In this editorial,we highlight the study by Xiao et al.Despite progress in the management of diabetic foot ulcers(DFUs),impaired wound healing remains a significant clinical challenge.Recent studies have highlighted t...In this editorial,we highlight the study by Xiao et al.Despite progress in the management of diabetic foot ulcers(DFUs),impaired wound healing remains a significant clinical challenge.Recent studies have highlighted the critical role of epigenetic modifications in diabetic wound healing,with particular emphasis on DNA and RNA methylation pathways.This editorial discusses the findings of Xiao et al,who identified the Wilms tumor 1-associated protein(WTAP)-DNA methyltransferase 1(DNMT1)axis as a pivotal regulator of endothelial dys-function in DFUs.WTAP,a regulatory subunit of N6-methyladenosine(m6A)methyltransferase,is upregulated under high-glucose conditions and drives the excessive expression of DNMT1 via m6A modification.This contributes to im-paired angiogenesis,reduced cell viability,and delayed wound closure.WTAP knockdown restored endothelial function and significantly improved wound healing in a diabetic mouse model.Furthermore,DNMT1 overexpression ab-rogated the benefits of WTAP suppression,confirming its downstream effector role.Thus,targeting the WTAP-DNMT1 axis provides a new avenue for DFU management.Moreover,epigenetic interventions that modulate both the m6A and RNA methylation pathways could restore endothelial function and enhance tissue repair in patients with diabetes.展开更多
BACKGROUND Diabetic wound injury is a significant and common complication in individuals with diabetes.N6-methyladenosine(m6A)-related epigenetic regulation is widely involved in the pathogenesis of diabetes complicat...BACKGROUND Diabetic wound injury is a significant and common complication in individuals with diabetes.N6-methyladenosine(m6A)-related epigenetic regulation is widely involved in the pathogenesis of diabetes complications.However,the function of m6A methyltransferase Wilms tumor 1-associated protein(WTAP)in diabetic wound healing remains elusive.AIM To investigate the potential epigenetic regulatory mechanism of WTAP during diabetic wound healing.METHODS Human umbilical vein endothelial cells(HUVECs)were induced with high glucose(HG)to establish in vitro cell model.Male BALB/c mice were intraperitoneally injected with streptozotocin to mimic diabetes,and full-thickness excision was made to mimic diabetic wound healing.HG-induced HUVECs and mouse models were treated with WTAP siRNAs and DNA methyltransferase 1(DNMT1)overexpression vectors.Cell viability and migration ability were detected by cell counting kit-8 and Transwell assays.In vitro angiogenesis was measured using a tube formation experiment.The images of wounds were captured,and re-epithelialization and collagen deposition of skin tissues were analyzed using hematoxylin and eosin staining and Masson’s trichrome staining.RESULTS The expression of several m6A methyltransferases,including METTL3,METTL14,METTL16,KIAA1429,WTAP,and RBM15,were measured.WTAP exhibited the most significant elevation in HG-induced HUVECs compared with the normal control.WTAP depletion notably restored cell viability and enhanced tube formation ability and migration of HUVECs suppressed by HG.The unclosed wound area of mice was smaller in WTAP knockdowntreated mice than in control mice at nine days post-wounding,along with enhanced re-epithelialization rate and collagen deposition.The m6A levels on DNMT1 mRNA in HUVECs were repressed by WTAP knockdown in HUVECs.The mRNA levels and expression of DNMT1 were inhibited by WTAP depletion in HUVECs.Overexpression of DNMT1 in HUVECs notably reversed the effects of WTAP depletion on HG-induced HUVECs.CONCLUSION WTAP expression is elevated in HG-induced HUVECs and epigenetically regulates the m6A modification of DNMT1 to impair diabetic wound healing.展开更多
Messenger RNA （mRNA） turnover in eukaryotic cells begins with shortening of the poly （A） tail at the 3＇ end, a process called deadenylation. In yeast, the deadenylation reaction is predominantly mediated by CCR4 ...Messenger RNA （mRNA） turnover in eukaryotic cells begins with shortening of the poly （A） tail at the 3＇ end, a process called deadenylation. In yeast, the deadenylation reaction is predominantly mediated by CCR4 and CCR4- associated factor 1 （CAF1）, two components of the well-characterised protein complex named CCR4-NOT. We report here that AtCAF1a and AtCAF1b, putative Arabidopsis homologs of the yeast CAF1 gene, partially complement the growth defect of the yeast call mutant in the presence of caffeine or at high temperatures. The expression of At-CAF1a and AtCAFlb is induced by multiple stress-related hormones and stimuli. Both AtCAF1a and AtCAFlb show deadenylation activity in vitro and point mutations in the predicted active sites disrupt this activity. T-DNA insertion mutants disrupting the expression of AtCAF1a and/or AtCAF1b are defective in deadenylation of stress-related mRNAs, indicating that the two AtCAF1 proteins are involved in regulated mRNA deadenylation in vivo. Interestingly, the single and double mutants of AtCAF1a and AtCAFlb show reduced expression of pathogenesis-related （PR） genes PR1 and PR2 and are more susceptible to Pseudomonas syringae pv tomato DC3000 （Pst DC3000） infection, whereas transgenic plants over-expressing AtCAFla show elevated expression of PR1 and PR2 and increased resis-tance to the same pathogen. Our results suggest roles of the AtCAF1 proteins in regulated mRNA deadenylation and defence responses to pathogen infections.展开更多
