Cyclin-dependent kinase 9(CDK9) activity is correlated with worse outcomes of triplenegative breast cancer(TNBC) patients. The heterodimer between CDK9 with cyclin T1 is essential for maintaining the active state of t...Cyclin-dependent kinase 9(CDK9) activity is correlated with worse outcomes of triplenegative breast cancer(TNBC) patients. The heterodimer between CDK9 with cyclin T1 is essential for maintaining the active state of the kinase and targeting this protein-protein interaction(PPI) may offer promising avenues for selective CDK9 inhibition. Herein, we designed and generated a library of metal complexes bearing the 7-chloro-2-phenylquinoline CN ligand and tested their activity against the CDK9cyclin T1 PPI. Complex 1 bound to CDK9 via an enthalpically-driven binding mode, leading to disruption of the CDK9-cyclin T1 interaction in vitro and in cellulo. Importantly, complex 1 showed promising anti-metastatic activity against TNBC allografts in mice and was comparably active compared to cisplatin. To our knowledge, 1 is the first CDK9-cyclin T1 PPI inhibitor with anti-metastatic activity against TNBC. Complex 1 could serve as a new platform for the future design of more efficacious kinase inhibitors against cancer, including TNBC.展开更多
Plants associate with diverse microbes that exert beneficial,neutral,or pathogenic effects inside the host.During the initial stages of invasion,the plant apoplast constitutes a hospitable environment for invading mic...Plants associate with diverse microbes that exert beneficial,neutral,or pathogenic effects inside the host.During the initial stages of invasion,the plant apoplast constitutes a hospitable environment for invading microbes,providing both water and nutrients.In response to microbial infection,a number of secreted proteins from host cells accumulate in the apoplastic space,which is related to microbial association or colonization processes.However,the molecular mechanisms underlying plant modulation of the apoplast environment and how plant-secreted proteases are involved in pathogen resistance are still poorly understood.Recently,several studies have reported the roles of apoplastic proteases in plant resistance against bacteria,fungi,and oomycetes.On the other hand,microbe-secreted proteins directly and/or indirectly inhibit host-derived apoplastic proteases to promote infection.These findings illustrate the importance of apoplastic proteases in plant–microbe interactions.Therefore,understanding the protease-mediated apoplastic battle between hosts and pathogens is of fundamental importance for understanding plant–pathogen interactions.Here,we provide an overviewof plant–microbe interactions in the apoplastic space.We define the apoplast,summarize the physical and chemical properties of these structures,and discuss the roles of plant apoplastic proteases and pathogen protease inhibitors in host–microbe interactions.Challenges and future perspectives for research into protease-mediated apoplastic interactions are discussed,which may facilitate the engineering of resistant crops.展开更多
Background: Interaction between proton pump inhibitors (PPI) and warfarin is controversial. Previous clinical studies have only a short follow-up period. Methods and Results: All patients (n = 716) for whom warfarin w...Background: Interaction between proton pump inhibitors (PPI) and warfarin is controversial. Previous clinical studies have only a short follow-up period. Methods and Results: All patients (n = 716) for whom warfarin was prescribed from November 1, 2010 to October 30, 2011 were extracted from electronic health records. In retrospective analysis for 1 year, PPI were prescribed to 404 patients. Among them, 108 patients were taking warfarin for more than 6 weeks before and after PPI. The profile of these patients was analyzed: 63 patients took lansoprazole;15 patients took omeprazole;30 patients took rabeprazole. No statistical difference was observed among 3 groups in age, body weight, concomitant use of other drugs, and comorbidity. Warfarin dose and INR did not change after PPI. Multivariate stepwise logistic regression analysis revealed that upper quartile of increment of INR was associated with the presence of atrial fibrillation (OR 3.77, 95% CI 1.16 - 12.27). The patients who had warfarin for shorter periods before PPI, or those who had PPI first (n = 141) had similar dose of warfarin and INR. In all patients analyzed (n = 404), including patients whose follow-up periods were shorter than 6 weeks (n = 155), a patient had cerebral bleeding, and 2 patients had cerebral infarction. Conclusions: Unfavorable interaction between warfarin and PPI was negligible in clinical use. Relatively higher INR was achieved after PPI in the presence of atrial fibrillation.展开更多
Ebola virus(EBOV)infection leads to staggeringly high mortality rate.Effective and low-cost treatments are urgently needed to control frequent EBOV outbreaks in Africa.In this study,we report that a natural compound c...Ebola virus(EBOV)infection leads to staggeringly high mortality rate.Effective and low-cost treatments are urgently needed to control frequent EBOV outbreaks in Africa.In this study,we report that a natural compound called berbamine hydrochloride strongly inhibits EBOV replication in vitro and in vivo.Our work further showed that berbamine hydrochloride acts by directly binding to the cleaved EBOV glycoprotein(GPcl),disrupting GPcl interaction with viral receptor Niemann-Pick C1,thus blocking the fusion of viral and cellular membranes.Our data support the probability of developing anti-EBOV small molecule drugs by targeting viral GPcl.More importantly,since berbamine hydrochloride has been used in clinic to treat leukopenia,it holds great promise of being quickly repurposed as an anti-EBOV drug.展开更多
