Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug development.However,it is extremely challenging to develop small-molecule inhibitors to target abnormally express...Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug development.However,it is extremely challenging to develop small-molecule inhibitors to target abnormally expressed transcription factors(TFs)except for the nuclear receptor family of TFs.Little is known about the interaction between TFs and transcription cofactors in gastroesophageal adenocarcinoma(GEA)or the therapeutic effects of targeting TF and transcription cofactor complexes.In this study,we found that ETS homologous factor(EHF)expression is promoted by a core transcriptional regulatory circuitry(CRC),specifically ELF3-KLF5-GATA6,and interference with its expression suppressed the malignant biological behavior of GEA cells.Importantly,we identified Ajuba LIM protein(AJUBA)as a new coactivator of EHF that cooperatively orchestrates transcriptional network activity in GEA.Furthermore,we identified KRAS signaling as a common pathway downstream of EHF and AJUBA.Applicably,dual targeting of EHF and AJUBA by lipid nanoparticles cooperatively attenuated the malignant biological behaviors of GEA in vitro and in vivo.In conclusion,EHF is upregulated by the CRC and promotes GEA malignancy by interacting with AJUBA through the KRAS pathway.Targeting of both EHF and its coactivator AJUBA through lipid nanoparticles is a novel potential therapeutic strategy.展开更多
In the present study, we explored the therapeutic potential of Cang Zhu-Huang Bai (CZ-HB) against rheumatoid arthritis (RA) and elucidated the associated mechanisms. The approach involved a systematic examination of t...In the present study, we explored the therapeutic potential of Cang Zhu-Huang Bai (CZ-HB) against rheumatoid arthritis (RA) and elucidated the associated mechanisms. The approach involved a systematic examination of the chemical ingredients of CZ-HB using TCMSP database. Subsequently, we predicted the targets corresponding to the active ingredients through the SwissTargetPrediction database. We constructed a comprehensive drug-ingredient-target network using Cytoscape (v 3.8.0), with the main ingredients of the drugs identified based on their degree values. We conducted a meticulous search across GEO, GeneCards, Therapeutic Target Database (TTD), and PharmGkb databases to identify target proteins associated with RA. The intersection of targets corresponding to the drugs' active ingredients and those associated with RA provided crucial insights. Functional analysis, including GO and KEGG pathway enrichment analyses, was performed on the intersecting targets using R (v 4.2.2). Additionally, a protein-protein interaction (PPI) network of the intersecting targets was constructed using the String platform. The resulting drug-ingredient-target-disease topology network was visualized using Cytoscape (v 3.8.0), and the Cytohubba plugin facilitated the identification of hub genes. The study revealed 35 active ingredients of CZ-HB and their corresponding 673 targets. We identified 14 major active ingredients crucial to the drug’s effects by focusing on the degree values. Furthermore, our investigation uncovered 784 targets associated with RA. Through the intersection of drug and disease targets, we pinpointed 34 active ingredients of CZ-HB capable of acting on 126 targets implicated in RA. The topological network analysis of the intersected genes identified five hub genes. The binding affinity of these hub genes to the 14 primary active ingredients of the drug was confirmed through molecular docking. The enrichment results of the intersecting genes suggested that CZ-HB exerted its anti-RA effects through a multi-component, multi-target, and multi-pathway approach.展开更多
This study aimed to systematically analyze the research status and trends in animal models for gout and hyperuricemia(HUA)through a bibliometric approach.We retrieved relevant literature on animal models of gout and H...This study aimed to systematically analyze the research status and trends in animal models for gout and hyperuricemia(HUA)through a bibliometric approach.We retrieved relevant literature on animal models of gout and HUA from the Web of Science(WOS)database.Utilizing analysis software such as Citespace and VOSviewer,we conducted a comprehensive examination of annual publication trends,contributing countries,institutions,and authors.Our analysis revealed a steady increase in the number of publications in this field.China emerged as the leading country,with 113 publications.Zhen Liu was identified as the most influential author,while Nanjing University stood out as the most influential institution.Keyword analysis elucidated current focal points,uncovering evolving patterns and emerging hotspots within the research landscape.Current research predominantly centered on understanding the pathogenesis and exploring new treatment modalities for gout and HUA.This study offered valuable insights into research trends and hotspots related to animal models for gout and HUA,enabling researchers to stay informed about the latest developments in this field.展开更多
