Constraint-induced movement therapy(CIMT)can promote the recovery of motor function in injured upper limbs following stroke,which may be associated with upregulation ofα-amino-3-hydroxy-5-methyl-4-isoxazole propionic...Constraint-induced movement therapy(CIMT)can promote the recovery of motor function in injured upper limbs following stroke,which may be associated with upregulation ofα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor(AMPAR)at synapses in the ipsilateral sensorimotor cortex in our previous study.However,AMPAR distribution is tightly regulated,and only AMPARs on the postsynaptic membrane can mediate synaptic transmission.We speculated that synaptic remodeling induced by movement-associated synaptic activity can promote functional recovery from stroke.To test this hypothesis,we compared AMPAR expression on the postsynaptic membrane surface in a rat model of ischemic stroke induced by middle cerebral artery occlusion(MCAO)with versus without CIMT,which consisted of daily running wheel training for 2 weeks starting on day 7 after MCAO.The results showed that CIMT increased the number of glutamate receptor(Glu R)2-containing functional synapses in the ipsilateral sensorimotor cortex,and reduced non-Glu R2 AMPARs in the ipsilateral sensorimotor cortex and hippocampal CA3 region.In addition,CIMT enhanced AMPAR expression on the surface of post-synaptic membrane in the ipsilateral sensorimotor cortex and hippocampus.Thus,CIMT promotes the recovery of motor function of injured upper limbs following stroke by enhancing AMPAR-mediated synaptic transmission in the ischemic hemisphere.These findings provide supporting evidence for the clinical value of CIMT for restoring limb movement in stroke patients.All experimental procedures and protocols were approved by the Department of Laboratory Animal Science of Fudan University,China(approval No.201802173 S)on March 3,2018.展开更多
Background: Soil and vegetation have a direct impact on the process and direction of plant community succession, and determine the structure, function, and productivity of ecosystems. However, little is known about th...Background: Soil and vegetation have a direct impact on the process and direction of plant community succession, and determine the structure, function, and productivity of ecosystems. However, little is known about the synergistic influence of soil physicochemical properties and vegetation features on vegetation restoration. The aim of this study was to investigate the co-evolution of soil physicochemical properties and vegetation features in the process of vegetation restoration, and to distinguish the primary and secondary relationships between soil and vegetation in their collaborative effects on promoting vegetation restoration in a subtropical area of China.Methods: Soil samples were collected to 40 cm in four distinct plant communities along a restoration gradient from herb(4–5 years), to shrub(11–12 years), to Pinus massoniana coniferous and broadleaved mixed forest(45–46 years), and to evergreen broadleaved forest(old growth forest). Measurements were taken of the soil physicochemical properties and Shannon–Wiener index(SD), diameter at breast height(DBH), height(H), and biomass. Principal component analysis, linear function analysis, and variation partitioning analysis were then performed to prioritize the relative importance of the leading factors affecting vegetation restoration.Results: Soil physicochemical properties and vegetation features showed a significant trend of improvement across the vegetation restoration gradient, reflected mainly in the high response rates of soil organic carbon(SOC)(140.76%), total nitrogen(TN)(222.48%), total phosphorus(TP)(59.54%), alkaline hydrolysis nitrogen(AN)(544.65%),available phosphorus(AP)(53.28%), species diversity(86.3%), biomass(2906.52%), DBH(128.11%), and H(596.97%).The soil properties(pH, SOC, TN, AN, and TP) and vegetation features(biomass, DBH, and H) had a clear coevolutionary relationship over the course of restoration. The synergistic interaction between soil properties and vegetation features had the greatest effect on biomass(55.55%–72.37%), and the soil properties contributed secondarily(3.30%–31.44%). The main impact factors of biomass varied with the restoration periods.Conclusions: In the process of vegetation restoration, soil and vegetation promoted each other. Vegetation restoration was the cumulative result of changes in soil fertility and vegetation features.展开更多