Proteins usually associate with other molecules physically to execute their functions.Identifying these interactions is important for the functional analysis of proteins.Previously,we reported the parallel analysis of...Proteins usually associate with other molecules physically to execute their functions.Identifying these interactions is important for the functional analysis of proteins.Previously,we reported the parallel analysis of translated ORFs(PLATO)to couple ribosome display of full-length ORFs with affinity enrichment of mRNA/protein/ribosome complexes for the “bait”molecules,followed by the deep sequencing analysis of mRNA.However,the sample processing,from extraction of precipitated mRNA to generation of DNA libraries,includes numerous steps,which is tedious and may cause the loss of materials.Barcoded PLATO(PLATO-BC),an improved platform was further developed to test its application for protein interaction discovery.In this report,we tested the antisera-antigen interaction using serum samples from patients with inclusion body myositis(IBM).Tripartite motif containing 21(TRIM21)was identified as a potentially new IBM autoantigen.We also expanded the application of PLATO-BC to identify protein interactions for JQ1,single ubiquitin peptide,and NS5 protein of Zika virus.From PLATO-BC analyses,we identified new protein interactions for these “bait”molecules.We demonstrate that Ewing sarcoma breakpoint region 1(EWSR1)binds to JQ1 and their interactions may interrupt the EWSR1 association with acetylated histone H4.RIO kinase 3(RIOK3),a newly identified ubiquitin-binding protein,is preferentially associated with K63-ubiquitin chain.We also find that Zika NS5 protein interacts with two previously unreported host proteins,par-3 family cell polarity regulator(PARD3)and chromosome 19 open reading frame 53(C19orf53),whose attenuated expression benefits the replication of Zika virus.These results further demonstrate that PLATO-BC is capable of identifying novel protein interactions for various types of “bait”molecules.展开更多
基金supported by Hong Kong Baptist University,the Health and Medical Research Fund(HMRF/14150561)the National Natural Science Foundation of China(22077109 and 21775131)+3 种基金the Science and Technology Development Fund,Macao SAR(File no.0007/2020/A),SKL-QRCM(UM)-20202022the University of Macao(MYRG2019-00002-ICMS,China)Foshan Medicine Dengfeng Project of China(2019-2021)2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund(Guangdong-Hong KongMacao Joint Lab,No:2020B1212030006,China)。
文摘Cyclin-dependent kinase 9(CDK9) activity is correlated with worse outcomes of triplenegative breast cancer(TNBC) patients. The heterodimer between CDK9 with cyclin T1 is essential for maintaining the active state of the kinase and targeting this protein-protein interaction(PPI) may offer promising avenues for selective CDK9 inhibition. Herein, we designed and generated a library of metal complexes bearing the 7-chloro-2-phenylquinoline CN ligand and tested their activity against the CDK9cyclin T1 PPI. Complex 1 bound to CDK9 via an enthalpically-driven binding mode, leading to disruption of the CDK9-cyclin T1 interaction in vitro and in cellulo. Importantly, complex 1 showed promising anti-metastatic activity against TNBC allografts in mice and was comparably active compared to cisplatin. To our knowledge, 1 is the first CDK9-cyclin T1 PPI inhibitor with anti-metastatic activity against TNBC. Complex 1 could serve as a new platform for the future design of more efficacious kinase inhibitors against cancer, including TNBC.
文摘Plants associate with diverse microbes that exert beneficial,neutral,or pathogenic effects inside the host.During the initial stages of invasion,the plant apoplast constitutes a hospitable environment for invading microbes,providing both water and nutrients.In response to microbial infection,a number of secreted proteins from host cells accumulate in the apoplastic space,which is related to microbial association or colonization processes.However,the molecular mechanisms underlying plant modulation of the apoplast environment and how plant-secreted proteases are involved in pathogen resistance are still poorly understood.Recently,several studies have reported the roles of apoplastic proteases in plant resistance against bacteria,fungi,and oomycetes.On the other hand,microbe-secreted proteins directly and/or indirectly inhibit host-derived apoplastic proteases to promote infection.These findings illustrate the importance of apoplastic proteases in plant–microbe interactions.Therefore,understanding the protease-mediated apoplastic battle between hosts and pathogens is of fundamental importance for understanding plant–pathogen interactions.Here,we provide an overviewof plant–microbe interactions in the apoplastic space.We define the apoplast,summarize the physical and chemical properties of these structures,and discuss the roles of plant apoplastic proteases and pathogen protease inhibitors in host–microbe interactions.Challenges and future perspectives for research into protease-mediated apoplastic interactions are discussed,which may facilitate the engineering of resistant crops.
