The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regul...The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regulates diverse aspects of neural development and function. Genetic mutations within the m TOR pathway lead to severe neurodevelopmental disorders, collectively known as “mTORopathies”(Crino, 2020). Dysfunctions of m TOR, including both its hyperactivation and hypoactivation, have also been implicated in a wide spectrum of other neurodevelopmental and neurodegenerative conditions, highlighting its importance in CNS health.展开更多
Objective To investigate the effects of electroacupuncture(EA)on the expression and phosphorylation of insulin signal transduction-related proteins in the hypothalamus of insulin resistance(IR)rats.Methods There were ...Objective To investigate the effects of electroacupuncture(EA)on the expression and phosphorylation of insulin signal transduction-related proteins in the hypothalamus of insulin resistance(IR)rats.Methods There were totally seventy-five Wistar rats.Ten rats were randomly assigned to the Normal group(N).The remaining 65 rats were fed a high-fat diet,fifty successfully modeled rats were randomly divided into the Model(M),EA,Sham EA(S+EA),l-leucine(L),and l-leucine+EA(L+EA)groups,with 10 rats in each group.EA was applied at acupoints“Guanyuan(CV 4)”,“Zhongwan(CV 12)”,“Zusanli(ST 36)”,and“Fenglong(ST 40)”,with each session lasting 10 min,three times per week for 8 weeks.The S+EA group received needle insertion to a depth of≤2 mm without electrical stimulation,with the same treatment duration and same acupoint selection.Body weight,fasting blood glucose(FBG),and insulin sensitivity(glucose infusion rate,GIR)were measured.Western blot analysis was used to assess insulin receptor substrate-1(IRS-1),(Protein kinase B)Akt,glycogen synthase kinase-3β(GSK-3β),mechanistic target of rapamycin complex 1(mTORC1),and Ribosomal S6 kinase 1(S6K1),along with their phosphorylated forms.PCR was used to evaluate mRNA expression of IRS-1,Akt,and GSK-3β.Immunofluorescence was used to detect hypothalamic Akt localization.Results(1)Compared to the N group,the M group exhibited increased body weight,FBG,and phosphorylation of GSK-3β,mTORC1,and S6K1,with decreased GIR,IRS-1,Akt phosphorylation,and mRNA expression(P<0.05,P<0.01).(2)Compared to the M group,the EA and S+EA groups showed reduced body weight,FBG,GSK-3β,mTORC1,and S6K1 phosphorylation,with increased GIR,IRS-1,Akt phosphorylation,and mRNA expression(P<0.05,P<0.01).(3)Compared to the EA group,the S+EA group had higher body weight,GSK-3βphosphorylation,and mRNA expression,with reduced p-IRS-1 and p-Akt expression(P<0.05);the L and L+EA groups showed increased GSK-3β,mTORC1,and S6K1 phosphorylation,with decreased GIR,IRS-1,and Akt mRNA expression(P<0.05).(4)Compared to the L+EA group,the L group exhibited higher GSK-3β,mTORC1,and S6K1 phosphorylation,with lower GIR,Akt mRNA,and p-Akt expression(P<0.05,P<0.01).Conclusion EA positively influences body weight,glucose-lipid metabolism,and insulin sensitivity in IR rats,with regulatory effects on central insulin signal transduction-related proteins,potentially linked to its suppression of hypothalamic mTORC1/S6K1 pathway activity.展开更多
Thoracic aortic aneurysm(TAA)significantly endangers the lives of individuals with Marfan syndrome(MFS),yet the intricacies of their biomechanical origins remain elusive.Our investigation delves into the pivotal role ...Thoracic aortic aneurysm(TAA)significantly endangers the lives of individuals with Marfan syndrome(MFS),yet the intricacies of their biomechanical origins remain elusive.Our investigation delves into the pivotal role of hemodynamic disturbance in the pathogenesis of TAA,with a particular emphasis on the mechanistic contributions of the mammalian target of rapamycin(mTOR)signaling cascade.We uncovered that activation of the mTOR complex 1(mTORC1)within smooth muscle cells,instigated by the oscillatory wall shear stress(OSS)that stems from disturbed flow(DF),is a catalyst for TAA progression.This revelation was corroborated through both an MFS mouse model(Fbn1+/C1039G)and clinical MFS specimens.Crucially,our research demonstrates a direct linkage between the activation of the mTORC1 pathway and the intensity in OSS.Therapeutic administration of rapamycin suppresses mTORC1 activity,leading to the attenuation of aberrant SMC behavior,reduced inflammatory infiltration,and restoration of extracellular matrix integrity—collectively decelerating TAA advancement in our mouse model.These insights posit the mTORC1 axis as a strategic target for intervention,offering a novel approach to manage TAAs in MFS and potentially pave insights for current treatment paradigms.展开更多
基金supported by grants from Simons Foundation (SFARI 479754),CIHR (PJT-180565)the Scottish Rite Charitable Foundation of Canada (to YL)funding from the Canada Research Chairs program。
文摘The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regulates diverse aspects of neural development and function. Genetic mutations within the m TOR pathway lead to severe neurodevelopmental disorders, collectively known as “mTORopathies”(Crino, 2020). Dysfunctions of m TOR, including both its hyperactivation and hypoactivation, have also been implicated in a wide spectrum of other neurodevelopmental and neurodegenerative conditions, highlighting its importance in CNS health.
