Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The...Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The long noncoding RNA growth arrest-specific 5(GAS5) is a member of the 5′-terminal oligopyrimidine gene family that may be involved in neurological disorders, but its role in Alzheimer's disease remains unclear. This study aimed to investigate the function of GAS5 and construct a GAS5-associated competitive endogenous RNA network comprising potential targets. RNA sequencing results showed that GAS5 was upregulated in five familial Alzheimer's disease(5×FAD) mice, APPswe/PSEN1dE9(APP/PS1) mice, Alzheimer's disease-related APPswe cells, and serum from patients with Alzheimer's disease. Functional experiments with targeted overexpression and silencing demonstrated that GAS5 played a role in cognitive dysfunction and multiple Alzheimer's disease-associated pathologies, including tau hyperphosphorylation, amyloid-beta accumulation, and neuronal apoptosis. Mechanistic studies indicated that GAS5 acted as an endogenous sponge by competing for microRNA-23b-3p(miR-23b-3p) binding to regulate its targets glycogen synthase kinase 3beta(GSK-3β) and phosphatase and tensin homologue deleted on chromosome 10(PTEN) expression in an Argonaute 2-induced RNA silencing complex(RISC)-dependent manner. GAS5 inhibited miR-23b-3p-mediated GSK-3β and PTEN cascades with a feedforward PTEN/protein kinase B(Akt)/GSK-3β linkage. Furthermore, recovery of GAS5/miR-23b-3p/GSK-3β/PTEN pathways relieved Alzheimer's disease-like symptoms in vivo, indicated by the amelioration of spatial cognition, neuronal degeneration, amyloid-beta load, and tau phosphorylation. Together, these findings suggest that GAS5 promotes Alzheimer's disease pathogenesis. This study establishes the functional convergence of the GAS5/miR-23b-3p/GSK-3β/PTEN pathway on multiple pathologies, suggesting a candidate therapeutic target in Alzheimer's disease.展开更多
BACKGROUND Diabetic cardiomyopathy(DCM)is the leading cause of cardiovascular diseaserelated mortality.Farrerol(FA)possesses anti-inflammatory and antioxidant properties.However,its role in regulating endothelial ferr...BACKGROUND Diabetic cardiomyopathy(DCM)is the leading cause of cardiovascular diseaserelated mortality.Farrerol(FA)possesses anti-inflammatory and antioxidant properties.However,its role in regulating endothelial ferroptosis in DCM remains unknown.AIM To investigate the beneficial effects of FA on cardiac microvascular dysfunction in DCM from the perspective of ferroptosis in endothelial cells(ECs).METHODS The mice were fed a high-fat diet and injected with streptozotocin to induce DCM.DCM mice were orally administered FA(10 and 40 mg/kg/day)and a tail vein injection of the miR-29b-3p mimic or inhibitor for 24 weeks.Cardiac function and myocardial fibrosis were also analyzed.Cardiac microvascular function was assessed using immunofluorescence and transmission electron microscopy.Ferroptosis was analyzed using RNA sequencing,immunofluorescence,and western blotting.RESULTS FA administration improved cardiac function,alleviated myocardial fibrosis,strengthened endothelial barrier function,suppressed endothelial inflammation,and preserved the microvascular structure in DCM mice.This improvement was associated with the inhibition of endothelial ferroptosis and downregulation of miR-29b-3p in ECs.Similar efficacy was observed after tail vein injection of the miR-29b-3p inhibitor.Inhibition of miR-29b-3p in vivo showed an anti-cardiac fibrotic effect by improving microvascular dysfunction and ferroptosis in ECs,whereas overexpression of miR-29b-3p showed the opposite effects in DCM mice.Luciferase reporter assay revealed that miR-29b-3p binds to SIRT1.In cultured ECs,FA reduced high glucose and free fatty acid(HG/FFA)-induced lipid peroxidation and ferroptosis and inhibited endothelial-mediated inflammation.However,the overexpression of miR-29b-3p partially abolished the protective effects of FA against HG/FFA-induced injury in ECs.This finding suggests that the mechanism of action of FA in improving DCM is related to the downregulation of miR-29b-3p and activation of SIRT1 expression.CONCLUSION Therefore,FA has a potential therapeutic effect on cardiac microvascular dysfunction by suppressing EC ferroptosis through the miR-29b-3p/SIRT1 axis.展开更多
基金supported by the National Natural Science Foundation of China,Nos. 82173806 and U1803281Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science,Nos. 2021-I2M-1-030 and 2022-I2M-2-002Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences,No. 2022-JKCS-08 (all to RL)。