Human T-cell lymphotropic virus type 1(HTLV-1)is associated with the development of HTLV-1-associated myelopathy/tropical spastic paraparesis(HAM/TSP).It has been reported that the HTLV-1 proteins(specifically TAX and...Human T-cell lymphotropic virus type 1(HTLV-1)is associated with the development of HTLV-1-associated myelopathy/tropical spastic paraparesis(HAM/TSP).It has been reported that the HTLV-1 proteins(specifically TAX and HBZ)can modulate FOXp3,resulting in an immune imbalance that can favor the progression of HAM/TSP.This review aims to summarize the literature in order to clarify the relationship between the expression of HTLV-1 m RNAs and/or viral proteins(TAX and HBZ)with the expression of mRNA and/or protein FOXp3 and their correlation with HAM/TSP development.This systematic review was conducted according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis.The search strategy was performed on the Medical Literature Analysis and Retrieval System Online and Latin American and Caribbean Literature in Health Sciences Platform using subject descriptors.After screening,six articles were included in this review.The studies suggested that TAX and HBZ have a directly proportional correlation with FOXp3 in individuals with HAM/TSP,which also presented an increased expression of FOXp3 compared to asymptomatic controls and/or healthy donors.This systematic review indicates that TAX and HBZ can interact with FOXp3 and that interaction may influence HAM/TSP development.展开更多
Human T-cell lymphotropic virus type 1(HTLV-1)-associated myelopathy/tropical spastic paraparesis(HAM/TSP) is a slowly progressive neurodegenerative disorder in which lesions of the central nervous system cause progre...Human T-cell lymphotropic virus type 1(HTLV-1)-associated myelopathy/tropical spastic paraparesis(HAM/TSP) is a slowly progressive neurodegenerative disorder in which lesions of the central nervous system cause progressive weakness, stiffness, and a lower limb spastic paraparesis. In some cases, polymyositis, inclusion bodymyositis, or amyotrophic lateral sclerosis-like syndromes are associated with HTLV-1. TSP was first described in Jamaica in 1888 and known as Jamaican peripheral neuritis before TSP was related to HTLV-1 virus, the first retrovirus being identified, and the disease is since named HAM/TSP. There is no established treatment program for HAM/TSP. Prevention is difficult in lowincome patients(i.e., HTLV-1 infected breast feeding mothers in rural areas, sex workers). Thus, there is a need for new therapeutic avenues. Therapeutic approaches must be based on a better understanding, not only of clinical and clinicopathological data, but also of the pathophysiology of the affection. Consequently, a better understanding of existing or newly developed animal models of HAM/TSP is a prerequisite step in the development of new treatments.展开更多
Background:The DNA damage repair mechanism plays a crucial role in the occurrence and development of hepatocellular carcinoma(HCC),and RAD51-associated protein 1(RAD51AP1)has received increasing attention as an import...Background:The DNA damage repair mechanism plays a crucial role in the occurrence and development of hepatocellular carcinoma(HCC),and RAD51-associated protein 1(RAD51AP1)has received increasing attention as an important protein in the homologous recombination repair pathway.However,the role of RAD51AP1 and its molecular regulatory mechanism in HCC still need further investigation.Methods:We first analysed RAD51AP1 expression,functional enrichment and prognostic value in HCC.Then,the miRWalk,miRDB,and Encyclopedia of RNA Interactomes databases were used to predict the corresponding microRNAs and long noncoding RNAs of RAD51AP1,and their expression levels and prognostic value were analysed.Results:RAD51AP1 was upregulated in the majority of cancers include HCC.The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that RAD51AP1 was mainly involved in pathways related to the cell cycle and repair in HCC.Moreover,the expression level of RAD51AP1 was significantly correlated with T stage,pathologic stage,histologic grade and the level of alpha-fetoprotein.In addition,RAD51AP1 was an independent risk factor significantly and had a high predictive value in HCC.Based on ceRNA network,RAD51AP1 may be regulated by upstream MSC-AS1 and hsa-miR-23c to affect the HCC occurrence and development.Conclusions:High expression of RAD51AP1 plays an important biological role in the cell cycle and repair pathways,and has important diagnostic and prognostic value in HCC.Based on the regulatory mechanism of ceRNA network,we speculate that lncRNA MSC-AS1 acts on hsa-miR-23c and regulates DNA damage repair of HCC through RAD51AP1.It provides a new perspective for further study of DNA damage repair mechanism and potential related treatment of HCC.展开更多
基金Supported by the Kuwait Foundation for the Advancement of Sciences and Dasman Diabetes Institute,No.RACB-2021-007.