Background:Chronic heart failure(CHF)is characterized by insufficient blood supply from heart to meet the body’s metabolic demands.Integrating Western and traditional Chinese medicine to treat CHF has proved a valida...Background:Chronic heart failure(CHF)is characterized by insufficient blood supply from heart to meet the body’s metabolic demands.Integrating Western and traditional Chinese medicine to treat CHF has proved a validated therapeutic approach.In recent years,metabolomics has been regarded as a potential platform to provide biomarkers for diseasesubtypes.Objective:To examine 38 patients,combined NMR plasma metabolomics and traditional Chinese medicine diagnosis in order to identify diagnostic biomarkers for two CHF syndrome subtypes.Methods:After processing the spectra,orthogonal partial least square discriminant analysis was performed,and the contributing NMR signals were analyzed using Y-scrambling statistical validation with good reliability.Results:Plasma metabolic patterns of yin deficiency and yang deficiency patients were clearly discriminated.The yin-deficiency group had increased level of lactate,glycoprotein,lipoprotein and lower levels of glucose,valine and proline.The yang-deficiency group had higher levels of lactate,glycoprotein and pyruvic acid,and lower levels of glucose and lipoprotein.Potential biomarkers of CHF based on the two traditional Chinese medicine syndromes indicated alternative modes of metabolites and metabolic pathways in the disease,e.g.dysfunction of energy utilization and disturbance in fatty acids,amino acids.Conclusion:This study suggests that combining metabolomics with traditional Chinese medicine diagnosis can reveal metabolic signatures for CHF syndrome subtypes.The plasma metabolites identified might be of special clinical relevance for subtypes of CHF,which could lead to further understanding of mechanisms involved and an improvement in personalized treatment for CHF.展开更多
Objective:The purpose of this study was to assess the efficacy and safety of Chinese herbal medicine(CHM)in the treatment of chronic heart failure(CHF)patients according to syndrome differentiation.Methods:In this mul...Objective:The purpose of this study was to assess the efficacy and safety of Chinese herbal medicine(CHM)in the treatment of chronic heart failure(CHF)patients according to syndrome differentiation.Methods:In this multicenter,randomized,double-blind,placebo-controlled clinical trial,a total of 220 CHF patients were assigned to receive CHM or placebo granules without decoction according to syndrome differentiation in addition to their standard western treatment for 4 weeks.The change in the left ventricular ejection fraction(LVEF)was the primary outcome,and the changes in the TCM syndrome scores(TCM-SS)and New York Heart Association functional classification(NYHA-FC)were the secondary outcomes.展开更多
Sudden cardiac death(SCD)is the leading cause of death from out-of-hospital cardiovascular disease worldwide,with an annual incidence of 1.4 per 100,000 in females and 6.8 per 100,000 in males.1 Most cases of SCD in o...Sudden cardiac death(SCD)is the leading cause of death from out-of-hospital cardiovascular disease worldwide,with an annual incidence of 1.4 per 100,000 in females and 6.8 per 100,000 in males.1 Most cases of SCD in older patients(>45 years)are caused by atherosclerotic coronary artery disease.SCD in younger patients(<45 years)is caused by inherited cardiovascular diseases.展开更多
CD38 is the main enzyme for nicotinamide adenine dinucleotide(NAD)degradation in mammalian cells.Decreased NAD levels are closely related to metabolic syndromes and aging-related diseases.Our study showed that CD38 de...CD38 is the main enzyme for nicotinamide adenine dinucleotide(NAD)degradation in mammalian cells.Decreased NAD levels are closely related to metabolic syndromes and aging-related diseases.Our study showed that CD38 deficiency significantly alleviated angiotensin II(Ang ll)-induced vascular remodeling in mice,as shown by decreased blood pressures;reduced vascular media thickness,media-to-lumen ratio,and collagen deposition;and restored elastin expression.However,our bone marrow transplantation assay showed that CD38 deficiency in lymphocytes led to lack of protection against Ang ll-induced vascular remodeling,suggesting that the effects of CD38 on Ang ll-induced vascular remodeling might rely primarily on vascular smooth muscle cells(VSMCs),not lymphocytes.In addition,we observed that CD38 deficiency or NAD supplementation remarkably mitigated Ang ll-induced vascular senescence by suppressing the biogenesis,secretion,and internalization of senescence-associated small extracellular vesicles(SA-sEVs),which facilitated the senescence of neighboring non-damaged VSMCs.Furthermore,we found that the protective effects of CD38 deficiency on VSMC senescence were related to restoration of lysosome dysfunction,particularly with respect to the maintenance of sirtuin-mediated mitochondrial homeostasis and activation of the mitochondria-lysosomal axis in VSMCs.In conclusion,our findings demonstrated that CD38 and its associated intracellular NAD decline are critical for Ang ll-induced VSMC senescence and vascular remodeling.展开更多
