Colitis is a chronic bowel disease characterized by damage to the lining of the large intestine,with its precise underlying causes remaining incompletely understood.In this study,we provide evidence that circular RNA ...Colitis is a chronic bowel disease characterized by damage to the lining of the large intestine,with its precise underlying causes remaining incompletely understood.In this study,we provide evidence that circular RNA circNlgn plays a pivotal role in promoting the development of colitis.Colitis patients produce significant higher levels of circNign.Transgenic mice expressing circNlgn exhibit heightened susceptibility to colitis development and progression,primarily attributed to the presence of the protein isoform Nlgn173 encoded by circNign.Nlgn173 undergoes translocation into cellnuclei,where it interacts with actin,impeding the binding of actin-related protein 2 and 3(Arp2/3)complex to actin molecules.Consequently,this leads to a reduction in actin polymerization.Mechanistically,Nlgn173 enhances tyrosine-53 phosphorylation of nuclear actin,diminishing its capacity to interact with the Arp2/3 complex and causing a decrease in filamentous actin levels.These alterations in actin dynamics result in inhibited cell cycle progression,increased apoptosis,and decreased proliferation of colonic epithelial cells,thereby exacerbating colitis development and progression.In contrast,the silencing of circNign or the targeted inhibition of Nlgn173 translation and nuclear translocation leads to the promotion of nuclear actin polymerization,enhanced cell survival,and reduced apoptosis and ultimately improves the outcome of colitis in vivo.Interestingly,nuclear actin polymerization is highly related with expression of PIAS3,which modulates signal transducer and activator of transcription 3 and NF-kB activity in colitis.Strategies such as circNlgn knockdown and targeting nuclear actin polymerization of the colonic epithelium may explore a novel avenue for acute ulcerativecolitisclinical intervention.展开更多
Since the outbreak of the COVID-19,various regions of China have been rapidly deployed under the leadership of the Central Committee of the Party to actively prevent and control the COVID-19.The rural areas of my coun...Since the outbreak of the COVID-19,various regions of China have been rapidly deployed under the leadership of the Central Committee of the Party to actively prevent and control the COVID-19.The rural areas of my country have weak links to the prevention and management of public health emergencies.Problems include lack of medical and health resources and farmers’low awareness of epidemic prevention.Situations that correspond to the prevention and management of the COVID-19 are more serious.As the patient’s first contact and“gatekeeper”in the fight against the epidemic,the general practitioner is responsible for the“first visit-subsequent ongoing intervention”.This article is about the prevention and control of the COVID-19 epidemics and epidemic prevention in terms of dissemination of knowledge,informed crowd control,joint prevention and control,and standardized management of people.This is a summary of the efforts of general practitioners.Quarantine at home,interactive referrals to medical consortiums,special care for contracted families.The function during the management period aims to analyze the role played by general practitioners during the epidemic and to provide new ideas for the prevention and management of the epidemic.Provide more targeted general practitioner-style services in rural areas to promote the implementation and improvement of health and poverty alleviation.The health level of the rural population provides a theoretical standard.展开更多
Recent studies have highlighted the pivotal roles of circular RNAs(circRNAs)in cardiovascular diseases.Through high-throughput circRNA sequencing of both normal myocardial tissues and hypertrophic patients,we unveiled...Recent studies have highlighted the pivotal roles of circular RNAs(circRNAs)in cardiovascular diseases.Through high-throughput circRNA sequencing of both normal myocardial tissues and hypertrophic patients,we unveiled 32,034 previously undiscovered circRNAs with distinct cardiac expression patterns.Notably,circITGa9,a circRNA derived from integrin-α9,exhibited substantial up-regulation in cardiac hypertrophy patients.This elevation was validated across extensive sample pools from cardiac patients and donors.In vivo experiments revealed heightened cardiac fibrosis in mice subjected to transverse aortic constriction(TAC)after