AIM:To examine the regulatory role of microRNA-204(miR-204)on silent information regulator 1(SIRT1)and vascular endothelial growth factor(VEGF)under highglucose-induced metabolic memory in human retinal pigment epithe...AIM:To examine the regulatory role of microRNA-204(miR-204)on silent information regulator 1(SIRT1)and vascular endothelial growth factor(VEGF)under highglucose-induced metabolic memory in human retinal pigment epithelial(hRPE)cells.METHODS:Cells were cultured with either normal(5 mmol/L)or high D-glucose(25 mmol/L)concentrations for 8d to establish control and high-glucose groups,respectively.To induce metabolic memory,cells were cultured with 25 mmol/L D-glucose for 4d followed by culture with 5 mmol/L D-glucose for 4d.In addition,exposed in 25 mmol/L D-glucose for 4d and then transfected with 100 nmol/L miR-204 control,miR-204 inhibitor or miR-204 mimic in 5 mmol/L D-glucose for 4d.Quantitative reverse transcription-polymerase chain reaction(RT-qPCR)was used to detect miR-204 mRNA levels.SIRT1 and VEGF protein levels were assessed by immunohistochemical and Western blot.Flow cytometry was used to investigate apoptosis rate.RESULTS:It was found that high glucose promoted miR-204 and VEGF expression,and inhibited SIRT1 activity,even after the return to normal glucose culture conditions.Upregulation of miR-204 promoted apoptosis inhibiting SIRT1 and increasing VEGF expression.However,downregulation of miR-204 produced the opposite effects.CONCLUSION:The study identifies that miR-204 is the upstream target of SIRT1and VEGF,and that miR-204 can protect hRPE cells from the damage caused by metabolic memory through increasing SIRT1 and inhibiting VEGF expression.展开更多
Epigenetics focuses on DNA methylation,histone modification,chromatin remodeling,noncoding RNAs,and other gene regulation mechanisms beyond the DNA sequence.In the past decade,epigenetic modifications have drawn more ...Epigenetics focuses on DNA methylation,histone modification,chromatin remodeling,noncoding RNAs,and other gene regulation mechanisms beyond the DNA sequence.In the past decade,epigenetic modifications have drawn more attention as they participate in the development and progression of diabetic retinopathy despite tight control of glucose levels.The underlying mechanisms of epigenetic modifications in diabetic retinopathy still urgently need to be elucidated.The diabetic condition facilitates epigenetic changes and influences target gene expression.In this review,we summarize the involvement of epigenetic modifications and metabolic memory in the development and progression of diabetic retinopathy and propose novel insights into the treatment of diabetic retinopathy.展开更多
Diabetic kidney disease(DKD)is a clinical syndrome that is one of the major causes of end-stage renal disease(ESRD).The pathogenesis of DKD is complex and multifaceted,with most studies indicating its association with...Diabetic kidney disease(DKD)is a clinical syndrome that is one of the major causes of end-stage renal disease(ESRD).The pathogenesis of DKD is complex and multifaceted,with most studies indicating its association with genetics,advanced glycosylation end-product deposition,polyol pathway and protein C activation,lipid metabolism abnormalities,microcirculatory dysfunction,oxidative stress,inflammatory factors,and the kallikrein-kinin system.Epigenetics is the science studying gene expression regulation without changes in the DNA sequence.In recent years,increasing evidence has shown that epigenetic mechanisms play a crucial role in the initiation and progression of DKD.For instance,epigenetic modifications such as DNA methylation,histone modifications,and non-coding RNAs can influence the expression of DKD-related genes,thereby regulating the development and progression of DKD.On the other hand,metabolic memory is an important concept in DKD research.Metabolic memory refers to the phenomenon where cells maintain a certain metabolic state even after the disappearance of metabolic stress factors.This state can influence cell function and fate.In DKD,metabolic stress factors such as hyperglycemia can lead to metabolic memory in renal cells,affecting their function and fate,ultimately leading to the development and progression of DKD.Therefore,to further explore the pathogenesis of DKD,research on epigenetics should be strengthened,aiming to provide new ideas and methods for the prevention and treatment of DKD.展开更多
In the past decades,a persistent progression of diabetic vascular complications despite reversal of hyperglycemia has been observed in both experimental and clinical studies.This durable effect of prior hyperglycemia ...In the past decades,a persistent progression of diabetic vascular complications despite reversal of hyperglycemia has been observed in both experimental and clinical studies.This durable effect of prior hyperglycemia on the initiation and progression of diabetic vasculopathies was defined as"metabolic memory".Subsequently,enhanced glycation of cellular proteins and lipids,sustained oxidative stress,and prolonged inflammation were demonstrated to mediate this phenomenon.Recently,emerging evidence strongly suggests that epigenetic modifications may account for the molecular and phenotypic changes associated with hyperglycemic memory.In this review,we presented an overview on the discovery of metabolic memory,the recent progress in its molecular mechanisms,and the future implications related to its fundamental research and clinical application.展开更多