文摘In this editorial,we highlight the study by Xiao et al.Despite progress in the management of diabetic foot ulcers(DFUs),impaired wound healing remains a significant clinical challenge.Recent studies have highlighted the critical role of epigenetic modifications in diabetic wound healing,with particular emphasis on DNA and RNA methylation pathways.This editorial discusses the findings of Xiao et al,who identified the Wilms tumor 1-associated protein(WTAP)-DNA methyltransferase 1(DNMT1)axis as a pivotal regulator of endothelial dys-function in DFUs.WTAP,a regulatory subunit of N6-methyladenosine(m6A)methyltransferase,is upregulated under high-glucose conditions and drives the excessive expression of DNMT1 via m6A modification.This contributes to im-paired angiogenesis,reduced cell viability,and delayed wound closure.WTAP knockdown restored endothelial function and significantly improved wound healing in a diabetic mouse model.Furthermore,DNMT1 overexpression ab-rogated the benefits of WTAP suppression,confirming its downstream effector role.Thus,targeting the WTAP-DNMT1 axis provides a new avenue for DFU management.Moreover,epigenetic interventions that modulate both the m6A and RNA methylation pathways could restore endothelial function and enhance tissue repair in patients with diabetes.
文摘BACKGROUND Diabetic wound injury is a significant and common complication in individuals with diabetes.N6-methyladenosine(m6A)-related epigenetic regulation is widely involved in the pathogenesis of diabetes complications.However,the function of m6A methyltransferase Wilms tumor 1-associated protein(WTAP)in diabetic wound healing remains elusive.AIM To investigate the potential epigenetic regulatory mechanism of WTAP during diabetic wound healing.METHODS Human umbilical vein endothelial cells(HUVECs)were induced with high glucose(HG)to establish in vitro cell model.Male BALB/c mice were intraperitoneally injected with streptozotocin to mimic diabetes,and full-thickness excision was made to mimic diabetic wound healing.HG-induced HUVECs and mouse models were treated with WTAP siRNAs and DNA methyltransferase 1(DNMT1)overexpression vectors.Cell viability and migration ability were detected by cell counting kit-8 and Transwell assays.In vitro angiogenesis was measured using a tube formation experiment.The images of wounds were captured,and re-epithelialization and collagen deposition of skin tissues were analyzed using hematoxylin and eosin staining and Masson’s trichrome staining.RESULTS The expression of several m6A methyltransferases,including METTL3,METTL14,METTL16,KIAA1429,WTAP,and RBM15,were measured.WTAP exhibited the most significant elevation in HG-induced HUVECs compared with the normal control.WTAP depletion notably restored cell viability and enhanced tube formation ability and migration of HUVECs suppressed by HG.The unclosed wound area of mice was smaller in WTAP knockdowntreated mice than in control mice at nine days post-wounding,along with enhanced re-epithelialization rate and collagen deposition.The m6A levels on DNMT1 mRNA in HUVECs were repressed by WTAP knockdown in HUVECs.The mRNA levels and expression of DNMT1 were inhibited by WTAP depletion in HUVECs.Overexpression of DNMT1 in HUVECs notably reversed the effects of WTAP depletion on HG-induced HUVECs.CONCLUSION WTAP expression is elevated in HG-induced HUVECs and epigenetically regulates the m6A modification of DNMT1 to impair diabetic wound healing.
文摘Messenger RNA （mRNA） turnover in eukaryotic cells begins with shortening of the poly （A） tail at the 3＇ end, a process called deadenylation. In yeast, the deadenylation reaction is predominantly mediated by CCR4 and CCR4- associated factor 1 （CAF1）, two components of the well-characterised protein complex named CCR4-NOT. We report here that AtCAF1a and AtCAF1b, putative Arabidopsis homologs of the yeast CAF1 gene, partially complement the growth defect of the yeast call mutant in the presence of caffeine or at high temperatures. The expression of At-CAF1a and AtCAFlb is induced by multiple stress-related hormones and stimuli. Both AtCAF1a and AtCAFlb show deadenylation activity in vitro and point mutations in the predicted active sites disrupt this activity. T-DNA insertion mutants disrupting the expression of AtCAF1a and/or AtCAF1b are defective in deadenylation of stress-related mRNAs, indicating that the two AtCAF1 proteins are involved in regulated mRNA deadenylation in vivo. Interestingly, the single and double mutants of AtCAF1a and AtCAFlb show reduced expression of pathogenesis-related （PR） genes PR1 and PR2 and are more susceptible to Pseudomonas syringae pv tomato DC3000 （Pst DC3000） infection, whereas transgenic plants over-expressing AtCAFla show elevated expression of PR1 and PR2 and increased resis-tance to the same pathogen. Our results suggest roles of the AtCAF1 proteins in regulated mRNA deadenylation and defence responses to pathogen infections.
