licochalcone D ameliorates STING-driven inflammatory diseases

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science china life sciences 2024年

作者： Yinghui Zhang Yadan Liu Bing Jiang Lifan chen jie Hu Buying Niu jie Chang Zisheng Fan Jingyi Zhou Yajie Wang Dan Teng Ning Ma Xiaofeng Wang Ruirui yang Mingyue Zheng Sulin Zhang Drug Discovery and Design Center State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences university of Chinese Academy of sciences School of Chinese Materia Medica Nanjing University of Chinese Medicine Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology Shanghai Tech University School of Physical science and Technology ShanghaiTech University School of pharmaceutical science and Technology Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences state key laboratory of pharmaceutical biotechnology Nanjing University

The development of STING inhibitors for the treatment of STING-related inflammatory diseases continues to encounter significant challenges. The activation of STING is a multi-step process that includes binding with cGAMP, self-oligomerization, and translocation from the endoplasmic reticulum to the Golgi apparatus, ultimately inducing the expression of IRF3 and NF-κB-mediated interferons and inflammatory cytokines. It has been demonstrated that disruption of any of these steps can effectively inhibit STING activation. Traditional structure-based drug screening methodologies generally focus on specific binding sites. In this study, a TransformerCPI model based on protein primary sequences and independent of binding sites is employed to identify compounds capable of binding to the STING protein. The natural product Licochalcone D（LicoD） is identified as a potent and selective STING inhibitor. LicoD does not bind to the classical ligandbinding pocket; instead, it covalently modifies the Cys148 residue of STING. This modification inhibits STING oligomerization, consequently suppressing the recruitment of TBK1 and the nuclear translocation of IRF3 and NF-κB. LicoD treatment ameliorates the inflammatory phenotype in Trex1-/-mice and inhibits the progression of DSS-induced colitis and AOM/DSS-induced colitis-associated colon cancer（CAC）.In summary, this study reveals the potential of LicoD in treating STING-driven inflammatory diseases. It also demonstrates the utility of the TransformerCPI model in discovering allosteric compounds beyond the conventional binding pockets.

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The p38/MAPK pathway as a therapeutic target to prevent therapeutic escape of breast cancer stem cells

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science china(life sciences) 2024年第9期67卷 1867-1880页

作者： Weixiao Yan Xiaotong Wang Wenjing Wang Qi Guo Na Huang Hao chen Xing-jie Liang Yu Han Dandan Liu Jinchao Zhang state key laboratory of New pharmaceutical Preparations and Excipients/key laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education/college of Chemistry and Materials science Chemical Biology Key Laboratory of Hebei ProvinceHebei UniversityBaoding 071002China CAS key laboratory for Biological Effects of Nanomaterials and Nanosafety National Center for Nanoscience and TechnologyBeijing 100190China

Cancer stem cells(CSCs)play an important role in metastasis development,tumor recurrence,and treatment resistance,and are essential for the eradication of ***,therapies fail to eradicate CSCs due to their therapeutic stress-induced cellular escape,which leads to enhanced aggressive behaviors compared with CSCs that have never been ***,the underlying mechanisms regulating the therapeutic escape remain *** this end,we established a model to isolate the therapeutic escaped CSCs(TSCSCs)from breast CSCs and performed the transcription profile to reveal the ***,we demonstrated that the behavior of therapeutic escape was regulated through the p38/MAPK signaling pathway,resulting in TSCSCs exhibiting enhanced motility and ***,blocking the p38/MAPK signaling pathway effectively reduced motility and metastasis ability both in vitro and in vivo,which were further supported by downregulated motility-related genes and epithelial-mesenchymal transition(EMT)-related proteins vimentin and *** obtained findings reveal the p38/MAPK pathway as a potential therapeutic target for TSCSCs and would provide profound implications for cancer therapy.

关键词： therapeutic escape breast cancer stem cells motility p38/MAPK signaling pathway molecular mechanism

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SARS-CoV-2 envelope protein impairs airway epithelial barrier function and exacerbates airway inflammation via increased intracellular Cl^(-)concentration

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1745-1759页

作者： Jian-Bang Xu Wei-jie Guan Yi-Lin Zhang Zhuo-Er Qiu Lei chen Xiao-Chun Hou Junqing Yue Yu-Yun Zhou jie Sheng Lei Zhao Yun-Xin Zhu Jing Sun Jincun Zhao Wen-Liang Zhou Nan-Shan Zhong state key laboratory of Respiratory Disease National Clinical Research Center for Respiratory DiseaseNational Center for Respiratory MedicineDepartment of Respiratory and Critical Care MedicineGuangzhou Institute of Respiratory HealthThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouP.R.China Department of Thoracic Surgery Guangzhou Institute for Respiratory HealthThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouP.R.China Guangzhou National laboratory GuangzhouP.R.China School of life sciences Sun Yat-sen UniversityGuangzhouP.R.China Guangdong Provincial key laboratory of pharmaceutical Functional Genes School of Life SciencesSun Yat-sen UniversityGuangzhouP.R.China Department of Physiology School of Basic Medical SciencesGuangzhou Medical UniversityGuangzhouP.R.China