Diabetic neuropathy (DN) and impaired wound healing in diabetic foot ulcers(DFUs) are major complications of diabetes mellitus, driven by complex molecularmechanisms, including epigenetic modifications. Recent researc...Diabetic neuropathy (DN) and impaired wound healing in diabetic foot ulcers(DFUs) are major complications of diabetes mellitus, driven by complex molecularmechanisms, including epigenetic modifications. Recent research highlights therole of epigenetic markers including DNA methylation, histone modifications,and non-coding RNAs in regulating inflammatory responses, neuronal degeneration,and tissue repair. This review explores the epigenetics of DN and DFUs,emphasizing key regulatory pathways that influence disease progression andwound healing outcomes. Genome-wide DNA methylation studies reveal acceleratedepigenetic aging and metabolic memory effects in DN, contributing tosensory neuron dysfunction and neuropathic pain. Epigenetic dysregulation ofinflammatory mediators such as Toll-like receptors and the Nod-like receptorfamily, pyrin domain-containing 3 inflammasome further exacerbates neuronaldamage and delays wound healing. Additionally, histone deacetylases play apivotal role in oxidative stress regulation via the Nrf2 pathway, which is critical for both neuronal protection and angiogenesis in DFUs. Non-coding RNAs, particularly microRNAs (miRNAs),long non-coding RNAs (lncRNAs), and circular RNAs, are emerging as central regulators of the epigeneticcrosstalk between DN and DFUs. Several miRNAs, including miR-146a-5p and miR-518d-3p, are implicated inneuropathy severity, while lncRNAs such as nuclear enriched abundant transcript 1 modulate angiogenesis andwound repair. Cellular reprogramming of DFU fibroblasts has also been shown to induce pro-healing miRNAsignatures, offering potential therapeutic avenues. Furthermore, recent whole-genome and transcriptomic analysesof DFU-derived monocytes and Charcot foot lesions reveal unique epigenetic signatures that may serve as biomarkersfor early detection and personalized interventions. This epigenetic interplay between DN and DFUpathogenesis not only enhances our knowledge of disease mechanisms but also opens avenues for targetedepigenetic therapies to improve clinical outcomes.展开更多
Diabetic retinopathy(DR)is a major microvascular complication of diabetes,with its pathogenesis involving metabolic memory,epigenetic dysregulation,and multi-cellular microenvironmental disorders.This study systematic...Diabetic retinopathy(DR)is a major microvascular complication of diabetes,with its pathogenesis involving metabolic memory,epigenetic dysregulation,and multi-cellular microenvironmental disorders.This study systematically invest-igates the mechanism by which curcumol ameliorates DR through regulation of the FTO/MAFG-AS1 epigenetic axis and reveals its therapeutic potential in tar-geting the retinal microenvironment via a nano-delivery system.Experimental results demonstrate that curcumol activates the demethylase activity of FTO,sta-bilizing the expression of the long non-coding RNA MAFG-AS1,thereby inhi-biting high glucose-induced retinal endothelial cell inflammation,migration,and vascular leakage.Single-cell transcriptomic analysis further uncovered the dual role of FTO in DR:On the one hand,it promotes pathological angiogenesis in endothelial cells,while on the other hand,it exerts protective effects through MAFG-AS1-mediated antioxidative and anti-inflammatory functions.Moreover,this study proposes a multidimensional epigenetic regulatory network based on histone lactylation,N6-methyladenosine modification,and DNA methylation,and verifies that curcumol delays DR progression by coordinately modulating these modifications.To overcome the limitations of conventional therapies,this study innovatively designed a macrophage membrane-coated nano-delivery system,significantly enhancing the retinal targeting and bioavailability of curcumol.Finally,the study advocates a paradigm shift from passive treatment to early prevention,proposing a three-tiered intervention strategy that integrates epigenetic biomarkers with artificial intelligence-based risk assessment.These findings not only elucidate the multi-target regulatory mechanisms of curcumol but also provide a theoretical foundation for the development of precision therapies for DR based on epigenetic remodeling and microenvironmental synergistic intervention.展开更多
Cardiovascular disease including stroke is a major complication that tremendously increases the morbidity and mortality in patients with diabetes mellitus(DM). DM poses about four times higher risk for stroke. Cardiom...Cardiovascular disease including stroke is a major complication that tremendously increases the morbidity and mortality in patients with diabetes mellitus(DM). DM poses about four times higher risk for stroke. Cardiometabolic risk factors including obesity, hypertension, and dyslipidaemia often co-exist in patients with DM that add on to stroke risk. Because of the strong association between DM and other stroke risk factors, physicians and diabetologists managing patients should have thorough understanding of these risk factors and management. This review is an evidence-based approach to the epidemiological aspects, pathophysiology, diagnostic work up and management algorithms for patients with diabetes and stroke.展开更多
基金Supported by the Training Project for Young and Middleaged Core Talents in Health System of Fujian Province(No.2016-ZQN-62)Natural Science Foundation of Fujian Province(No.2020J01652).