Emerging evidence suggests that Toll-like receptors(TLRs)ligands pretreatment may play a vital role in the progress of myocardial ischemia/reperfusion(I/R)injury.As the ligand of TLR3,polyinosinic-polycytidylic acid(p...Emerging evidence suggests that Toll-like receptors(TLRs)ligands pretreatment may play a vital role in the progress of myocardial ischemia/reperfusion(I/R)injury.As the ligand of TLR3,polyinosinic-polycytidylic acid(poly(I:C)),a synthetic double-stranded RNA,whether its preconditioning can exhibit a cardioprotective phenotype remains unknown.Here,we report the protective effect of poly(I:C)pretreatment in acute myocardial I/R injury by activating TLR3/PI3K/Akt signaling pathway.Poly(I:C)pretreatment leads to a significant reduction of infarct size,improvement of cardiac function,and downregulation of inflammatory cytokines and apoptotic molecules compared with controls.Subsequently,our data demonstrate that phosphorylation of TLR3 tyrosine residue and its interaction with PI3K is enhanced,and protein levels of phospho-PI3K and phospho-Akt are both increased after poly(I:C)pretreatment,while knock out of TLR3 suppresses the cardioprotection of poly(I:C)preconditioning through a decreased activation of PI3K/Akt signaling.Moreover,inhibition of p85 PI3K by the administration of LY294002 in vivo and knockdown of Akt by siRNA in vitro significantly abolish poly(I:C)preconditioning-induced cardioprotective effect.In conclusion,our results reveal that poly(I:C)preconditioning exhibits essential protection in myocardial I/R injury via its modulation of TLR3,and the downstream PI3K/Akt signaling,which may provide a potential pharmacologic target for perioperative cardioprotection.展开更多
Chronic pain is often associated with cognitive decline,which could influence the quality of the patient’s life.Recent studies have suggested that Toll-like receptor 3(TLR3)is crucial for memory and learning.Nonethel...Chronic pain is often associated with cognitive decline,which could influence the quality of the patient’s life.Recent studies have suggested that Toll-like receptor 3(TLR3)is crucial for memory and learning.Nonetheless,the contribution of TLR3 to the pathogenesis of cognitive decline after chronic pain remains unclear.The level of TLR3 in hippocampal neurons increased in the chronic constriction injury(CCI)group than in the sham group in this study.Importantly,compared to the wild-type(WT)mice,TLR3 knockout(KO)mice and TLR3-specific neuronal knockdown mice both displayed improved cognitive function,reduced levels of inflammatory cytokines and neuronal apoptosis and attenuated injury to hippocampal neuroplasticity.Notably,extracellular RNAs(exRNAs),specifically double-stranded RNAs(dsRNAs),were increased in the sciatic nerve,serum,and hippocampus after CCI.The co-localization of dsRNA with TLR3 was also increased in hippocampal neurons.And the administration of poly(I:C),a dsRNA analog,elevated the levels of dsRNAs and TLR3 in the hippocampus,exacerbating hippocampus-dependent memory.In additon,the dsRNA/TLR3 inhibitor improved cognitive function after CCI.Together,our findings suggested that exRNAs,particularly dsRNAs,that were present in the condition of chronic neuropathic pain,activated TLR3,initiated downstream inflammatory and apoptotic signaling,caused damage to synaptic plasticity,and contributed to the etiology of cognitive impairment after chronic neuropathic pain.展开更多
Background:Pulmonary fibrosis is a respiratory disease caused by the proliferation of fibroblasts and accumulation of the extracellular matrix(ECM).It is known that the lung ECM is mainly composed of a three-dimension...Background:Pulmonary fibrosis is a respiratory disease caused by the proliferation of fibroblasts and accumulation of the extracellular matrix(ECM).It is known that the lung ECM is mainly composed of a three-dimensional fiber mesh filled with various high-molecular-weight proteins.However,the small-molecular-weight proteins in the lung ECM and their differences between normal and fibrotic lung ECM are largely unknown.Methods::Healthy adult male Sprague-Dawley rats(Rattus norvegicus)weighing about 150 to 200 g were randomly divided into three groups using random number table:A,B,and C and each group contained five rats.The rats in Group A were administered a single intragastric(i.g.)dose of 500μL of saline as control,and those in Groups B and C were administered a single i.g.dose of paraquat(PQ)dissolved in 500μL of saline(20 mg/kg).After 2 weeks,the lungs of rats in Group B were harvested for histological observation,preparation of de-cellularized lung scaffolds,and proteomic analysis for small-molecular-weight proteins,and similar procedures were performed on Group C and A after 4 weeks.The differentially expressed small-molecular-weight proteins(DESMPs)between different groups and the subcellular locations were analyzed.Results::Of the 1626 small-molecular-weight proteins identified,1047 were quantifiable.There were 97 up-regulated and 45 downregulated proteins in B vs.A,274 up-regulated and 31 down-regulated proteins in C vs.A,and 237 up-regulated and 28 downregulated proteins identified in C vs.B.Both the up-regulated and down-regulated proteins in the three comparisons were mainly distributed in single-organism processes and cellular processes within biological process,cell and organelle within cellular component,and binding within molecular function.Further,more up-regulated than down-regulated proteins were identified in most sub-cellular locations.The interactions of DESMPs identified in extracellular