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection disrupts the epithelial barrier and triggers airway *** envelope(E)protein,a core virulence structural component of coronaviruses,may play a role in this *** could interfere with transepithelial Cl^(-)transport via impairment of the cystic fibrosis transmembrane conductance regulator(CFTR),which modulates nuclear factor kB(NF-kB)***,the pathological effects of SARS-CoV-2 E protein on airway epithelial barrier function,Cl^(-)transport and the robust inflammatory response remain to be ***,we have demonstrated that E protein down-regulated the expression of tight junctional proteins,leading to the disruption of the airway epithelial *** addition,E protein triggered the activation of Toll-like receptor(TLR)2/4 and downstream c-Jun N-terminal kinase(JNK)signaling,resulting in an increased intracellular Cl^(-)concentration([Cl^(-)]_(i))via up-regulating phosphodiesterase 4D(PDE4D)expression in airway epithelial *** elevated[Cl^(-)]_(i);contributed to the heightened airway inflammation through promoting the phosphorylation of serum/glucocorticoid regulated kinase 1(SGK1).Moreover,blockade of SGK1 or PDE4 alleviated the robust inflammatory response induced by E ***,these findings provide novel insights into the pathogenic role of SARS-CoV-2 E protein in airway epithelial damage and the ongoing airway inflammation during SARS-CoV-2 infection.

关键词： airway inflammation elevated

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调控Ru的电子态以促进乙烯在酸中高选择性电氧化合成乙二醇

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Chinese Journal of Catalysis 2024年第5期60卷 376-385页

作者：王杰陈怡和王宇达赵浩叶进裕程庆庆杨辉上海科技大学物质科学与技术学院上海201210 中国科学院上海高等研究院上海201210 厦门大学化学化工学院福建厦门361005

乙二醇(EG)是一种重要的化工产品,由于在化学品制造行业的广泛应用而备受关注.然而,目前工业上制备乙二醇主要采用乙烯作为原料,经过环氧化和水解两步反应,这一过程不仅需要高温高压,还需使用成本高的氧化剂(如H_(2)O_(2)),这违背了绿... 详细信息

乙二醇(EG)是一种重要的化工产品,由于在化学品制造行业的广泛应用而备受关注.然而,目前工业上制备乙二醇主要采用乙烯作为原料,经过环氧化和水解两步反应,这一过程不仅需要高温高压,还需使用成本高的氧化剂(如H_(2)O_(2)),这违背了绿色化学的原则.因此,电催化阳极氧化作为一种新兴的合成策略,正逐渐受到研究者的青睐.该技术仅通过电子转移并利用水作为氧源,就能够高效合成高附加值含氧化学品.特别是,阳极氧化反应可与阴极还原反应(例如氢析出反应)相耦合,实现能量的高效利用.尽管电催化阳极氧化具有诸多优势,但目前在乙烯电氧化合成乙二醇过程中,其选择性仍然较低,这导致后续的纯化过程变得复杂且成本高昂.因此,开发高选择性的电氧化合成乙二醇技术,成为了一项迫切且极具挑战性的任务.本文提出了一种Ir和Ru合金化策略,以提高乙烯电氧化制备乙二醇的选择性和耐久性.研究结果表明,当Ir和Ru的原子比达到适当的比例(即Ir_(0.54)Ru_(0.46))时,所制备的IrRu合金表现出近100%的乙二醇选择性,远远优于Ru NPs对照组样品(43.8%).此外,在1.475 V的电压下,Ir_(0.54)Ru_(0.46)催化生成乙二醇产率达到了60.62 mmolgRu^(-1) h^(-1),是Ru NPs上最高产率(21.75 mmolgRu^(-1) h^(-1))的2.8倍.在耐久性测试中,Ir_(0.54)Ru_(0.46)能够稳定催化生成乙二醇超过12 h,其生成速率为6μmol L^(-1) h^(-1).相比之下,对照组样品Ru NPs在电解反应3 h后已失去活性.能量损失谱分析显示,Ir_(0.54)Ru_(0.46)在电解2 h后形成了稳定的表面富Ir核壳结构IrRu@Ir,这是催化剂稳定性提升的关键.先进光谱研究进一步揭示,Ir的引入导致了电子由Ru位点向Ir流动,使Ru位点带正电荷,从而减弱了OH的吸附.OH脱附实验结果表明,随着Ir/Ru原子比的增加,OH更容易从Ru位点脱附,这促进了OH与乙烯的偶联反应.自由基淬灭和氘代同位素标记实验结果表明,在IrRu催化剂上,乙烯到乙二醇的转化并非级联反应,而是直接的表面催化反应,其中OH的转移是决速步骤.X射线光电子能谱分析显示,随着合金中Ir比例的增加,合金d带中心下移,这有利于关键中间体(*OH等)的转移.原位红外光谱表明,乙烯分子在Ru位点上通过Pauling型吸附构型被活化.值得注意的是,仅检测到*CH_(2)CH_(2)OH中间体,而未检测到其他氧基团(如羰基),这表明在反应过程中没有发生过氧化现象.密度泛函理论计算进一步证实,与Ir合金化不仅加速了OH的转移,还优化了反应途径,使乙二醇的选择性达到100%.综上,本文设计了不同Ir/Ru原子比的IrRu合金催化剂,通过有效调控活性位点Ru的电子结构,优化了OH的结合能,使乙烯可以100%选择性高效转化为乙二醇,这为开发高选择性电催化剂用于乙二醇电合成提供了新思路.