基金Supported by the Hubei Natural Science Foundation Joint Fund Project:2023AFD139,2023AFD140the "Shizhen Young Talent" Training Program of the College of Acupuncture and Orthopedics,Hubei University of Chinese Medicinethe National Famous Traditional Chinese Medicine Expert Inheritance Studio Construction Project。
文摘Objective To investigate the effects of electroacupuncture(EA)on the expression and phosphorylation of insulin signal transduction-related proteins in the hypothalamus of insulin resistance(IR)rats.Methods There were totally seventy-five Wistar rats.Ten rats were randomly assigned to the Normal group(N).The remaining 65 rats were fed a high-fat diet,fifty successfully modeled rats were randomly divided into the Model(M),EA,Sham EA(S+EA),l-leucine(L),and l-leucine+EA(L+EA)groups,with 10 rats in each group.EA was applied at acupoints“Guanyuan(CV 4)”,“Zhongwan(CV 12)”,“Zusanli(ST 36)”,and“Fenglong(ST 40)”,with each session lasting 10 min,three times per week for 8 weeks.The S+EA group received needle insertion to a depth of≤2 mm without electrical stimulation,with the same treatment duration and same acupoint selection.Body weight,fasting blood glucose(FBG),and insulin sensitivity(glucose infusion rate,GIR)were measured.Western blot analysis was used to assess insulin receptor substrate-1(IRS-1),(Protein kinase B)Akt,glycogen synthase kinase-3β(GSK-3β),mechanistic target of rapamycin complex 1(mTORC1),and Ribosomal S6 kinase 1(S6K1),along with their phosphorylated forms.PCR was used to evaluate mRNA expression of IRS-1,Akt,and GSK-3β.Immunofluorescence was used to detect hypothalamic Akt localization.Results(1)Compared to the N group,the M group exhibited increased body weight,FBG,and phosphorylation of GSK-3β,mTORC1,and S6K1,with decreased GIR,IRS-1,Akt phosphorylation,and mRNA expression(P<0.05,P<0.01).(2)Compared to the M group,the EA and S+EA groups showed reduced body weight,FBG,GSK-3β,mTORC1,and S6K1 phosphorylation,with increased GIR,IRS-1,Akt phosphorylation,and mRNA expression(P<0.05,P<0.01).(3)Compared to the EA group,the S+EA group had higher body weight,GSK-3βphosphorylation,and mRNA expression,with reduced p-IRS-1 and p-Akt expression(P<0.05);the L and L+EA groups showed increased GSK-3β,mTORC1,and S6K1 phosphorylation,with decreased GIR,IRS-1,and Akt mRNA expression(P<0.05).(4)Compared to the L+EA group,the L group exhibited higher GSK-3β,mTORC1,and S6K1 phosphorylation,with lower GIR,Akt mRNA,and p-Akt expression(P<0.05,P<0.01).Conclusion EA positively influences body weight,glucose-lipid metabolism,and insulin sensitivity in IR rats,with regulatory effects on central insulin signal transduction-related proteins,potentially linked to its suppression of hypothalamic mTORC1/S6K1 pathway activity.
基金supported by the National Natural Science Foundation of China(Grant Nos.:82000429 and 81470574)Young Elite Scientists Sponsorship Program by CAST,China(Program No.:YESS20230395/2023QNRC001)+4 种基金Beijing Nova Program,China(Program No.:20230484308)Youth Elite Program of Beijing Friendship Hospital,China(Program No.:YYQCJH2022-9)Young Elite Scientists Sponsorship Program by BAST,China(Program No.:BYESS2024045)Capital's Funds for Health Improvement and Research,China(Grant No.:CFH2022-4-20217)Chinese Institutes for Medical Research,Beijing(CIMR)Organized Research Project,China(Project No.:CX23YQ07)。
文摘Thoracic aortic aneurysm(TAA)significantly endangers the lives of individuals with Marfan syndrome(MFS),yet the intricacies of their biomechanical origins remain elusive.Our investigation delves into the pivotal role of hemodynamic disturbance in the pathogenesis of TAA,with a particular emphasis on the mechanistic contributions of the mammalian target of rapamycin(mTOR)signaling cascade.We uncovered that activation of the mTOR complex 1(mTORC1)within smooth muscle cells,instigated by the oscillatory wall shear stress(OSS)that stems from disturbed flow(DF),is a catalyst for TAA progression.This revelation was corroborated through both an MFS mouse model(Fbn1+/C1039G)and clinical MFS specimens.Crucially,our research demonstrates a direct linkage between the activation of the mTORC1 pathway and the intensity in OSS.Therapeutic administration of rapamycin suppresses mTORC1 activity,leading to the attenuation of aberrant SMC behavior,reduced inflammatory infiltration,and restoration of extracellular matrix integrity—collectively decelerating TAA advancement in our mouse model.These insights posit the mTORC1 axis as a strategic target for intervention,offering a novel approach to manage TAAs in MFS and potentially pave insights for current treatment paradigms.