location in all comparisons showed that serum albumin(Alb)harbored the highest degree of node(25),followed by prolyl 4-hydroxylase beta polypeptide(12),integrinβ1(10),apolipoprotein A1(9),and fibrinogen gamma chain(9).Conclusions::Numerous PQ-induced DESMPs were identified in de-cellularized lungs of rats by high throughput proteomics analysis.The DESMPs between the control and treatment groups showed diversity in molecular functions,biological processes,and pathways.In addition,the interactions of extracellular DESMPs suggested that the extracellular proteins Alb,Itgb1,Apoa1,P4hb,and Fgg in ECM could be potentially used as biomarker candidates for pulmonary fibrosis.These results provided useful information and new insights regarding pulmonary fibrosis.展开更多
基金the National Natural Science Foundation of China,Nos.81871841(to YLB)and 81601960(to CC)。
文摘Constraint-induced movement therapy(CIMT)can promote the recovery of motor function in injured upper limbs following stroke,which may be associated with upregulation ofα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor(AMPAR)at synapses in the ipsilateral sensorimotor cortex in our previous study.However,AMPAR distribution is tightly regulated,and only AMPARs on the postsynaptic membrane can mediate synaptic transmission.We speculated that synaptic remodeling induced by movement-associated synaptic activity can promote functional recovery from stroke.To test this hypothesis,we compared AMPAR expression on the postsynaptic membrane surface in a rat model of ischemic stroke induced by middle cerebral artery occlusion(MCAO)with versus without CIMT,which consisted of daily running wheel training for 2 weeks starting on day 7 after MCAO.The results showed that CIMT increased the number of glutamate receptor(Glu R)2-containing functional synapses in the ipsilateral sensorimotor cortex,and reduced non-Glu R2 AMPARs in the ipsilateral sensorimotor cortex and hippocampal CA3 region.In addition,CIMT enhanced AMPAR expression on the surface of post-synaptic membrane in the ipsilateral sensorimotor cortex and hippocampus.Thus,CIMT promotes the recovery of motor function of injured upper limbs following stroke by enhancing AMPAR-mediated synaptic transmission in the ischemic hemisphere.These findings provide supporting evidence for the clinical value of CIMT for restoring limb movement in stroke patients.All experimental procedures and protocols were approved by the Department of Laboratory Animal Science of Fudan University,China(approval No.201802173 S)on March 3,2018.
基金supported by the National Forestry Public Welfare Industry Research Project (grant no. 201504411)the National Natural Science Foundation of China (grant nos. 31570447 and 31300524)。
文摘Background: Soil and vegetation have a direct impact on the process and direction of plant community succession, and determine the structure, function, and productivity of ecosystems. However, little is known about the synergistic influence of soil physicochemical properties and vegetation features on vegetation restoration. The aim of this study was to investigate the co-evolution of soil physicochemical properties and vegetation features in the process of vegetation restoration, and to distinguish the primary and secondary relationships between soil and vegetation in their collaborative effects on promoting vegetation restoration in a subtropical area of China.Methods: Soil samples were collected to 40 cm in four distinct plant communities along a restoration gradient from herb(4–5 years), to shrub(11–12 years), to Pinus massoniana coniferous and broadleaved mixed forest(45–46 years), and to evergreen broadleaved forest(old growth forest). Measurements were taken of the soil physicochemical properties and Shannon–Wiener index(SD), diameter at breast height(DBH), height(H), and biomass. Principal component analysis, linear function analysis, and variation partitioning analysis were then performed to prioritize the relative importance of the leading factors affecting vegetation restoration.Results: Soil physicochemical properties and vegetation features showed a significant trend of improvement across the vegetation restoration gradient, reflected mainly in the high response rates of soil organic carbon(SOC)(140.76%), total nitrogen(TN)(222.48%), total phosphorus(TP)(59.54%), alkaline hydrolysis nitrogen(AN)(544.65%),available phosphorus(AP)(53.28%), species diversity(86.3%), biomass(2906.52%), DBH(128.11%), and H(596.97%).The soil properties(pH, SOC, TN, AN, and TP) and vegetation features(biomass, DBH, and H) had a clear coevolutionary relationship over the course of restoration. The synergistic interaction between soil properties and vegetation features had the greatest effect on biomass(55.55%–72.37%), and the soil properties contributed secondarily(3.30%–31.44%). The main impact factors of biomass varied with the restoration periods.Conclusions: In the process of vegetation restoration, soil and vegetation promoted each other. Vegetation restoration was the cumulative result of changes in soil fertility and vegetation features.