文摘AIM:To examine the regulatory role of microRNA-204(miR-204)on silent information regulator 1(SIRT1)and vascular endothelial growth factor(VEGF)under highglucose-induced metabolic memory in human retinal pigment epithelial(hRPE)cells.METHODS:Cells were cultured with either normal(5 mmol/L)or high D-glucose(25 mmol/L)concentrations for 8d to establish control and high-glucose groups,respectively.To induce metabolic memory,cells were cultured with 25 mmol/L D-glucose for 4d followed by culture with 5 mmol/L D-glucose for 4d.In addition,exposed in 25 mmol/L D-glucose for 4d and then transfected with 100 nmol/L miR-204 control,miR-204 inhibitor or miR-204 mimic in 5 mmol/L D-glucose for 4d.Quantitative reverse transcription-polymerase chain reaction(RT-qPCR)was used to detect miR-204 mRNA levels.SIRT1 and VEGF protein levels were assessed by immunohistochemical and Western blot.Flow cytometry was used to investigate apoptosis rate.RESULTS:It was found that high glucose promoted miR-204 and VEGF expression,and inhibited SIRT1 activity,even after the return to normal glucose culture conditions.Upregulation of miR-204 promoted apoptosis inhibiting SIRT1 and increasing VEGF expression.However,downregulation of miR-204 produced the opposite effects.CONCLUSION:The study identifies that miR-204 is the upstream target of SIRT1and VEGF,and that miR-204 can protect hRPE cells from the damage caused by metabolic memory through increasing SIRT1 and inhibiting VEGF expression.
基金supported by the National Natural Science Foundation of China,No.82171062(to JFZ)Aier Eye Hospital Group Scientific Research Fund,No.AF2101D8(to LMG).
文摘Epigenetics focuses on DNA methylation,histone modification,chromatin remodeling,noncoding RNAs,and other gene regulation mechanisms beyond the DNA sequence.In the past decade,epigenetic modifications have drawn more attention as they participate in the development and progression of diabetic retinopathy despite tight control of glucose levels.The underlying mechanisms of epigenetic modifications in diabetic retinopathy still urgently need to be elucidated.The diabetic condition facilitates epigenetic changes and influences target gene expression.In this review,we summarize the involvement of epigenetic modifications and metabolic memory in the development and progression of diabetic retinopathy and propose novel insights into the treatment of diabetic retinopathy.
文摘Diabetic kidney disease(DKD)is a clinical syndrome that is one of the major causes of end-stage renal disease(ESRD).The pathogenesis of DKD is complex and multifaceted,with most studies indicating its association with genetics,advanced glycosylation end-product deposition,polyol pathway and protein C activation,lipid metabolism abnormalities,microcirculatory dysfunction,oxidative stress,inflammatory factors,and the kallikrein-kinin system.Epigenetics is the science studying gene expression regulation without changes in the DNA sequence.In recent years,increasing evidence has shown that epigenetic mechanisms play a crucial role in the initiation and progression of DKD.For instance,epigenetic modifications such as DNA methylation,histone modifications,and non-coding RNAs can influence the expression of DKD-related genes,thereby regulating the development and progression of DKD.On the other hand,metabolic memory is an important concept in DKD research.Metabolic memory refers to the phenomenon where cells maintain a certain metabolic state even after the disappearance of metabolic stress factors.This state can influence cell function and fate.In DKD,metabolic stress factors such as hyperglycemia can lead to metabolic memory in renal cells,affecting their function and fate,ultimately leading to the development and progression of DKD.Therefore,to further explore the pathogenesis of DKD,research on epigenetics should be strengthened,aiming to provide new ideas and methods for the prevention and treatment of DKD.