文摘Background: Interaction between proton pump inhibitors (PPI) and warfarin is controversial. Previous clinical studies have only a short follow-up period. Methods and Results: All patients (n = 716) for whom warfarin was prescribed from November 1, 2010 to October 30, 2011 were extracted from electronic health records. In retrospective analysis for 1 year, PPI were prescribed to 404 patients. Among them, 108 patients were taking warfarin for more than 6 weeks before and after PPI. The profile of these patients was analyzed: 63 patients took lansoprazole;15 patients took omeprazole;30 patients took rabeprazole. No statistical difference was observed among 3 groups in age, body weight, concomitant use of other drugs, and comorbidity. Warfarin dose and INR did not change after PPI. Multivariate stepwise logistic regression analysis revealed that upper quartile of increment of INR was associated with the presence of atrial fibrillation (OR 3.77, 95% CI 1.16 - 12.27). The patients who had warfarin for shorter periods before PPI, or those who had PPI first (n = 141) had similar dose of warfarin and INR. In all patients analyzed (n = 404), including patients whose follow-up periods were shorter than 6 weeks (n = 155), a patient had cerebral bleeding, and 2 patients had cerebral infarction. Conclusions: Unfavorable interaction between warfarin and PPI was negligible in clinical use. Relatively higher INR was achieved after PPI in the presence of atrial fibrillation.
基金This research was funded by the CAMS Innovation Fund for Medical Sciences(Grant Nos.2021-I2M-1-030 and CAMS-I2M-1-012,China)the National Natural Science Foundation of China(Grant Nos.81802019,81902075 and 81673358)+5 种基金the National Mega-project for Innovative Drugs(Grant No.2018ZX09711003-002-002,China)the Beijing Natural Science Foundation(Grant No.7184228,China)the Peking Union Medical College Youth Fund(Grant Nos.3332016063 and 3332018096,China)the China Ministry of Science and Technology National 973 Project(Grant No.2014CB542503)the Excellent Young Scientist Program from the NSFC(Grant No.81622031,China)the National Key Research and Development program of China(Grant No.2016YFD0500307).
文摘Ebola virus(EBOV)infection leads to staggeringly high mortality rate.Effective and low-cost treatments are urgently needed to control frequent EBOV outbreaks in Africa.In this study,we report that a natural compound called berbamine hydrochloride strongly inhibits EBOV replication in vitro and in vivo.Our work further showed that berbamine hydrochloride acts by directly binding to the cleaved EBOV glycoprotein(GPcl),disrupting GPcl interaction with viral receptor Niemann-Pick C1,thus blocking the fusion of viral and cellular membranes.Our data support the probability of developing anti-EBOV small molecule drugs by targeting viral GPcl.More importantly,since berbamine hydrochloride has been used in clinic to treat leukopenia,it holds great promise of being quickly repurposed as an anti-EBOV drug.
基金supported by grants from National Institute of Health(Grant Nos.R33AI116180,R01DE025447,and R01GM117838)
文摘Proteins usually associate with other molecules physically to execute their functions.Identifying these interactions is important for the functional analysis of proteins.Previously,we reported the parallel analysis of translated ORFs(PLATO)to couple ribosome display of full-length ORFs with affinity enrichment of mRNA/protein/ribosome complexes for the “bait”molecules,followed by the deep sequencing analysis of mRNA.However,the sample processing,from extraction of precipitated mRNA to generation of DNA libraries,includes numerous steps,which is tedious and may cause the loss of materials.Barcoded PLATO(PLATO-BC),an improved platform was further developed to test its application for protein interaction discovery.In this report,we tested the antisera-antigen interaction using serum samples from patients with inclusion body myositis(IBM).Tripartite motif containing 21(TRIM21)was identified as a potentially new IBM autoantigen.We also expanded the application of PLATO-BC to identify protein interactions for JQ1,single ubiquitin peptide,and NS5 protein of Zika virus.From PLATO-BC analyses,we identified new protein interactions for these “bait”molecules.We demonstrate that Ewing sarcoma breakpoint region 1(EWSR1)binds to JQ1 and their interactions may interrupt the EWSR1 association with acetylated histone H4.RIO kinase 3(RIOK3),a newly identified ubiquitin-binding protein,is preferentially associated with K63-ubiquitin chain.We also find that Zika NS5 protein interacts with two previously unreported host proteins,par-3 family cell polarity regulator(PARD3)and chromosome 19 open reading frame 53(C19orf53),whose attenuated expression benefits the replication of Zika virus.These results further demonstrate that PLATO-BC is capable of identifying novel protein interactions for various types of “bait”molecules.
