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| 1 | Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer's disease progression显示文摘Recently,increasing evidence has suggested the association between gut dysbiosis and Alzheimer's disease(AD)progression,yet the role of gut microbiota in AD pathogenesis remains obscure.Herein,we provide a potential mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression.Using AD mouse models,we discovered that,during AD progression,the alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine,which stimulates the differentiation and proliferation of pro-inflammatory T helper 1(Thl)cells.The brain-infiltrated peripheral Th1 immune cells are associated with the Ml microglia aaivation,contributing to AD-associated neuroinflammation.Importantly,the elevation of phenylalanine and isoleucine concentrations and the increase of Th1 cell frequency in the blood were also observed in two small independent cohorts of patients with mild cognitive impairment(MCI)due to AD.Furthermore,GV-971,a sodium oligomannate that has demonstrated solid and consistent cognition improvement in a phase 3 clinical trial in China,suppresses gut dysbiosis and the associated phenylalanine/isoleucine accumulation,harnesses neuroinflammation and reverses the cognition impairment.Together,our findings highlight the role of gut dysbiosis-promoted neuroinflammation in AD progression and suggest a novel strategy for AD therapy by remodelling the gut microbiota. | Xinyi Wang Guangqiang Sun Teng Feng Jing Zhang Xun Huang Tao Wang Zuoquan Xie Xingkun Chu Jun Yang Huan Wang Shuaishuai Chang Yanxue Gong Lingfei Ruan Guanqun Zhang Siyuan Yan Wen Lian Chen Du Dabing Yang Qingli Zhang Feifei Lin Jia Liu Haiyan Zhang Changrong Ge Shifu Xiao Jian Ding Meiyu Geng | 2019 | Cell Research2019，29，10： | 192 |
| 2 | The China Alzheimer Report 2022显示文摘China’s population has rapidly aged over the recent decades of social and economic development as neurodegenerative disorders have proliferated,especially Alzheimer’s disease(AD)and related dementias(ADRD).AD’s incidence rate,morbidity,and mortality have steadily increased to make it presently the fifth leading cause of death among urban and rural residents in China and magnify the resulting financial burdens on individuals,families and society.The‘Healthy China Action’plan of 2019-2030 promotes the transition from disease treatment to health maintenance for this expanding population with ADRD.This report describes related epidemiological trends,evaluates the economic burden of the disease,outlines current clinical diagnosis and treatment status and delineates existing available public health resources.More specifically,it examines the public health impact of ADRD,including prevalence,mortality,costs,usage of care,and the overall effect on caregivers and society.In addition,this special report presents technical guidance and supports for the prevention and treatment of AD,provides expertise to guide relevant governmental healthcare policy development and suggests an information platform for international exchange and cooperation. | Rujing Ren Jinlei Qi Shaohui Lin Xinya Liu Peng Yin Zhihui Wang Ran Tang Jintao Wang Qiang Huang Jianping Li Xinyi Xie Yongbo Hu Shishuang Cui Yuan Zhu Xiaoping Yu Pengfei Wang Yikang Zhu Yiran Wang Yanyan Huang Yisong Hu Ying Wang Chunbo Li Maigeng Zhou Gang Wang | 2022 | General Psychiatry2022，35，1： | 20 |
| 3 | Dosage effect of multiple genes accounts for multisystem disorder of myotonic dystrophy type 1显示文摘Multisystem manifestations in myotonic dystrophy type 1(DM1)may be due to dosage reduction in multiple genes induced by aberrant expansion of CTG repeats in DMPK,including DMPK,its neighboring genes(SIX5 or DMWD)and downstream MBNLh However,direct evidence is lacking.Here,we develop a new strategy to generate mice carrying multigene heterozygous mutations to mimic dosage reduction in one step by injection of haploid embryonic stem cells with mutant Dmpk,Six5 and Mbnll into oocytes.The triple heterozygous mutant mice exhibit adult-onset DM1 phenotypes.With the additional mutation in Dmwd,the quadruple heterozygous mutant mice recapitulate many major manifestations in congenital DM1.Moreover,muscle stem cells in both models display reduced sternness,providing a unique model for screening small molecules for treatment of DM1.Our results suggest that the complex symptoms of DM1 result from the reduced dosage of multiple genes. | Qi Yin Hongye Wang Na Li Yifu Ding Zhenfei Xie Lifang Jin Yan Li Qiong Wang Xinyi Liu Liuqing Xu Qing Li Yongjian Ma Yanbo Cheng Kai Wang Cuiqing Zhong Qian Yu Wei Tang Wanjin Chen Wenjun Yang Fan Zhang Chen Ding Lan Bao Bin Zhou Ping Hu Jinsong Li | 2020 | Cell Research2020，30，2： | 7 |