Mitochondrial diseases are maternally inherited hetero- geneous disorders that are primarily caused by mitochondrial DNA (mtDNA) mutations. Depending on the ratio of mutant to wild-type mtDNA, known as heteroplasmy,...Mitochondrial diseases are maternally inherited hetero- geneous disorders that are primarily caused by mitochondrial DNA (mtDNA) mutations. Depending on the ratio of mutant to wild-type mtDNA, known as heteroplasmy, mitochondrial defects can result in a wide spectrum of clinical manifestations. Mitochondria-targeted endonucleases provide an alternative avenue for treating mitochondrial disorders via targeted destruc- tion of the mutant mtDNA and induction of heteroplasmic shifting. Here, we generated mitochondrial disease patient-specific induced pluripotent stem cells (MiPSCs) that harbored a high proportion of m.3243A〉G mtDNA mutations and caused mitochondrial encephalomyopathy and stroke-like episodes (MELAS). We engineered mitochondrial-targeted transcription activator-like effector nucleases (mitoTALENs) and successfully eliminated the m.3243A〉G mutation in MiPSCs. Off-target mutagenesis was not detected in the targeted MiPSC clones. Utilizing a dual fluorescence iPSC reporter cell line expressing a 3243G mutant mtDNA sequence in the nuclear genome, mitoTALENs displayed a significantly limited ability to target the nuclear genome compared with nuclear-localized TALENs. Moreover, genetically rescued MiPSCs displayed normal mitochondrial respiration and energy production. Moreover, neuronal progenitor cells differentiated from the rescued MiPSCs also demonstrated normal metabolic profiles. Further- more, we successfully achieved reduction in the human m.3243A〉G mtDNA mutation in porcine oocytes via injection of mitoTALEN mRNA. Our study shows the great potential for using mitoTALENs for specific targeting of mutant mtDNA both in iPSCs and mammalian oocytes, which not only provides a new avenue for studying mitochondrial biology and disease but also suggests a potential therapeutic approach for the treatment of mitochondrial disease, as well as the prevention of germline transmission of mutant mtDNA.展开更多
Abnormal glucose and lipid metabolism in COVID-19 patients were recently reported with unclear mechanism.In this study,we retrospectively investigated a cohort of COVID-19 patients without pre-existing metabolic-relat...Abnormal glucose and lipid metabolism in COVID-19 patients were recently reported with unclear mechanism.In this study,we retrospectively investigated a cohort of COVID-19 patients without pre-existing metabolic-related diseases,and found new-onset in suli n resista nee,hyperglycemia,and decreased HDL-C in these patie nts.Mecha nistically,SARS-CoV-2 infecti on in creased the expression of RE1-silencing transcription factor(REST),which modulated the expression of secreted metabolic factors including myeloperoxidase,apelin,and myostatin at the transcriptional level,resulting in the perturbation of glucose and lipid metabolism.Furthermore,several lipids,including(±)5-HETE,(±)12-HETE,propionic acid,and isobutyric acid were identified as the potential biomarkers of COVID-19-induced metabolic dysregulation,especially in insulin resistance.Taken together,our study revealed insulin resistance as the direct cause of hyperglycemia upon COVID-19,and further illustrated the underlying mechanisms,providing potential therapeutic targets for COVID-19-induced metabolic complications.展开更多
基金This work was supported by grants from the National Key Research and Development Program of China(2021YFA0909300 to Dong Yin)the National Natural Science Foundation of China(82372617,81972658 and 81802812 to Li Peng,81803636 to Xiaoqing Yuan,82073067 and 81872140 to Dong Yin)+5 种基金Guangdong Basic and Applied Basic Research Foundation(2024B1515020090,2023A1515012683,2019A1515012114 and 2018A030313129 to Li Peng,2024A1515030038 to Xiaoqing Yuan,2021A0505030084 and 2019B020226003 to Dong Yin)Basic and Applied Basic Research of Guangzhou Municipal Basic Research Plan(2024A03J0845 and 2023A04J2098 to Li Peng)National Postdoctoral Program for Innovation Talents(grant no.BX20190395 to Li Peng)China Postdoctoral Science Foundation(grant no.2019M663254 to Li Peng)the Fundamental Research Funds for the Central Universities(grant no.20ykpy105 to Li Peng)the Science and Technology Planning Project of Guangdong Province(2023B1212060013 and 2020B1212030004).