关键词：乙烯电氧化电合成乙二醇高选择性 IrRu合金电子结构

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life's essential 8 and risk of subclinical atherosclerosis progression: a prospective cohort study

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Journal of Geriatric Cardiology 2024年第7期21卷 751-759页

作者： Shi-Yu ZHOU Fang-Chao LIU Shu-Feng chen Jian-Xin LI jie CAO Ke-Yong HUANG Zheng-Hao TANG Feng-Chao LIANG Dong-Sheng HU Lian-cheng ZHAO Ying LI Jian-Feng HUANG Xiang-Feng LU Bin LU Dong-Feng GU Department of Epidemiology&key laboratory of Cardiovascular Epidemiology State Key Laboratory of Cardiovas-cular DiseaseFuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijingChina School of Public Health and Emergency Management School of Medi-cineSouthern University of Science and TechnologyShenzhenChina Department of Epidemiology and Health Stat-istics School of Public HealthZhengzhou UniversityZhengzhouChina Department of Biostatistics and Epidemi-ology School of Public HealthShenzhen University Health Science CenterShenzhenChina Department of Radi-ology State Key Laboratory of Cardiovascular DiseaseFuwai HospitalNational Center for Cardiovascular DiseasesChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijingChina

BACKGROUND Previous studies have demonstrated the benefits of ideal cardiovascular health(CVH) in reducing cardiovascular ***,its role in subclinical atherosclerosis(SA) progression remains *** aim to examine the association of CVH,estimated by the American Heart Association's new life's Essential 8(LE8),with the progression of *** This prospective cohort study was conducted among 972 asymptomatic Chinese participants and followed up for5.7 *** LE8 score(range,0–100) consisted of blood pressure,lipids,glucose,body mass index,smoking status,diet health,physical activity and sleep health was evaluated in 1998 and 2008–*** of SA was determined by carotid plaque and coronary artery calcification(CAC) in 2008–2009 and 2013–***-binomial regression model was used to estimate the association of LE8 score with SA *** Each 10 points increment in LE8 score was associated with 15.2%(RR:0.848,95% CI:0.797–0.902),17.7%(RR:0.823,95% CI:0.766–0.884) and 12.0%(RR:0.880,95% CI:0.845–0.916) lower risks of carotid plaque,CAC and overall SA progression,*** with participants with non-ideal CVH at both visits,the participants with ideal CVH at both visits had39.1%(RR:0.609,95% CI:0.494–0.752),41.0%(RR:0.590,95% CI:0.456–0.764) and 29.7%(RR:0.703,95% CI:0.598–0.825) lower risks of carotid plaque,CAC and overall SA progression,*** Higher LE8 scores were associated with lower risks of SA ***,long-term maintenance of optimal CVH was more beneficial to prevent SA progression.

关键词： atherosclerosis prospective cardiovascular

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OsNLP3 enhances grain weight and reduces grain chalkiness in rice

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Plant Communications 2024年第10期5卷 82-99页

作者： Liang-Qi Sun Yu Bai jie Wu Shi-Jun Fan Si-Yan chen Zheng-Yi Zhang Jin-Qiu Xia Shi-Mei Wang Yu-Ping Wang Peng Qin Shi-Gui Li Ping Xu Zhong Zhao chengBin Xiang Zi-Sheng Zhang Division of life sciences and Medicine Division of Molecular&Cell BiophysicsHefei National Science Center for Interdisciplinary Sciences at the MicroscaleUniversity of Science and Technology of ChinaThe Innovation Academy of Seed DesignChinese Academy of SciencesHefeiAnhui Province 230027China Experimental Center of Engineering and Materials science University of Science and Technology of ChinaHefei 230027China Rice Research Institute Anhui Academy of Agricultural ScienceHefeiChina state key laboratory of Crop Gene Exploration and Utilization in Southwest china Rice Research InstituteSichuan Agricultural UniversityChengduSichuanChina Shanghai key laboratory of Plant Functional Genomics and Resources Shanghai Chenshan Botanical GardenShanghai Chenshan Plant Science Research CenterChinese Academy of SciencesShanghaiChina