| 4 | Dietary Enteromorpha polysaccharide-Zn supplementation regulates amino acid and fatty acid metabolism by improving the antioxidant activity in chicken显示文摘Background:Enteromorpha prolifera(E.prolifera)polysaccharide has become a promising feed additive with a variety of physiological activities,such as anti-oxidant,anti-cancer,anti-diabetic,immunomodulatory,hypolipidemic,and cation chelating ability.However,whether Enteromorpha polysaccharide-trace element complex supplementation regulates amino acid and fatty acid metabolism in chicken is largely unknown.This study was conducted to investigate the effects of E.prolifera polysaccharide(EP)-Zn supplementation on growth performance,amino acid,and fatty acid metabolism in chicken.Methods:A total of 184 one-day-old Ross-308 broiler chickens were randomly divided into two treatment groups with 8 replicates,12 chickens per replicate,and fed either the basal diet(control group)or basal diet plus E.prolifera polysaccharide-Zinc(400 mg EP-Zn/kg diet).Results:Dietary EP-Zn supplementation significantly increased(P<0.05)the body weight,average daily gain,muscle antioxidant activity,serum HDL level,and reduced serum TG and LDL concentration.In addition,dietary EPZn supplementation could modulate ileal amino acid digestibility and upregulate the mRNA expression of amino acid transporter genes in the jejunum,ileum,breast muscle,and liver tissues(P<0.05).Compared with the control group,breast meat from chickens fed EP-Zn had higher(P<0.05)Pro and Asp content,and lower(P<0.05)Val,Phe,Gly,and Cys free amino acid content.Furthermore,EP-Zn supplementation upregulated(P<0.05)the mRNA expressions of mTOR and anti-oxidant related genes,while down-regulated protein degradation related genes in the breast muscle.Breast meat from EP-Zn supplemented group had significantly lower(P<0.05)proportions ofΣn-3 PUFA,and a higher percentage ofΣn-6 PUFA and the ratio of n-6/n-3 PUFA.Besides,EP-Zn supplementation regulated lipid metabolism by inhibiting the gene expression of key enzymes involved in the fatty acid synthesis and activating genes that participated in fatty acid oxidation in the liver tissue.Conclusions:It is concluded that EP-Zn complex supplementation regulates apparent ileal amino acid digestibility,enhances amino acid metabolism,and decreases oxidative stress-associated protein breakdown,thereby improving the growth performance.Furthermore,it promotes fatty acid oxidation and restrains fat synthesis through modulating lipid metabolism-related gene expression. | Teketay Wassie Xinyi Duan Chunyan Xie Ruxia Wang Xin Wu | 2022 | Journal of Animal Science and Biotechnology2022，13，3： | 3 |
| 5 | Polymyxin resistance caused by large-scale genomic inversion due to IS26 intramolecular translocation in Klebsiella pneumoniae显示文摘Polymyxin B and polymyxin E(colistin)are presently considered the last line of defense against human infections caused by multidrug-resistant Gram-negative organisms such as carbapenemase-producer Enterobacterales,Acinetobacter baumannii,and Klebsiella pneumoniae.Yet resistance to this last-line drugs is a major public health threat and is rapidly increasing.Polymyxin S2(S2)is a polymyxin B analogue previously synthesized in our institute with obviously high antibacterial activity and lower toxicity than polymyxin B and colistin.To predict the possible resistant mechanism of S2for wide clinical application,we experimentally induced bacterial resistant mutants and studied the preliminary resistance mechanisms.Mut-S,a resistant mutant of K.pneumoniae ATCC BAA-2146(Kpn2146)induced by S2,was analyzed by whole genome sequencing,transcriptomics,mass spectrometry and complementation experiment.Surprisingly,large-scale genomic inversion(LSGI)of approximately 1.1 Mbp in the chromosome caused by IS26mediated intramolecular transposition was found in Mut-S,which led to mgrB truncation,lipid A modification and hence S2resistance.The resistance can be complemented by plasmid carrying intact mgrB.The same mechanism was also found in polymyxin B and colistin induced drug-resistant mutants of Kpn2146(Mut-B and Mut-E,respectively).This is the first report of polymyxin resistance caused by IS26 intramolecular transposition mediated mgrB truncation in chromosome in K.pneumoniae.The findings broaden our scope of knowledge for polymyxin resistance and enriched our understanding of how bacteria can manage to survive in the presence of antibiotics. | Haibin Li Lang Sun Han Qiao Zongti Sun Penghe Wang Chunyang Xie Xinxin Hu Tongying Nie Xinyi Yang Guoqing Li Youwen Zhang Xiukun Wang Zhuorong Li Jiandong Jiang Congran Li Xuefu You | 2023 | Acta Pharmaceutica Sinica B2023，13，9： | 1 |
