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| 1 | DNAH2 facilitates the homologous recombination repair of Fanconi anemia pathway through modulating FANCD2 ubiquitination显示文摘Fanconi anemia(FA),an X-linked genetic or autosomal recessive disease,exhibits complicated pathogenesis.Previously,we detected the mutated Dynein Axonemal Heavy Chain 2(DNAH2)gene in 2 FA cases.Herein,we further investigated the potential association between DNAH2 and the homologous recombination repair pathway of FA.The assays of homologous recombination repair,mitomycin C(MMC)sensitivity,immunofluorescence,and ubiquitination modification were performed in U2OS and DR-U2OS cell lines.In MMC-treated U2OS cells,the downregulation of the DNAH2 gene increased the sensitivity of cells to DNA inter-strand crosslinks.We also observed the reduced enrichment of FANCD2 protein to DNA damage sites.Furthermore,the ubiquitination modification level of FANCD2 was influenced by the deficiency of DNAH2.Thus,our results suggest that DNAH2 may modulate the cell homologous recombination repair partially by increasing the ubiquitination and the enrichment to DNA damage sites of FANCD2.DNAH2 may act as a novel co-pathogenic gene of FA patients. | Lixian Chang Xingjie Gao Yuxia Wang Chunmin Huang Min Gao Xiaomin Wang Chao Liu Wenqi Wu Wenbin An Yang Wan Aoli Zhang Yingchi Zhang Weiping Yuan Xiaofan Zhu | 2021 | Blood Science2021，3，3： | 0 |
| 2 | Discovery of IHMT-337 as a potent irreversible EZH2 inhibitor targeting CDK4 transcription for malignancies显示文摘Enhancer of zeste homolog 2(EZH2),an enzymatic subunit of PRC2 complex,plays an important role in tumor development and progression through its catalytic and noncatalytic activities.Overexpression or gain-of-function mutations of EZH2 have been significantly associated with tumor cell proliferation of triple-negative breast cancer(TNBC)and diffuse large B-cell lymphoma(DLBCL).As a result,it has gained interest as a potential therapeutic target.The currently available EZH2 inhibitors,such as EPZ6438 and GSK126,are of benefit for clinical using or reached clinical trials.However,certain cancers are resistant to these enzymatic inhibitors due to its noncatalytic or transcriptional activity through modulating nonhistone proteins.Thus,it may be more effective to synergistically degrade EZH2 in addition to enzymatic inhibition.Here,through a rational design and chemical screening,we discovered a new irreversible EZH2 inhibitor,IHMT-337,which covalently bounds to and degrades EZH2 via the E3 ligase CHIP-mediated ubiquitination pathway.Moreover,we revealed that IHMT-337 affects cell cycle progression in TNBC cells through targeting transcriptional regulating of CDK4,a novel PRC2 complex-and enzymatic activity-independent function of EZH2.More significantly,our compound inhibits both DLBCL and TNBC cell proliferation in different preclinical models in vitro and in vivo.Taken together,our findings demonstrate that in addition to enzymatic inhibition,destroying of EZH2 by IHMT-337 could be a promising therapeutic strategy for TNBC and other malignancies that are independent of EZH2 enzymatic activity. | Husheng Mei Hong Wu Jing Yang Bin Zhou Aoli Wang Chen Hu Shuang Qi Zongru Jiang Fengming Zou Beilei Wang Feiyang Liu Yongfei Chen Wenchao Wang Jing Liu Qingsong Liu | 2023 | Signal Transduction and Targeted Therapy2023，8，2： | 0 |
| 3 | Overexpression of miR390b promotes stem elongation and height growth in Populus显示文摘MicroRNA390(miR390)is involved in plant growth and development by down-regulating the expression of the downstream genes trans-acting short interfering RNA3(TAS3)and AUXIN RESPONSE FACTORs(ARFs).There is a scarcity of research on the involvement of the miR390-TAS3-ARFs pathway in the stem development of Populus.Here,differentially expressedmiRNAs during poplar stem development were screened by small RNA sequencing analysis,and a novel function of miR390b in stem development was revealed.Overexpression of miR390b(OE-miR390b)resulted in a large increase in the number of xylem fiber cells and a slight decrease in the cell length at the longitudinal axis.Overall increases in stem elongation and plant height were observed in the OE-miR390b plants.According to transcriptome sequencing results and transient co-expression analysis,TAS3.1 and TAS3.2 were identified as the target genes of miR390 in poplar and were negatively regulated by miR390 in the apex.The transcription levels of ARF3.2 and ARF4 were significantly repressed in OE-miR390b plants and strongly negatively correlatedwith the number of xylem fiber cells along the longitudinal axis.These findings indicate that the conserved miR390-TAS3-ARFs pathway in poplar is involved in stem elongation and plant height growth. | Qiaofang Shi Dongdong Tian Jieyu Wang Aoli Chen Yuqing Miao Yiming Chen Jun Li Xiaomeng Wu Bo Zheng Wenwu Guo Xueping Shi | 2023 | Horticulture Research2023，10，2： | 0 |