circITGa9 injection.We identified circITGa9 binding proteins through circRNA precipitation followed by liquid chromatography tandem-mass spectrometry.Furthermore,circRNA pull-down/precipitation assays demonstrated that increased circITGa9 expression facilitated binding with tropomyosin 3(TPM3).Specific binding sites between circITGa9 and TPM3 were identified through computational algorithms and further validated by site-directed mutagenesis.We further showed that circITGa9 induced actin polymerization,characteristic of tissue fibrosis.Finally,we developed approaches that improved cardiac function and decreased fibrosis by delivering small interfering RNA targeting circITGa9 or blocking oligo inhibiting the interaction of circITGa9 and TPM3 into TAC mice,which is amenable for further preclinical and translational development.We conclude that elevated circITGa9 levels drive cardiac remodeling and fibrosis.By pinpointing circITGa9 as a therapeutic target,we open doors to innovative interventions for mitigating cardiac remodeling and fibrosis.展开更多
Significant progress has been made in circular RNA(circRNA)research in recent years.Increasing evidence suggests that circRNAs play important roles in many cellular processes,and their dysregulation is implicated in t...Significant progress has been made in circular RNA(circRNA)research in recent years.Increasing evidence suggests that circRNAs play important roles in many cellular processes,and their dysregulation is implicated in the pathogenesis of various diseases.CircRNAs are highly stable and usually expressed in a tissue-or cell type-specific manner.Therefore,they are currently being explored as potential therapeutic targets.Gain-of-function and loss-of-function approaches are typically performed using circRNA expression plasmids and RNA interference-based strategies,respectively.These strategies have limitations that can be mitigated using nanoparticle and exosome delivery systems.Furthermore,recent developments show that the cre-lox system can be used to knockdown circRNAs in a cell-specific manner.While still in the early stages of development,the CRISPR/Cas13 system has shown promise in knocking down circRNAs with high specificity and efficiency.In this review,we describe circRNA properties and functions and highlight their significance in disease.We summarize strategies that can be used to overexpress or knockdown circRNAs as a therapeutic approach.Lastly,we discuss major challenges and propose future directions for the development of circRNA-based therapeutics.展开更多
基金supported by the grants from Canadian Institutes of Health Research(PJT-155962 and PJT-166107)to B.B.Y.
文摘Colitis is a chronic bowel disease characterized by damage to the lining of the large intestine,with its precise underlying causes remaining incompletely understood.In this study,we provide evidence that circular RNA circNlgn plays a pivotal role in promoting the development of colitis.Colitis patients produce significant higher levels of circNign.Transgenic mice expressing circNlgn exhibit heightened susceptibility to colitis development and progression,primarily attributed to the presence of the protein isoform Nlgn173 encoded by circNign.Nlgn173 undergoes translocation into cellnuclei,where it interacts with actin,impeding the binding of actin-related protein 2 and 3(Arp2/3)complex to actin molecules.Consequently,this leads to a reduction in actin polymerization.Mechanistically,Nlgn173 enhances tyrosine-53 phosphorylation of nuclear actin,diminishing its capacity to interact with the Arp2/3 complex and causing a decrease in filamentous actin levels.These alterations in actin dynamics result in inhibited cell cycle progression,increased apoptosis,and decreased proliferation of colonic epithelial cells,thereby exacerbating colitis development and progression.In contrast,the silencing of circNign or the targeted inhibition of Nlgn173 translation and nuclear translocation leads to the promotion of nuclear actin polymerization,enhanced cell survival,and reduced apoptosis and ultimately improves the outcome of colitis in vivo.Interestingly,nuclear actin polymerization is highly related with expression of PIAS3,which modulates signal transducer and activator of transcription 3 and NF-kB activity in colitis.Strategies such as circNlgn knockdown and targeting nuclear actin polymerization of the colonic epithelium may explore a novel avenue for acute ulcerativecolitisclinical intervention.
基金Innovation and Entrepreneurship Training Program of Sichuan University Students,fund number:S202010634125.