| 6 | Discovery of the mechanisms of acupuncture in the treatment of migraine based on functional magnetic resonance imaging and omics显示文摘Migraine is one of the most prevalent and disabling neurological disease,but the current pharmacotherapies show limited efficacy and often accompanied by adverse effects.Acupuncture is a promising complementary therapy,but further clinical evidence is needed.The influence of acupuncture on migraine is not an immediate effect,and its mechanism remains unclear.This study aims to provide further clinical evidence for the anti-migraine effects of acupuncture and explore the mechanism involved.A randomized controlled trial was performed among 10 normal controls and 38 migraineurs.The migraineurs were divided into blank control,sham acupuncture,and acupuncture groups.Patients were subjected to two courses of treatment,and each treatment lasted for 5 days,with an interval of 1 day between the two courses.The effectiveness of treatment was evaluated using pain questionnaire.The functional magnetic resonance imaging(fMRI)data were analyzed for investigating brain changes induced by treatments.Blood plasma was collected for metabolomics and proteomics studies.Correlation and mediation analyses were performed to investigate the interaction between clinical,fMRI and omics changes.Results showed that acupuncture effectively relieved migraine symptoms in a way different from sham acupuncture in terms of curative effect,affected brain regions,and signaling pathways.The anti-migraine mechanism involves a complex network related to the regulation of the response to hypoxic stress,reversal of brain energy imbalance,and regulation of inflammation.The brain regions of migraineurs affected by acupuncture include the lingual gyrus,default mode network,and cerebellum.The effect of acupuncture on patients’metabolites/proteins may precede that of the brain. | Chong Li Xinyi Li Ke He Yang Wu Xiaoming Xie Jiju Yang Fan Zhang Yang Yue Huifeng Hao Shaokun Zhao Xin Li Guihua Tian | 2023 | Frontiers of Medicine2023，17，5： | 1 |
| 7 | Construction of Ideal Self-driven Synchronous Rectification Circuits显示文摘 | Xiaogao Xie J M Zhang XinYi Zhang etc | 2006 | IEEE APEC2006，23，19： | 1 |
| 8 | Regeneration of acid orange 7-exhausted granular activated carbons with microwave irradiation显示文摘 | Xie Quan Xitao Liu Longli Bo Shuo Chen Yazhi Zhao Xinyi Cui | 2004 | Water Research2004，，20： | 1 |
| 9 | Construction of Ideal Self- driven Synchronous Rectification Circuits显示文摘 | Xiaogao Xie J M Zhang XinYi Zhang etc | 2006 | IEEE APEC2006，23，19： | 1 |
| 10 | Solid tumor penetration by integrin-mediated pegylated poly(trimethylene carbonate) nanoparticles loaded with paclitaxel显示文摘 | Xinyi Jiang Hongliang Xin Jijin Gu Ximing Xu Weiyi Xia Shuo Chen Yike Xie Liangcen Chen Yanzuo Chen Xianyi Sha Xiaoling Fang | 2013 | Biomaterials2013，，6： | 1 |
| 11 | Electrochemical nitrate reduction to produce ammonia integrated into wastewater treatment:Investigations and challenges显示文摘Nitrate(NO_(3)^(-))is widely found in wastewater,which is harmful to human health and water environmental.Electrochemical reduction can convert NO_(3)^(-)to high value-added ammonia(NH)3)/ammonium(NH_(4)^(+))for pollutant removal and resource recovery.Currently,electrochemical nitrate reduction to produce ammonia(ENRA)is mostly focused on the preparation of high-performance catalysts,while ignoring the prerequisite for industrial application as the stable operation and optimal regulation of the process.Therefore,the review focused on wastewater treatment,based on the mechanism of electrochemical nitrate reduction for ammonia production and reactor construction(reactor,power supply system),then summarized the operation control strategies(such as reduction potential,nitrate concentration,inorganic ions,p H)that should be noted for ENRA.Finally,the challenges(system structure,economy)and prospects(ammonia recovery process,construction of large-scale ENRA system,application of real wastewater)of the field as it moves towards commercialization were discussed.It is hoped that this review will facilitate the scaling up of ENRA in the wastewater treatment field. | Xinyi Zou Jiawei Xie Changhong Wang Guangming Jiang Kai Tang Chongjun Chen | 2023 | Chinese Chemical Letters2023，34，6： | 1 |