文摘Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug development.However,it is extremely challenging to develop small-molecule inhibitors to target abnormally expressed transcription factors(TFs)except for the nuclear receptor family of TFs.Little is known about the interaction between TFs and transcription cofactors in gastroesophageal adenocarcinoma(GEA)or the therapeutic effects of targeting TF and transcription cofactor complexes.In this study,we found that ETS homologous factor(EHF)expression is promoted by a core transcriptional regulatory circuitry(CRC),specifically ELF3-KLF5-GATA6,and interference with its expression suppressed the malignant biological behavior of GEA cells.Importantly,we identified Ajuba LIM protein(AJUBA)as a new coactivator of EHF that cooperatively orchestrates transcriptional network activity in GEA.Furthermore,we identified KRAS signaling as a common pathway downstream of EHF and AJUBA.Applicably,dual targeting of EHF and AJUBA by lipid nanoparticles cooperatively attenuated the malignant biological behaviors of GEA in vitro and in vivo.In conclusion,EHF is upregulated by the CRC and promotes GEA malignancy by interacting with AJUBA through the KRAS pathway.Targeting of both EHF and its coactivator AJUBA through lipid nanoparticles is a novel potential therapeutic strategy.
基金National Natural Science Foundations of China (Grant No. 81960863)the Education Department of Yunnan Province (Grant No. 2023Y0463)。
文摘In the present study, we explored the therapeutic potential of Cang Zhu-Huang Bai (CZ-HB) against rheumatoid arthritis (RA) and elucidated the associated mechanisms. The approach involved a systematic examination of the chemical ingredients of CZ-HB using TCMSP database. Subsequently, we predicted the targets corresponding to the active ingredients through the SwissTargetPrediction database. We constructed a comprehensive drug-ingredient-target network using Cytoscape (v 3.8.0), with the main ingredients of the drugs identified based on their degree values. We conducted a meticulous search across GEO, GeneCards, Therapeutic Target Database (TTD), and PharmGkb databases to identify target proteins associated with RA. The intersection of targets corresponding to the drugs' active ingredients and those associated with RA provided crucial insights. Functional analysis, including GO and KEGG pathway enrichment analyses, was performed on the intersecting targets using R (v 4.2.2). Additionally, a protein-protein interaction (PPI) network of the intersecting targets was constructed using the String platform. The resulting drug-ingredient-target-disease topology network was visualized using Cytoscape (v 3.8.0), and the Cytohubba plugin facilitated the identification of hub genes. The study revealed 35 active ingredients of CZ-HB and their corresponding 673 targets. We identified 14 major active ingredients crucial to the drug’s effects by focusing on the degree values. Furthermore, our investigation uncovered 784 targets associated with RA. Through the intersection of drug and disease targets, we pinpointed 34 active ingredients of CZ-HB capable of acting on 126 targets implicated in RA. The topological network analysis of the intersected genes identified five hub genes. The binding affinity of these hub genes to the 14 primary active ingredients of the drug was confirmed through molecular docking. The enrichment results of the intersecting genes suggested that CZ-HB exerted its anti-RA effects through a multi-component, multi-target, and multi-pathway approach.
基金The National Natural Science Foundation of China(Grant No.82160901)Special Project for Social Development under the Key Research and Development Plan of the Yunnan Provincial Science and Technology Department(Grant No.202403AC100019)supported by Yunnan Key Laboratory of Dai and Yi Medicines(Yunnan University of Chinese Medicine)(Grant No.2024SS24032)。
文摘This study aimed to systematically analyze the research status and trends in animal models for gout and hyperuricemia(HUA)through a bibliometric approach.We retrieved relevant literature on animal models of gout and HUA from the Web of Science(WOS)database.Utilizing analysis software such as Citespace and VOSviewer,we conducted a comprehensive examination of annual publication trends,contributing countries,institutions,and authors.Our analysis revealed a steady increase in the number of publications in this field.China emerged as the leading country,with 113 publications.Zhen Liu was identified as the most influential author,while Nanjing University stood out as the most influential institution.Keyword analysis elucidated current focal points,uncovering evolving patterns and emerging hotspots within the research landscape.Current research predominantly centered on understanding the pathogenesis and exploring new treatment modalities for gout and HUA.This study offered valuable insights into research trends and hotspots related to animal models for gout and HUA,enabling researchers to stay informed about the latest developments in this field.