| 4 | Predicting and overcoming resistance to CDK9 inhibitors for cancer therapy显示文摘Abnormally activated CDK9 participates in the super-enhancer mediated transcription of short-lived proteins required for cancer cell survival.Targeting CDK9 has shown potent anti-tumor activity in clinical trials among different cancers.However,the study and knowledge on drug resistance to CDK9 inhibitors are very limited.In this study,we established an AML cell line with acquired resistance to a highly selective CDK9 inhibitor BAY1251152.Through genomic sequencing,we identified in the kinase domain of CDK9 a mutation L156F,which is also a coding SNP in the CDK9 gene.By knocking in L156F into cancer cells using CRISPR/Cas9,we found that single CDK9 L156F could drive the resistance to CDK9 inhibitors,not only ATP competitive inhibitor but also PROTAC degrader.Mechanistically,CDK9 L156F disrupts the binding with inhibitors due to steric hindrance,further,the mutation affects the thermal stability and catalytic activity of CDK9 protein.To overcome the drug resistance mediated by the CDK9-L156F mutation,we discovered a compound,IHMT-CDK9-36 which showed potent inhibition activity both for CDK9 WT and L156F mutant.Together,we report a novel resistance mechanism for CDK9 inhibitors and provide a novel chemical scaffold for the future development of CDK9 inhibitors. | Chen Hu Lijuan Shen Fengming Zou Yun Wu Beilei Wang Aoli Wang Chao Wu Li Wang Jing Liu Wenchao Wang Qingsong Liu | 2023 | Acta Pharmaceutica Sinica B2023，13，9： | 0 |
| 5 | Clinical efficacy of low-dose emetine for patients with COVID-19:a real-world study显示文摘Objective:Emetine,an isoquinoline alkaloid that is enriched at high concentrations in the lung,has shown potent in vitro activity against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).The aim of this study was to better understand the effectiveness of low-dose emetine for patients with coronavirus disease 2019(COVID-19).Methods:In this real-world study,63 patients with mild or common COVID-19 were recruited from Wuhan Fangcang Shelter Hospital and five COVID-19-designated hospitals in Anhui Province,China from February to March 2020.Thirty-nine patients from Wuhan Fangcang Shelter Hospital were assigned to a pragmatic randomized controlled clinical trial,and 24 patients from the 5 COVID-19-designated hospitals in Anhui Province underwent a real-world study.The medication course of emetine was less than 10 days.The main symptoms and adverse reactions of all patients were observed and recorded.The primary outcome measure was the time required for a negative SARS-CoV-2 RNA result or the negative result rate on day 10.Secondary outcomes included axillary temperature,transcutaneous oxygen saturation,and respiratory frequency recovery.The study was approved by the Ethics Committee of The First Affiliated Hospital of Anhui Medical University on February 20,2019(approval No.PJ2020-03-19)and was registered with the Chinese Clinical Trial Registry on February 20,2019(registration number:ChiCTR2000030022).Results:The oxygen saturation values were higher in the treatment group than in the control group on the first day after enrollment for patients treated at Fangcang Shelter Hospital.The axillary body temperature,respiratory rate,and oxygen saturation among patients in Fangcang Shelter Hospital were related to the time effect but not to the intervention measures.The respiratory rate and oxygen saturation of patients in the Anhui designated hospitals were related to the intervention measures but not to the time effect.The axillary body temperature of patients in Anhui designated hospitals was related to the time effect but not to the intervention measures.Conclusion:Our preliminary study shows that low-dose emetine combined with basic conventional antiviral drugs improves clinical symptoms in patients with mild and common COVID-19 without apparent adverse effects,suggesting that moderately increased doses of emetine may have good potential for treatment and prevention of COVID-19. | Song Fan Qi Zhen Cheng Chen Wenjun Wang Qibing Wu Huihui Ma Chengyuan Zhang Li Zhang Baojing Lu Huiyao Ge Liang Yong Bao Li Yafen Yu Weiwei Chen Yiwen Mao Guangbo Qu Li Su Aoli Wang Zhen Ding Haiwen Li Jin Zhang Yonglian Wang Yufeng Gao Xihai Xu Zhongming Zhu Jun Chen Long Zhang Hongqiang Liang Song Wu Meng Huang Quan Xia Ping Li Yehuan Sun Chaozhao Liang Wei Wei Qingsong Liu Liangdan Sun | 2021 | Journal of Bio-X Research2021，4，2： | 0 |