| 12 | Optimization of COVID-19 prevention and control measures during the Beijing 2022 Winter Olympics:a model-based study显示文摘Background:The continuous mutation of severe acute respiratory syndrome coronavirus 2 has made the coronavirus disease 2019(COVID-19)pandemic complicated to predict and posed a severe challenge to the Beijing 2022Winter Olympics and Winter Paralympics held in February and March 2022.Methods:During the preparations for the Beijing 2022 Winter Olympics,we established a dynamic model with pulsedetection and isolation efect to evaluate the efect of epidemic prevention and control measures such as entry policies,contact reduction,nucleic acid testing,tracking,isolation,and health monitoring in a closed-loop managementenvironment,by simulating the transmission dynamics in assumed scenarios.We also compared the importance ofeach parameter in the combination of intervention measures through sensitivity analysis.Results:At the assumed baseline levels,the peak of the epidemic reached on the 57th day.During the simulationperiod(100 days),13,382 people infected COVID-19.The mean and peak values of hospitalized cases were 2650and 6746,respectively.The simulation and sensitivity analysis showed that:(1)the most important measures to stopCOVID-19 transmission during the event were daily nucleic acid testing,reducing contact among people,and dailyhealth monitoring,with cumulative infections at 0.04%,0.14%,and 14.92%of baseline levels,respectively(2)strictlyimplementing the entry policy and reducing the number of cases entering the closed-loop system could delay thepeak of the epidemic by 9 days and provide time for medical resources to be mobilized;(3)the risk of environmentaltransmission was low.Conclusions:Comprehensive measures under certain scenarios such as reducing contact,nucleic acid testing,health monitoring,and timely tracking and isolation could efectively prevent virus transmission.Our research resultsprovided an important reference for formulating prevention and control measures during the Winter Olympics,andno epidemic spread in the closed-loop during the games indirectly proved the rationality of our research results. | Lingcai Kong Mengwei Duan Jin Shi Jie Hong Xuan Zhou Xinyi Yang Zheng Zhao Jiaqi Huang Xi Chen Yun Yin Ke Li Yuanhua Liu Jinggang Liu Xiaozhe Wang Po Zhang Xiyang Xie Fei Li Zhaorui Chang Zhijie Zhang | 2022 | Infectious Diseases of Poverty2022，11，5： | 0 |
| 13 | Hydration of iodine adsorbed on the Au(111) surface显示文摘The hydration of halogens has been widely researched because of its close relation with the water desalination and biochemical reactions.In this work,by a combination of scanning tunneling microscopy and X-ray photoelectron spectroscopy,we have explored the hydration process of iodine via the Eley-Rideal process on the Au(111)surface.Moreover,the hydration process of iodine with the presence of the NiPc self-assembled network as a template has also been investigated,where the stepwise hydration of iodine at room temperature can be visualized on Au(111). | Yuanqi Ding Lei Xie Xinyi Yao Chi Zhang Wei Xu | 2022 | Fundamental Research2022，2，4： | 0 |
| 14 | Soft X-ray in-line holographic experiment显示文摘Water window' soft X-ray has some advantages in the microimaging of biological specimens. Soft X-ray holography can give us three-dimensional images of biological cells in their natural condition. Quasi-monochromatic soft X-ray from the polymonochromatic synchrotron radiation is obtained by a zone plate-pinhole linear monochromator at National Synchrotron Radiation Laboratory (NSRL) at Hefei. The pinhole is used to increase the temporal coherence of the soft X-ray, and also to increase the spatial coherence of it. An in-line holographic experiment has been finished with soft X-ray of main wavelength 4.5 nm and pinhole of diameter 0.03 mm. The magnified hologram is reconstructed with He-Ne laser. A smaller pinhole is wanted to be used to improve the coherence of the soft X-ray so as to improve the quality of the hologram. | Shaoguang Yang Xingshu Xie Chengzhi Jia Yongfei Zhao Shiping Jiang Yuxuan Zhang Xiaobin Shan Xinyi Zhang | 1998 | Chinese Science Bulletin1998，43，8： | 0 |
