In Alzheimer’s disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-βin the brain.Amyloid-βcorrelates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation...In Alzheimer’s disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-βin the brain.Amyloid-βcorrelates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation of P-glycoprotein.The amyloid cascade hypothesis describes amyloid-βas the central cause of Alzheimer’s disease neuropathology.Better understanding of the change of P-glycoprotein and sphingomyelin along with amyloid-βand their potential association in the pathological process of Alzheimer’s disease is critical.Herein,we found that the expression of P-glycoprotein in APP/PS1 mice tended to increase with age and was significantly higher at 9 and 12 months of age than that in wild-type mice at comparable age.The functionality of P-glycoprotein of APP/PS1 mice did not change with age but was significantly lower than that of wild-type mice at 12 months of age.Decreased sphingomyelin levels,increased ceramide levels,and the increased expression and activity of neutral sphingomyelinase 1 were observed in APP/PS1 mice at 9 and 12 months of age compared with the levels in wild-type mice.Similar results were observed in the Alzheimer’s disease mouse model induced by intracerebroventricular injection of amyloid-β1-42 and human cerebral microvascular endothelial cells treated with amyloid-β1-42.In human cerebral microvascular endothelial cells,neutral sphingomyelinase 1 inhibitor interfered with the changes of sphingomyelin metabolism and P-glycoprotein expression and functionality caused by amyloid-β1-42 treatment.Neutral sphingomyelinase 1 regulated the expression and functionality of P-glycoprotein and the levels of sphingomyelin and ceramide.Together,these findings indicate that neutral sphingomyelinase 1 regulates the expression and function of P-glycoprotein via the sphingomyelin/ceramide pathway.These studies may serve as new pursuits for the development of anti-Alzheimer’s disease drugs.展开更多
Lipid dysmetabolism is one of the main features of diabetes mellitus and manifests by dyslipidemia as well as the ectopic accumulation of lipids in various tissues and organs,including the kidney.Research suggests tha...Lipid dysmetabolism is one of the main features of diabetes mellitus and manifests by dyslipidemia as well as the ectopic accumulation of lipids in various tissues and organs,including the kidney.Research suggests that impaired cholesterol metabolism,increased lipid uptake or synthesis,increased fatty acid oxidation,lipid droplet accumulation and an imbalance in biologically active sphingolipids(such as ceramide,ceramide-1-phosphate and sphingosine-1-phosphate)contribute to the development of diabetic kidney disease(DKD).Currently,the literature suggests that both quality and quantity of lipids are associated with DKD and contribute to increased reactive oxygen species production,oxidative stress,inflammation,or cell death.Therefore,control of renal lipid dysmetabolism is a very important therapeutic goal,which needs to be archived.This article will review some of the recent advances leading to a better understanding of the mechanisms of dyslipidemia and the role of particular lipids and sphingolipids in DKD.展开更多
BACKGROUND The treatment of gastric cancer(GC)has caused an enormous social burden worldwide.Accumulating studies have reported that N6-methyladenosine(m6A)is closely related to tumor progression.METTL5 is a m6A methy...BACKGROUND The treatment of gastric cancer(GC)has caused an enormous social burden worldwide.Accumulating studies have reported that N6-methyladenosine(m6A)is closely related to tumor progression.METTL5 is a m6A methyltransferase that plays a pivotal role in maintaining the metabolic stability of cells.However,its aberrant regulation in GC has not been fully elucidated.AIM To excavate the role of METTL5 in the development of GC.METHODS METTL5 expression and clinicopathological characteristics were analyzed via The Cancer Genome Atlas dataset and further verified via immunohistochemistry,western blotting and real-time quantitative polymerase chain reaction in tissue microarrays and clinical samples.The tumor-promoting effect of METTL5 on HGC-27 and AGS cells was explored in vitro by Cell Counting Kit-8 assays,colony formation assays,scratch healing assays,transwell assays and flow cytometry.The tumor-promoting role of METTL5 in vivo was evaluated in a xenograft tumor model.The EpiQuik m6A RNA Methylation Quantification Kit was used for m6A quantification.Next,liquid chromatography-mass spectrometry was used to evaluate the association between METTL5 and sphingomyelin metabolism,which was confirmed by Enzyme-linked immunosorbent assay and rescue tests.In addition,we investigated whether METTL5 affects the sensitivity of GC cells to cisplatin via colony formation and transwell experiments.RESULTS Our research revealed substantial upregulation of METTL5,which suggested a poor prognosis of GC patients.Increased METTL5 expression indicated distant lymph node metastasis,advanced cancer stage and pathological grade.An increased level of METTL5 correlated with a high degree of m6A methylation.METTL5 markedly promotes the proliferation,migration,and invasion of GC cells in vitro.METTL5 also promotes the growth of GC in animal models.METTL5 knockdown resulted in significant changes in sphingomyelin metabolism,which implies that METTL5 may impact the development of GC via sphingomyelin metabolism.In addition,high METTL5 expr展开更多