| 6 | The COVID-19 Pandemic: A Double Threat to Chinese Americans’ Mental Health显示文摘Objective:To explore the double psychosocial threats of the COVID-19 pandemic,targeted behavior toward Chinese Americans,and the correlates to their mental health.Methods:A quantitative,cross-sectional,and descriptive design was utilized by using a purposive convenience sample of 301 Chinese Americans over the age of 18 residing in the United States.Online data collection was conducted through the social media platform WeChat from April 8–21,2021.Descriptive statistical analysis was used for the participants’demographic charac-teristics,Multidimensional Scale of Perceived Social Support(MSPSS),Double Threat Situations,COVID-19 Racial Discrimination,and General Anxiety Disorder-7(GAD-7).Stepwise logistic regression was conducted to verify predictors for anxiety levels by GAD-7.Results:In this sample(N=301),127(42.19%)were male and 174(57.81%)were female.The average age was 41.67(SD=5.89).Among MSPSS subscales,social support from family(MSPSS-Fam,79.73%,n=240)and social support from significant others(MSPSS-SO,73.75%,n=222)were high.231(76.74%)reported threats due to their Chinese ethnic background during the COVID-19 outbreak.Predictors for the high anxiety level by GAD-7 were COVID-19 racial discrimination from the local community(OR=0.47,95%CI=0.39–0.71,p<0.001),media/online(OR=0.36,95%CI=0.26–0.53,p<0.001),the perceived threat from the COVID-19 virus(OR=0.33,95%CI=0.23–0.51,p<0.001)and Perceived racism threat from Chinese back-ground related to COVID-19(OR=0.31,95%CI=0.21–0.49,p<0.001).Conclusions:COVID-19 double-threats(The virus and racial discrimination)situations are significantly related to the high level of anxiety among Chinese Americans.The sense of belonging and social perceptions of Chinese immigrants is closely related to public health problems in Western societies and needs to be addressed at all levels.Ourfindings call for the attention of health-care workers to specific racism double-threatened situations and high mental health risks,as well as direct and indirect ethnic discrimination that Chinese Americans are experiencing during this pandemic,the long-term influ-ences and effective coping ways related to this issue should be explored in further research. | Aoli Li Yan You Kunli Wu Huibin Shan Younglee Kim Qilian He | 2023 | International Journal of Mental Health Promotion2023，25，6： | 0 |
| 7 | Discovery of IHMT-MST1-39 as a novel MST1 kinase inhibitor and AMPK activator for the treatment of diabetes mellitus显示文摘Insulin-producing pancreaticβcell death is the fundamental cause of type 1 diabetes(T1D)and a contributing factor to type 2 diabetes(T2D).Moreover,metabolic disorder is another hallmark of T2D.Mammalian sterile 20-like kinase 1(MST1)contributes to the progression of diabetes mellitus through apoptosis induction and acceleration of pancreaticβcell dysfunction.AMP-activated protein kinase(AMPK)is an energy sensing kinase and its activation has been suggested as a treatment option for metabolic diseases.Thus,pharmacological inhibition of MST1 and activation of AMPK simultaneously represents a promising approach for diabetes therapy.Here,we discovered a novel selective MST1 kinase inhibitor IHMT-MST1-39,which exhibits anti-apoptosis efficacy and improves the survival of pancreaticβcells under diabetogenic conditions,as well as primary pancreatic islets in an ex vivo disease model.Mechanistically,IHMT-MST1-39 activated AMPK signaling pathway in hepatocytes in vitro,combination of IHMT-MST1-39 and metformin synergistically prevented hyperglycemia and significantly ameliorated glucose tolerance and insulin resistance in diabetic mice.Taken together,IHMT-MST1-39 is a promising anti-diabetic candidate as a single agent or in combination therapy for both T1D and T2D. | Junjie Wang Ziping Qi Yun Wu Aoli Wang Qingwang Liu Fengming Zou Beilei Wang Shuang Qi Jiangyan Cao Chen Hu Chenliang Shi Qianmao Liang Li Wang Jing Liu Wenchao Wang Qingsong Liu | 2023 | Signal Transduction and Targeted Therapy2023，8，5： | 0 |
| 8 | Gas-Induced Phase Transition of Dipeptide Supramolecular Assembly显示文摘The manipulation of supramolecular assembly enables single-component architectures to possess diverse structures and functions.Here,we report directed phase transitions of dipeptide supramolecular gel to crystals with excellent selectivity and tunable mechanical properties.To be specific,lamellar-to-orthorhombic rearrangement of dipeptide molecules in the supramolecular assembly was guided by application of ammonia gas,while lamellar-tohexagonal realignment was generated upon water vapor exposure of the assembly.Importantly,this crystal phase control originated from distinct gas-mediated reconstitution of hydrogen-bonding interactions,which endowed the dipeptide materials with remarkably modulated stiffness.The selective phase transformation offers a simple and effective platform for self-assembling peptide crystals with diverse long-range-ordered structures from a single gel-state aggregation.This work opens up new perspectives on peptide-based biomaterials via gas-directed hydrogen-bonding chemistry. | Huimin Xue Jinbo Fei Aoli Wu Xia Xu Junbai Li | 2021 | CCS Chemistry2021，3，11： | 0 |
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