| 15 | Detecting benign uterine tumors by autofuorescence lifetime imaging microscopy through adjacent healthy cervical tissues显示文摘The endogenous fluorophores such as reduced nicotinarmide adenine dinucleotide(phosphate)(NAD(P)H)and favin adenine dinucleotide(FAD)in cells and tissues can be imaged by fuo-rescence lifetime imaging microscopy(FLIM)to show the tisute morphology features,as well as the biomolecular changes in microenvironment.The two important coenzymes in cellular metabolism,NAD(P)H and FAD,can be used to monitor the cellular metabolic status.This work proposed a novel method to study the uterine metabolism at the adjacent site of healthy cervix.It was found that the benign uterine tumors such as leiomyomas and adenomyosis with abnormal cell growth can be detected by measuring the fluorescence lifetime of NAD(P)H and FAD in adjacent healthy cervical tisues.This method opened a novel strategy for alicted women to undergo the cervical biopsies instead of hysterectomies for detecting tumors,which can preserve the fertility of patients.The FLIM studying on NAD(P)H and FAD indicated the correlation between metabolism and some diseases,including diabetes,hyperthyroidism and obesity.It was also suggested that the metabolic level might be quite different for a patient with a malignant tumnor history. | Maojia Huang Zixiao Zhang Xinyi Wang Yonghui Xie Yiyan Fei Jiong Ma Jing Wang Li Chen Lan Mi Yulan Wang | 2019 | Journal of Innovative Optical Health Sciences2019，，5： | 0 |
| 16 | Signatures of functional constraint at Fgfr1a Genes in schizothoracine fishes (Pisces: Cypriniformes): The dermal skeleton variation adapted to high-altitude environments显示文摘Fishes harbor a huge resource of phenotypic diversity and are useful for understanding the genetic basis of morphological variation.However,it is difficult to transfer classical genetic mapping to most non-model species.In this study,we performed a comparative sequence analysis of Fgfr1a to first interpret the evolution of this candidate scale-loss gene in 15 schizothoracine fishes with various scale phenotypes.While considerable amino acid(AA)substitutions were observed,molecular evolution analysis indicates that the overall coding regions were subject to functional constraint.We also identified extra copies of Fgfr1a in 4 scale-loss fishes and detected accelerated evolution in one AA substitution specific to these duplicates.We speculate that Fgfr1a had accumulated mutations in the ancestral lineage of scale-loss schizothoracine fishes before experiencing duplication events,which was further followed by the diversification of species.In silico mutation analysis predicted deleterious effects of the mutations while no disruptive molecular mechanism was detected.Collectively,our results highlight the important role of Fgfr1a gene in the adaptive evolution of schizothoracine fishes during their radiation in the Qinghai-Tibetan Plateau. | Xinyi GUO Ling XIE Xuze ZHANG Yinfa JI Juan CHEN Bo PANG Yongtao XU Delin QI Songchang GUO | 2016 | Integrative Zoology2016，11，2： | 0 |
| 17 | SYK-mediated epithelial cell state is associated with response to c-Met inhibitors in c-Met-overexpressing lung cancer显示文摘Genomic MET amplification and exon 14 skipping are currently clinically recognized biomarkers for stratifying subsets of non-small cell lung cancer(NSCLC)patients according to the predicted response to c-Met inhibitors(c-Metis),yet the overall clinical benefit of this strategy is quite limited.Notably,c-Met protein overexpression,which occurs in approximately 20–25%of NSCLC patients,has not yet been clearly defined as a clinically useful biomarker.An optimized strategy for accurately classifying patients with c-Met overexpression for decision-making regarding c-Meti treatment is lacking.Herein,we found that SYK regulates the plasticity of cells in an epithelial state and is associated with their sensitivity to c-Metis both in vitro and in vivo in PDX models with c-Met overexpression regardless of MET gene status.Furthermore,TGF-β1 treatment resulted in SYK transcriptional downregulation,increased Sp1-mediated transcription of FRA1,and restored the mesenchymal state,which conferred resistance to c-Metis.Clinically,a subpopulation of NSCLC patients with c-Met overexpression coupled with SYK overexpression exhibited a high response rate of 73.3%and longer progression-free survival with c-Meti treatment than other patients.SYK negativity coupled with TGF-β1 positivity conferred de novo and acquired resistance.In summary,SYK regulates cell plasticity toward a therapy-sensitive epithelial cell state.Furthermore,our findings showed that SYK overexpression can aid in precisely stratifying NSCLC patients with c-Met overexpression regardless of MET alterations and expand the population predicted to benefit from c-Met-targeted therapy. | Ji Zhou Xu-Chao Zhang Shan Xue Mengdi Dai Yueliang Wang Xia Peng Jianjiao Chen Xinyi Wang Yanyan Shen Hui Qin Bi Chen Yu Zheng Xiwen Gao Zuoquan Xie Jian Ding Handong Jiang Yi-Long Wu Meiyu Geng Jing Ai | 2023 | Signal Transduction and Targeted Therapy2023，8，6： | 0 |