基金funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico(426196/2018-0)supported by a scholarship from the Conselho Nacional de Desenvolvimento Científico e Tecnológico(127049/2019-3 and 115208/2020-8)
文摘Human T-cell lymphotropic virus type 1(HTLV-1)is associated with the development of HTLV-1-associated myelopathy/tropical spastic paraparesis(HAM/TSP).It has been reported that the HTLV-1 proteins(specifically TAX and HBZ)can modulate FOXp3,resulting in an immune imbalance that can favor the progression of HAM/TSP.This review aims to summarize the literature in order to clarify the relationship between the expression of HTLV-1 m RNAs and/or viral proteins(TAX and HBZ)with the expression of mRNA and/or protein FOXp3 and their correlation with HAM/TSP development.This systematic review was conducted according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis.The search strategy was performed on the Medical Literature Analysis and Retrieval System Online and Latin American and Caribbean Literature in Health Sciences Platform using subject descriptors.After screening,six articles were included in this review.The studies suggested that TAX and HBZ have a directly proportional correlation with FOXp3 in individuals with HAM/TSP,which also presented an increased expression of FOXp3 compared to asymptomatic controls and/or healthy donors.This systematic review indicates that TAX and HBZ can interact with FOXp3 and that interaction may influence HAM/TSP development.
文摘Human T-cell lymphotropic virus type 1(HTLV-1)-associated myelopathy/tropical spastic paraparesis(HAM/TSP) is a slowly progressive neurodegenerative disorder in which lesions of the central nervous system cause progressive weakness, stiffness, and a lower limb spastic paraparesis. In some cases, polymyositis, inclusion bodymyositis, or amyotrophic lateral sclerosis-like syndromes are associated with HTLV-1. TSP was first described in Jamaica in 1888 and known as Jamaican peripheral neuritis before TSP was related to HTLV-1 virus, the first retrovirus being identified, and the disease is since named HAM/TSP. There is no established treatment program for HAM/TSP. Prevention is difficult in lowincome patients(i.e., HTLV-1 infected breast feeding mothers in rural areas, sex workers). Thus, there is a need for new therapeutic avenues. Therapeutic approaches must be based on a better understanding, not only of clinical and clinicopathological data, but also of the pathophysiology of the affection. Consequently, a better understanding of existing or newly developed animal models of HAM/TSP is a prerequisite step in the development of new treatments.
基金the financial support from Shandong Traditional Chinese Medicine Science and Technology Project(No.2020M139)the Scientific Research Project of Shandong College of Traditional Chinese Medicine(No.2021FY02)the Development Plan of Laizhou Science and Technology Project(No.2022L01).
文摘Background:The DNA damage repair mechanism plays a crucial role in the occurrence and development of hepatocellular carcinoma(HCC),and RAD51-associated protein 1(RAD51AP1)has received increasing attention as an important protein in the homologous recombination repair pathway.However,the role of RAD51AP1 and its molecular regulatory mechanism in HCC still need further investigation.Methods:We first analysed RAD51AP1 expression,functional enrichment and prognostic value in HCC.Then,the miRWalk,miRDB,and Encyclopedia of RNA Interactomes databases were used to predict the corresponding microRNAs and long noncoding RNAs of RAD51AP1,and their expression levels and prognostic value were analysed.Results:RAD51AP1 was upregulated in the majority of cancers include HCC.The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that RAD51AP1 was mainly involved in pathways related to the cell cycle and repair in HCC.Moreover,the expression level of RAD51AP1 was significantly correlated with T stage,pathologic stage,histologic grade and the level of alpha-fetoprotein.In addition,RAD51AP1 was an independent risk factor significantly and had a high predictive value in HCC.Based on ceRNA network,RAD51AP1 may be regulated by upstream MSC-AS1 and hsa-miR-23c to affect the HCC occurrence and development.Conclusions:High expression of RAD51AP1 plays an important biological role in the cell cycle and repair pathways,and has important diagnostic and prognostic value in HCC.Based on the regulatory mechanism of ceRNA network,we speculate that lncRNA MSC-AS1 acts on hsa-miR-23c and regulates DNA damage repair of HCC through RAD51AP1.It provides a new perspective for further study of DNA damage repair mechanism and potential related treatment of HCC.