文摘Since the outbreak of the COVID-19,various regions of China have been rapidly deployed under the leadership of the Central Committee of the Party to actively prevent and control the COVID-19.The rural areas of my country have weak links to the prevention and management of public health emergencies.Problems include lack of medical and health resources and farmers’low awareness of epidemic prevention.Situations that correspond to the prevention and management of the COVID-19 are more serious.As the patient’s first contact and“gatekeeper”in the fight against the epidemic,the general practitioner is responsible for the“first visit-subsequent ongoing intervention”.This article is about the prevention and control of the COVID-19 epidemics and epidemic prevention in terms of dissemination of knowledge,informed crowd control,joint prevention and control,and standardized management of people.This is a summary of the efforts of general practitioners.Quarantine at home,interactive referrals to medical consortiums,special care for contracted families.The function during the management period aims to analyze the role played by general practitioners during the epidemic and to provide new ideas for the prevention and management of the epidemic.Provide more targeted general practitioner-style services in rural areas to promote the implementation and improvement of health and poverty alleviation.The health level of the rural population provides a theoretical standard.
基金supported by grants from Canadian Institutes of Health Research(PJT-155962 and PJT-166107)to B.B.Y.
文摘Recent studies have highlighted the pivotal roles of circular RNAs(circRNAs)in cardiovascular diseases.Through high-throughput circRNA sequencing of both normal myocardial tissues and hypertrophic patients,we unveiled 32,034 previously undiscovered circRNAs with distinct cardiac expression patterns.Notably,circITGa9,a circRNA derived from integrin-α9,exhibited substantial up-regulation in cardiac hypertrophy patients.This elevation was validated across extensive sample pools from cardiac patients and donors.In vivo experiments revealed heightened cardiac fibrosis in mice subjected to transverse aortic constriction(TAC)after circITGa9 injection.We identified circITGa9 binding proteins through circRNA precipitation followed by liquid chromatography tandem-mass spectrometry.Furthermore,circRNA pull-down/precipitation assays demonstrated that increased circITGa9 expression facilitated binding with tropomyosin 3(TPM3).Specific binding sites between circITGa9 and TPM3 were identified through computational algorithms and further validated by site-directed mutagenesis.We further showed that circITGa9 induced actin polymerization,characteristic of tissue fibrosis.Finally,we developed approaches that improved cardiac function and decreased fibrosis by delivering small interfering RNA targeting circITGa9 or blocking oligo inhibiting the interaction of circITGa9 and TPM3 into TAC mice,which is amenable for further preclinical and translational development.We conclude that elevated circITGa9 levels drive cardiac remodeling and fibrosis.By pinpointing circITGa9 as a therapeutic target,we open doors to innovative interventions for mitigating cardiac remodeling and fibrosis.
基金supported by grants from Canadian Institutes of Health Research to BBY(PJT-153105,PJT-155962,and PJT-166107).
文摘Significant progress has been made in circular RNA(circRNA)research in recent years.Increasing evidence suggests that circRNAs play important roles in many cellular processes,and their dysregulation is implicated in the pathogenesis of various diseases.CircRNAs are highly stable and usually expressed in a tissue-or cell type-specific manner.Therefore,they are currently being explored as potential therapeutic targets.Gain-of-function and loss-of-function approaches are typically performed using circRNA expression plasmids and RNA interference-based strategies,respectively.These strategies have limitations that can be mitigated using nanoparticle and exosome delivery systems.Furthermore,recent developments show that the cre-lox system can be used to knockdown circRNAs in a cell-specific manner.While still in the early stages of development,the CRISPR/Cas13 system has shown promise in knocking down circRNAs with high specificity and efficiency.In this review,we describe circRNA properties and functions and highlight their significance in disease.We summarize strategies that can be used to overexpress or knockdown circRNAs as a therapeutic approach.Lastly,we discuss major challenges and propose future directions for the development of circRNA-based therapeutics.