文摘Long noncoding RNA and microRNA are regulatory noncoding RNAs that are implicated in Alzheimer's disease, but the role of long noncoding RNA-associated competitive endogenous RNA has not been fully elucidated. The long noncoding RNA growth arrest-specific 5(GAS5) is a member of the 5′-terminal oligopyrimidine gene family that may be involved in neurological disorders, but its role in Alzheimer's disease remains unclear. This study aimed to investigate the function of GAS5 and construct a GAS5-associated competitive endogenous RNA network comprising potential targets. RNA sequencing results showed that GAS5 was upregulated in five familial Alzheimer's disease(5×FAD) mice, APPswe/PSEN1dE9(APP/PS1) mice, Alzheimer's disease-related APPswe cells, and serum from patients with Alzheimer's disease. Functional experiments with targeted overexpression and silencing demonstrated that GAS5 played a role in cognitive dysfunction and multiple Alzheimer's disease-associated pathologies, including tau hyperphosphorylation, amyloid-beta accumulation, and neuronal apoptosis. Mechanistic studies indicated that GAS5 acted as an endogenous sponge by competing for microRNA-23b-3p(miR-23b-3p) binding to regulate its targets glycogen synthase kinase 3beta(GSK-3β) and phosphatase and tensin homologue deleted on chromosome 10(PTEN) expression in an Argonaute 2-induced RNA silencing complex(RISC)-dependent manner. GAS5 inhibited miR-23b-3p-mediated GSK-3β and PTEN cascades with a feedforward PTEN/protein kinase B(Akt)/GSK-3β linkage. Furthermore, recovery of GAS5/miR-23b-3p/GSK-3β/PTEN pathways relieved Alzheimer's disease-like symptoms in vivo, indicated by the amelioration of spatial cognition, neuronal degeneration, amyloid-beta load, and tau phosphorylation. Together, these findings suggest that GAS5 promotes Alzheimer's disease pathogenesis. This study establishes the functional convergence of the GAS5/miR-23b-3p/GSK-3β/PTEN pathway on multiple pathologies, suggesting a candidate therapeutic target in Alzheimer's disease.
基金Supported by Medical Health Science and Technology Project of Zhejiang Provincial,No.2025KY1721 and No.2022KY1292Science and Technology Projects of Shaoxing City,No.2022KY104.
文摘BACKGROUND Diabetic cardiomyopathy(DCM)is the leading cause of cardiovascular diseaserelated mortality.Farrerol(FA)possesses anti-inflammatory and antioxidant properties.However,its role in regulating endothelial ferroptosis in DCM remains unknown.AIM To investigate the beneficial effects of FA on cardiac microvascular dysfunction in DCM from the perspective of ferroptosis in endothelial cells(ECs).METHODS The mice were fed a high-fat diet and injected with streptozotocin to induce DCM.DCM mice were orally administered FA(10 and 40 mg/kg/day)and a tail vein injection of the miR-29b-3p mimic or inhibitor for 24 weeks.Cardiac function and myocardial fibrosis were also analyzed.Cardiac microvascular function was assessed using immunofluorescence and transmission electron microscopy.Ferroptosis was analyzed using RNA sequencing,immunofluorescence,and western blotting.RESULTS FA administration improved cardiac function,alleviated myocardial fibrosis,strengthened endothelial barrier function,suppressed endothelial inflammation,and preserved the microvascular structure in DCM mice.This improvement was associated with the inhibition of endothelial ferroptosis and downregulation of miR-29b-3p in ECs.Similar efficacy was observed after tail vein injection of the miR-29b-3p inhibitor.Inhibition of miR-29b-3p in vivo showed an anti-cardiac fibrotic effect by improving microvascular dysfunction and ferroptosis in ECs,whereas overexpression of miR-29b-3p showed the opposite effects in DCM mice.Luciferase reporter assay revealed that miR-29b-3p binds to SIRT1.In cultured ECs,FA reduced high glucose and free fatty acid(HG/FFA)-induced lipid peroxidation and ferroptosis and inhibited endothelial-mediated inflammation.However,the overexpression of miR-29b-3p partially abolished the protective effects of FA against HG/FFA-induced injury in ECs.This finding suggests that the mechanism of action of FA in improving DCM is related to the downregulation of miR-29b-3p and activation of SIRT1 expression.CONCLUSION Therefore,FA has a potential therapeutic effect on cardiac microvascular dysfunction by suppressing EC ferroptosis through the miR-29b-3p/SIRT1 axis.