基金The National High Technology Research and Development Program(No.2008007)National Science Foundation of China(No.81302914,81473521)+1 种基金Foundation of Beijing University of Chinese Medicine Basic Scientific Research Business Expenses(No.2011-CXTD-06)the Beijing Common special construction projects.
文摘Background:Chronic heart failure(CHF)is characterized by insufficient blood supply from heart to meet the body’s metabolic demands.Integrating Western and traditional Chinese medicine to treat CHF has proved a validated therapeutic approach.In recent years,metabolomics has been regarded as a potential platform to provide biomarkers for diseasesubtypes.Objective:To examine 38 patients,combined NMR plasma metabolomics and traditional Chinese medicine diagnosis in order to identify diagnostic biomarkers for two CHF syndrome subtypes.Methods:After processing the spectra,orthogonal partial least square discriminant analysis was performed,and the contributing NMR signals were analyzed using Y-scrambling statistical validation with good reliability.Results:Plasma metabolic patterns of yin deficiency and yang deficiency patients were clearly discriminated.The yin-deficiency group had increased level of lactate,glycoprotein,lipoprotein and lower levels of glucose,valine and proline.The yang-deficiency group had higher levels of lactate,glycoprotein and pyruvic acid,and lower levels of glucose and lipoprotein.Potential biomarkers of CHF based on the two traditional Chinese medicine syndromes indicated alternative modes of metabolites and metabolic pathways in the disease,e.g.dysfunction of energy utilization and disturbance in fatty acids,amino acids.Conclusion:This study suggests that combining metabolomics with traditional Chinese medicine diagnosis can reveal metabolic signatures for CHF syndrome subtypes.The plasma metabolites identified might be of special clinical relevance for subtypes of CHF,which could lead to further understanding of mechanisms involved and an improvement in personalized treatment for CHF.
基金the National Department Public Benefit Research Foundation(200807007)the National Basic Research Program of China(973 Program under grant 2011CB505106)+3 种基金the International Science and Technology Cooperation of China(2008DFA30610)the National“Twelfth Five-Year”Plan for Science and Technology Support(2012BAI29B07)the Foundation of Beijing University of Chinese Medicine Basic Scientific Research Business Expenses(2011-CXTD-06)the National Science Foundation of China(30902020 and 81173463).
文摘Objective:The purpose of this study was to assess the efficacy and safety of Chinese herbal medicine(CHM)in the treatment of chronic heart failure(CHF)patients according to syndrome differentiation.Methods:In this multicenter,randomized,double-blind,placebo-controlled clinical trial,a total of 220 CHF patients were assigned to receive CHM or placebo granules without decoction according to syndrome differentiation in addition to their standard western treatment for 4 weeks.The change in the left ventricular ejection fraction(LVEF)was the primary outcome,and the changes in the TCM syndrome scores(TCM-SS)and New York Heart Association functional classification(NYHA-FC)were the secondary outcomes.
基金supported by the National Natural Science Foundation of China(No.81800220 and 82000079)Hunan Province Natural Science Foundation(China)(No.2019JJ50890).
文摘Sudden cardiac death(SCD)is the leading cause of death from out-of-hospital cardiovascular disease worldwide,with an annual incidence of 1.4 per 100,000 in females and 6.8 per 100,000 in males.1 Most cases of SCD in older patients(>45 years)are caused by atherosclerotic coronary artery disease.SCD in younger patients(<45 years)is caused by inherited cardiovascular diseases.
基金This work was supported by the National Natural Science Foundation of China(81300108,81873659,91639106,81472808,81800432,81870221,82070421)supported by the National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University(Z20201012).