Grain weight,a key determinant of yield in rice(Oryza sativa L.),is governed primarily by genetic factors,whereas grain chalkiness,a detriment to grain quality,is intertwined with environmental factors such as mineral ***(N)is recognized for its effect on grain chalkiness,but the underlying molecular mechanisms remain to be *** study revealed the pivotal role of rice NODULE INCEPTION-LIKE PROTEIN 3(OsNLP3)in simultaneously regulating grain weight and grain *** investigation showed that loss of OsNLP3 leads to a reduction in both grain weight and dimension,in contrast to the enhancement observed with OsNLP3 ***3 directly suppresses the expression of OsCEP6.1 and OsNF-YA8,which were identified as negative regulators associated with grain ***,two novel regulatory modules,OsNLP3-OsCEP6.1 and OsNLP3-OsNF-YA8,were identified as key players in grain weight ***,the OsNLP3-OsNF-YA8 module not only increases grain weight but also mitigates grain chalkiness in response to *** research clarifies the molecular mechanisms that orchestrate grain weight through the OsNLP3-OsCEP6.1 and OsNLP3-OsNF-YA8 modules,highlighting the pivotal role of the OsNLP3-OsNF-YA8 module in alleviating grain *** findings reveal potential targets for simultaneous enhancement of rice yield and quality.

关键词： OsNLP3 OsCEP6.1 OsNF-YA8 grain weight grain chalkiness rice Oryza sativa L.

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Discovery and characterization of novel potent non-covalent small molecule inhibitors targeting papain-like protease from SARS-CoV-2

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3286-3290页

作者： Miao Zheng Bo Feng Yumin Zhang Xin Liu NaZhao Hui Liu Zichao Xu Xinheng He Zhiyan Qu Shizhaochen Zhidong Jiang Xi cheng Hong Liu Yi Zang Linxiang Zhao jie Zheng Leike Zhang Jia Li Yu Zhou key laboratory of Structure-Based Drugs Design&Discovery of Ministry of Education Shenyang Pharmaceutical UniversityShenyang 110016China School of life sciences and Biopharmaceuticals Shenyang Pharmaceutical UniversityShenyang 110016China Shanghai Institute of Materia Medica Chinese Academy of SciencesShanghai 201203and University of Chinese Academy of SciencesBeijing 100049China state key laboratory of Chemical Biology Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203and University of Chinese Academy of SciencesBeijing 100049China state key laboratory of Virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China Lingang laboratory Shanghai 200031China School of pharmaceutical science and Technology Hangzhou Institute for Advanced StudyUniversity of Chinese Academy of SciencesHangzhou 310024China Hubei Jiangxia laboratory Wuhan 430200China

To the Editor:The papain-like protease(PL^(pro)),as one of the most important proteases of SARS-CoV-2,has emerged as a highly promising target protein,its inhibitor probably holds dual potentials,namely blocking the cleavage of viral polyprotein and intercepting the deubiquitination and deISGylation functions to restore antiviral immunity1.

关键词： Non-covalent PL^(pro)inhibitors Antiviral activity Structural-based drug design Imidazo[4,5-b]pyridine scaffold

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Characterization of flavonoids in Millettia nitida var. hirsutissima by HPLC/DAD/ESI-MS^n

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Journal of pharmaceutical Analysis 2012年第1期2卷 35-42页

作者： Min Ye, Wen-Zhi yang, Ke-Di Liu, Xue Qiao, Bei-Jia Li, Jun cheng, jie Feng, De-An Guo, Yu-Ying Zhao state key laboratory of Natural and Biomimetic Drugs, School of pharmaceutical sciences, Peking university, 38 Xueyuan Road, Beijing 100191, china state key laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University 38 Xueyuan Road Beijing 100191 China

Millettia nitida var. hirsutissima is a Chinese herbal medicine used for the treatment of gynecological diseases. An HPLC/DAD/ESI-MSn method was established for the rapid separation and characterization of bioactive flavonoids in M. nitida var. hirsutissima. A total of 32 flavonoids were detected, of which 14 compounds were unambiguously characterized by comparing their retention time, UV, and MS spectra with those of the reference standards, and the others were tentatively identified based on their tandem mass spectrometry fragmentation data obtained in the negative ionization mode on line. Nineteen of these compounds characterized were reported from this plant for the first time.

关键词： HPLC/DAD/ESI-MSn Millettia nitida var. hirsutissima Mass spectrometry Flavonoids

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