| 18 | Flexible top-illuminated organic photodetector using an ultrathin-metal-based transparent electrode显示文摘Top-illuminated structure facilitates the integration of organic photodetectors(OPDs)into high-resolution flexible wearable light detection systems by allowing the OPDs to be deposited on the bottom readout circuit.However,constructing this structure poses a challenge as it demands metallic electrodes with both high optical transparency and high electrical conductivity.But to achieve practical sheet resistances,most semitransparent metallic electrodes tend to reflect a large portion of incident light instead of allowing it to be absorbed by the photoactive layer of the OPDs.This,in turn,results in reduced photocurrent generation.To address this issue,a semiconducting germanium(Ge)film is introduced into a sliver(Ag)film,effectively reducing its reflectivity by lessening scattering.The Ge film also changes how the Ag film grows,further reducing its absorption by lowering the critical thickness needed for forming a continuous film.This approach yields a 10 nm metallic electrode with a transmittance of 70%,a reflectivity of 12%,and a sheet resistance of 35.5Ω/□.Using this metallic electrode,flexible OPDs exhibit a high photo-to-dark current ratio of 2.9×10^(4)and improved mechanical properties.This finding highlights the benefits of the top-illuminated structure,which effectively reduces losses caused by waveguided modes of the incident light. | YUANHE WANG XINYI LI SHIHAO LIU LETIAN ZHANG WENFA XIE | 2023 | Photonics Research2023，11，12： | 0 |
| 19 | Rab22a-NeoF1:a promising target for osteosarcoma patients with lung metastasis显示文摘Osteosarcoma is the most common primary malignant bone tumor among adolescents and children,with high level of lung metastasis and poor prognosis.The treatment of metastatic cases remains a challenge in the clinic,leading to the dramatically decreased survival rate.However,the molecular mechanisms are still unclear.A recent article by Kang et al.demonstrated how chromosomal translocations in osteosarcoma facilitated lung metastasis,and shed new light on its therapeutic strategies1(Fig.1). | Kai Xie Xinyi Zhang Yongguang Tao | 2020 | Signal Transduction and Targeted Therapy2020，5，1： | 0 |
| 20 | Discovery of novel covalent selective estrogen receptor degraders against endocrine-resistant breast cancer显示文摘Endocrine-resistance remains a major challenge in estrogen receptorαpositive(ERα^(+))breast cancer(BC)treatment and constitutively active somatic mutations in ERαare a common mechanism.There is an urgent need to develop novel drugs with new mode of mechanism to fight endocrineresistance.Given aberrant ERαactivity,we herein report the identification of novel covalent selective estrogen receptor degraders(cSERDs)possessing the advantages of both covalent and degradation strategies.A highly potent cSERD 29c was identified with superior anti-proliferative activity than fulvestrant against a panel of ERa+breast cancer cell lines including mutant ERα.Crystal structure of ERα-29c complex alongside intact mass spectrometry revealed that 29c disrupted ERa protein homeostasis through covalent targeting C530 and strong hydrophobic interaction collied on H11,thus enforcing a unique antagonist conformation and driving the ERαdegradation.These significant effects of the cSERD on ERαhomeostasis,unlike typical ERαdegraders that occur directly via long side chains perturbing the morphology of H12,demonstrating a distinct mechanism of action(MoA).In vivo,29c showed potent antitumor activity in MCF-7 tumor xenograft models and low toxicity.This proof-of-principle study verifies that novel cSERDs offering new opportunities for the development of innovative therapies for endocrine-resistant BC. | Yubo Wang Jian Min Xiangping Deng Tian Feng Hebing Hu Xinyi Guo Yan Cheng Baohua Xie Yu Yang Chun-Chi Chen Rey-Ting Guo Chune Dong Hai-Bing Zhou | 2023 | Acta Pharmaceutica Sinica B2023，13，12： | 0 |
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