基金supported by the National Natural Science Foundation of China(91339103)
文摘In the past decades,a persistent progression of diabetic vascular complications despite reversal of hyperglycemia has been observed in both experimental and clinical studies.This durable effect of prior hyperglycemia on the initiation and progression of diabetic vasculopathies was defined as"metabolic memory".Subsequently,enhanced glycation of cellular proteins and lipids,sustained oxidative stress,and prolonged inflammation were demonstrated to mediate this phenomenon.Recently,emerging evidence strongly suggests that epigenetic modifications may account for the molecular and phenotypic changes associated with hyperglycemic memory.In this review,we presented an overview on the discovery of metabolic memory,the recent progress in its molecular mechanisms,and the future implications related to its fundamental research and clinical application.
文摘Diabetic neuropathy (DN) and impaired wound healing in diabetic foot ulcers(DFUs) are major complications of diabetes mellitus, driven by complex molecularmechanisms, including epigenetic modifications. Recent research highlights therole of epigenetic markers including DNA methylation, histone modifications,and non-coding RNAs in regulating inflammatory responses, neuronal degeneration,and tissue repair. This review explores the epigenetics of DN and DFUs,emphasizing key regulatory pathways that influence disease progression andwound healing outcomes. Genome-wide DNA methylation studies reveal acceleratedepigenetic aging and metabolic memory effects in DN, contributing tosensory neuron dysfunction and neuropathic pain. Epigenetic dysregulation ofinflammatory mediators such as Toll-like receptors and the Nod-like receptorfamily, pyrin domain-containing 3 inflammasome further exacerbates neuronaldamage and delays wound healing. Additionally, histone deacetylases play apivotal role in oxidative stress regulation via the Nrf2 pathway, which is critical for both neuronal protection and angiogenesis in DFUs. Non-coding RNAs, particularly microRNAs (miRNAs),long non-coding RNAs (lncRNAs), and circular RNAs, are emerging as central regulators of the epigeneticcrosstalk between DN and DFUs. Several miRNAs, including miR-146a-5p and miR-518d-3p, are implicated inneuropathy severity, while lncRNAs such as nuclear enriched abundant transcript 1 modulate angiogenesis andwound repair. Cellular reprogramming of DFU fibroblasts has also been shown to induce pro-healing miRNAsignatures, offering potential therapeutic avenues. Furthermore, recent whole-genome and transcriptomic analysesof DFU-derived monocytes and Charcot foot lesions reveal unique epigenetic signatures that may serve as biomarkersfor early detection and personalized interventions. This epigenetic interplay between DN and DFUpathogenesis not only enhances our knowledge of disease mechanisms but also opens avenues for targetedepigenetic therapies to improve clinical outcomes.
基金Supported by Quzhou Science and Technology Plan Project,No.2024K076.
文摘Diabetic retinopathy(DR)is a major microvascular complication of diabetes,with its pathogenesis involving metabolic memory,epigenetic dysregulation,and multi-cellular microenvironmental disorders.This study systematically invest-igates the mechanism by which curcumol ameliorates DR through regulation of the FTO/MAFG-AS1 epigenetic axis and reveals its therapeutic potential in tar-geting the retinal microenvironment via a nano-delivery system.Experimental results demonstrate that curcumol activates the demethylase activity of FTO,sta-bilizing the expression of the long non-coding RNA MAFG-AS1,thereby inhi-biting high glucose-induced retinal endothelial cell inflammation,migration,and vascular leakage.Single-cell transcriptomic analysis further uncovered the dual role of FTO in DR:On the one hand,it promotes pathological angiogenesis in endothelial cells,while on the other hand,it exerts protective effects through MAFG-AS1-mediated antioxidative and anti-inflammatory functions.Moreover,this study proposes a multidimensional epigenetic regulatory network based on histone lactylation,N6-methyladenosine modification,and DNA methylation,and verifies that curcumol delays DR progression by coordinately modulating these modifications.To overcome the limitations of conventional therapies,this study innovatively designed a macrophage membrane-coated nano-delivery system,significantly enhancing the retinal targeting and bioavailability of curcumol.Finally,the study advocates a paradigm shift from passive treatment to early prevention,proposing a three-tiered intervention strategy that integrates epigenetic biomarkers with artificial intelligence-based risk assessment.These findings not only elucidate the multi-target regulatory mechanisms of curcumol but also provide a theoretical foundation for the development of precision therapies for DR based on epigenetic remodeling and microenvironmental synergistic intervention.
文摘Cardiovascular disease including stroke is a major complication that tremendously increases the morbidity and mortality in patients with diabetes mellitus(DM). DM poses about four times higher risk for stroke. Cardiometabolic risk factors including obesity, hypertension, and dyslipidaemia often co-exist in patients with DM that add on to stroke risk. Because of the strong association between DM and other stroke risk factors, physicians and diabetologists managing patients should have thorough understanding of these risk factors and management. This review is an evidence-based approach to the epidemiological aspects, pathophysiology, diagnostic work up and management algorithms for patients with diabetes and stroke.