基金supported by the National Key Research and Development Program of ChinaNos.2021YFC2 701800 and 2021YFC2 701805 (to QY)+2 种基金Open Research Fund of State Key Laboratory of Genetic EngineeringFudan UniversityNo.SKLGE-21 19 (to TXH and QY)
文摘In Alzheimer’s disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-βin the brain.Amyloid-βcorrelates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation of P-glycoprotein.The amyloid cascade hypothesis describes amyloid-βas the central cause of Alzheimer’s disease neuropathology.Better understanding of the change of P-glycoprotein and sphingomyelin along with amyloid-βand their potential association in the pathological process of Alzheimer’s disease is critical.Herein,we found that the expression of P-glycoprotein in APP/PS1 mice tended to increase with age and was significantly higher at 9 and 12 months of age than that in wild-type mice at comparable age.The functionality of P-glycoprotein of APP/PS1 mice did not change with age but was significantly lower than that of wild-type mice at 12 months of age.Decreased sphingomyelin levels,increased ceramide levels,and the increased expression and activity of neutral sphingomyelinase 1 were observed in APP/PS1 mice at 9 and 12 months of age compared with the levels in wild-type mice.Similar results were observed in the Alzheimer’s disease mouse model induced by intracerebroventricular injection of amyloid-β1-42 and human cerebral microvascular endothelial cells treated with amyloid-β1-42.In human cerebral microvascular endothelial cells,neutral sphingomyelinase 1 inhibitor interfered with the changes of sphingomyelin metabolism and P-glycoprotein expression and functionality caused by amyloid-β1-42 treatment.Neutral sphingomyelinase 1 regulated the expression and functionality of P-glycoprotein and the levels of sphingomyelin and ceramide.Together,these findings indicate that neutral sphingomyelinase 1 regulates the expression and function of P-glycoprotein via the sphingomyelin/ceramide pathway.These studies may serve as new pursuits for the development of anti-Alzheimer’s disease drugs.
基金the National Institute of Health(Research in Dr.Alessia Fornoni’s laboratory),No.R01DK117599,No.R01DK104753,No.R01CA227493,No.U54DK083912,No.UM1DK100846,and No.U01DK116101the Miami Clinical Translational Science Institute,No.UL1TR000460and the Chernowitz Medical Research Foundation(Mitrofanova A and Burke G),No.GR016291.
文摘Lipid dysmetabolism is one of the main features of diabetes mellitus and manifests by dyslipidemia as well as the ectopic accumulation of lipids in various tissues and organs,including the kidney.Research suggests that impaired cholesterol metabolism,increased lipid uptake or synthesis,increased fatty acid oxidation,lipid droplet accumulation and an imbalance in biologically active sphingolipids(such as ceramide,ceramide-1-phosphate and sphingosine-1-phosphate)contribute to the development of diabetic kidney disease(DKD).Currently,the literature suggests that both quality and quantity of lipids are associated with DKD and contribute to increased reactive oxygen species production,oxidative stress,inflammation,or cell death.Therefore,control of renal lipid dysmetabolism is a very important therapeutic goal,which needs to be archived.This article will review some of the recent advances leading to a better understanding of the mechanisms of dyslipidemia and the role of particular lipids and sphingolipids in DKD.
文摘BACKGROUND The treatment of gastric cancer(GC)has caused an enormous social burden worldwide.Accumulating studies have reported that N6-methyladenosine(m6A)is closely related to tumor progression.METTL5 is a m6A methyltransferase that plays a pivotal role in maintaining the metabolic stability of cells.However,its aberrant regulation in GC has not been fully elucidated.AIM To excavate the role of METTL5 in the development of GC.METHODS METTL5 expression and clinicopathological characteristics were analyzed via The Cancer Genome Atlas dataset and further verified via immunohistochemistry,western blotting and real-time quantitative polymerase chain reaction in tissue microarrays and clinical samples.The tumor-promoting effect of METTL5 on HGC-27 and AGS cells was explored in vitro by Cell Counting Kit-8 assays,colony formation assays,scratch healing assays,transwell assays and flow cytometry.The tumor-promoting role of METTL5 in vivo was evaluated in a xenograft tumor model.The EpiQuik m6A RNA Methylation Quantification Kit was used for m6A quantification.Next,liquid chromatography-mass spectrometry was used to evaluate the association between METTL5 and sphingomyelin metabolism,which was confirmed by Enzyme-linked immunosorbent assay and rescue tests.In addition,we investigated whether METTL5 affects the sensitivity of GC cells to cisplatin via colony formation and transwell experiments.RESULTS Our research revealed substantial upregulation of METTL5,which suggested a poor prognosis of GC patients.Increased METTL5 expression indicated distant lymph node metastasis,advanced cancer stage and pathological grade.An increased level of METTL5 correlated with a high degree of m6A methylation.METTL5 markedly promotes the proliferation,migration,and invasion of GC cells in vitro.METTL5 also promotes the growth of GC in animal models.METTL5 knockdown resulted in significant changes in sphingomyelin metabolism,which implies that METTL5 may impact the development of GC via sphingomyelin metabolism.In addition,high METTL5 expr