基金This work was supported in part by the "Reproductive health and major birth defects prevention and control research" Key Special Fund (No. 2016YFC1000601), the National Natural Science Foundation of China (Grant Nos. 31371521, 81370766, 81401254, 81570101, 81671121, 31601187, 81521002), the Guangdong Province Science and Technology Project (2014TQ01R683, 2017A020 214005, 2016A020216023, 2015A030310119, 2016B030229008), the Bureau of Science and Technology of Guangzhou Municipality (201505011111498), the "Reproductive health and major birth defects prevention and control research" Key Special Fund (Nos. 2016YFC1000201 and 2016YFC1000302), the Ministry of Science and Technology of China Grants (973 program 2014CB943203), and the Beijing Nova Program (xxjh2015011).
文摘Mitochondrial diseases are maternally inherited hetero- geneous disorders that are primarily caused by mitochondrial DNA (mtDNA) mutations. Depending on the ratio of mutant to wild-type mtDNA, known as heteroplasmy, mitochondrial defects can result in a wide spectrum of clinical manifestations. Mitochondria-targeted endonucleases provide an alternative avenue for treating mitochondrial disorders via targeted destruc- tion of the mutant mtDNA and induction of heteroplasmic shifting. Here, we generated mitochondrial disease patient-specific induced pluripotent stem cells (MiPSCs) that harbored a high proportion of m.3243A〉G mtDNA mutations and caused mitochondrial encephalomyopathy and stroke-like episodes (MELAS). We engineered mitochondrial-targeted transcription activator-like effector nucleases (mitoTALENs) and successfully eliminated the m.3243A〉G mutation in MiPSCs. Off-target mutagenesis was not detected in the targeted MiPSC clones. Utilizing a dual fluorescence iPSC reporter cell line expressing a 3243G mutant mtDNA sequence in the nuclear genome, mitoTALENs displayed a significantly limited ability to target the nuclear genome compared with nuclear-localized TALENs. Moreover, genetically rescued MiPSCs displayed normal mitochondrial respiration and energy production. Moreover, neuronal progenitor cells differentiated from the rescued MiPSCs also demonstrated normal metabolic profiles. Further- more, we successfully achieved reduction in the human m.3243A〉G mtDNA mutation in porcine oocytes via injection of mitoTALEN mRNA. Our study shows the great potential for using mitoTALENs for specific targeting of mutant mtDNA both in iPSCs and mammalian oocytes, which not only provides a new avenue for studying mitochondrial biology and disease but also suggests a potential therapeutic approach for the treatment of mitochondrial disease, as well as the prevention of germline transmission of mutant mtDNA.
基金This study was supported by the joint emergency grants for prevention and control of SARS-CoV-2 of Ministry of Science and Technology of China,Guangdong Science and Technology Department and Guangzhou Municipal Science and Technology Bureau(2020B111108001)Guangdong Science and Technology Department(2020B121206001&2020B1212030004)The funders had no role in study design,data collection and analysis,or preparation of the manuscript.
文摘Abnormal glucose and lipid metabolism in COVID-19 patients were recently reported with unclear mechanism.In this study,we retrospectively investigated a cohort of COVID-19 patients without pre-existing metabolic-related diseases,and found new-onset in suli n resista nee,hyperglycemia,and decreased HDL-C in these patie nts.Mecha nistically,SARS-CoV-2 infecti on in creased the expression of RE1-silencing transcription factor(REST),which modulated the expression of secreted metabolic factors including myeloperoxidase,apelin,and myostatin at the transcriptional level,resulting in the perturbation of glucose and lipid metabolism.Furthermore,several lipids,including(±)5-HETE,(±)12-HETE,propionic acid,and isobutyric acid were identified as the potential biomarkers of COVID-19-induced metabolic dysregulation,especially in insulin resistance.Taken together,our study revealed insulin resistance as the direct cause of hyperglycemia upon COVID-19,and further illustrated the underlying mechanisms,providing potential therapeutic targets for COVID-19-induced metabolic complications.