文摘CD38 is the main enzyme for nicotinamide adenine dinucleotide(NAD)degradation in mammalian cells.Decreased NAD levels are closely related to metabolic syndromes and aging-related diseases.Our study showed that CD38 deficiency significantly alleviated angiotensin II(Ang ll)-induced vascular remodeling in mice,as shown by decreased blood pressures;reduced vascular media thickness,media-to-lumen ratio,and collagen deposition;and restored elastin expression.However,our bone marrow transplantation assay showed that CD38 deficiency in lymphocytes led to lack of protection against Ang ll-induced vascular remodeling,suggesting that the effects of CD38 on Ang ll-induced vascular remodeling might rely primarily on vascular smooth muscle cells(VSMCs),not lymphocytes.In addition,we observed that CD38 deficiency or NAD supplementation remarkably mitigated Ang ll-induced vascular senescence by suppressing the biogenesis,secretion,and internalization of senescence-associated small extracellular vesicles(SA-sEVs),which facilitated the senescence of neighboring non-damaged VSMCs.Furthermore,we found that the protective effects of CD38 deficiency on VSMC senescence were related to restoration of lysosome dysfunction,particularly with respect to the maintenance of sirtuin-mediated mitochondrial homeostasis and activation of the mitochondria-lysosomal axis in VSMCs.In conclusion,our findings demonstrated that CD38 and its associated intracellular NAD decline are critical for Ang ll-induced VSMC senescence and vascular remodeling.
基金supported by the National Natural Science Foundation of China(Grant nos.81870858 and 81500937 to Dr.Chan ChenNo.81671062 to Dr.Tao Zhu)+1 种基金the National Key R&D Program of China(Grant no.2018YFC2001800 to Dr.Tao Zhu),China Postdoctoral Science Foundation(Grant no.2017M610603 to Dr.Chan Chen)Postdoctoral Science Foundation of Sichuan University(Grant no.2017SCU12030 to Dr.Chan Chen).
文摘Emerging evidence suggests that Toll-like receptors(TLRs)ligands pretreatment may play a vital role in the progress of myocardial ischemia/reperfusion(I/R)injury.As the ligand of TLR3,polyinosinic-polycytidylic acid(poly(I:C)),a synthetic double-stranded RNA,whether its preconditioning can exhibit a cardioprotective phenotype remains unknown.Here,we report the protective effect of poly(I:C)pretreatment in acute myocardial I/R injury by activating TLR3/PI3K/Akt signaling pathway.Poly(I:C)pretreatment leads to a significant reduction of infarct size,improvement of cardiac function,and downregulation of inflammatory cytokines and apoptotic molecules compared with controls.Subsequently,our data demonstrate that phosphorylation of TLR3 tyrosine residue and its interaction with PI3K is enhanced,and protein levels of phospho-PI3K and phospho-Akt are both increased after poly(I:C)pretreatment,while knock out of TLR3 suppresses the cardioprotection of poly(I:C)preconditioning through a decreased activation of PI3K/Akt signaling.Moreover,inhibition of p85 PI3K by the administration of LY294002 in vivo and knockdown of Akt by siRNA in vitro significantly abolish poly(I:C)preconditioning-induced cardioprotective effect.In conclusion,our results reveal that poly(I:C)preconditioning exhibits essential protection in myocardial I/R injury via its modulation of TLR3,and the downstream PI3K/Akt signaling,which may provide a potential pharmacologic target for perioperative cardioprotection.
基金This study received support from some sources,including the National Natural Science Foundation of China(No.82171185,No.81870858 to C.C.)the National Key R&D Program of China(No.2018YFC2001800 to T.Z.)+3 种基金the National Natural Science Foundation of China(No.81671062 to T.Z.)the Natural Science Foundation of Sichuan Province(No.2022NSFSC1322,to R.G.)the China Postdoctoral Science Foundation(No.2020M673234 to R.G.)the Postdoctoral Research Project,West China Hospital,Sichuan University(No.2020HXBH022 to R.G.).
文摘Chronic pain is often associated with cognitive decline,which could influence the quality of the patient’s life.Recent studies have suggested that Toll-like receptor 3(TLR3)is crucial for memory and learning.Nonetheless,the contribution of TLR3 to the pathogenesis of cognitive decline after chronic pain remains unclear.The level of TLR3 in hippocampal neurons increased in the chronic constriction injury(CCI)group than in the sham group in this study.Importantly,compared to the wild-type(WT)mice,TLR3 knockout(KO)mice and TLR3-specific neuronal knockdown mice both displayed improved cognitive function,reduced levels of inflammatory cytokines and neuronal apoptosis and attenuated injury to hippocampal neuroplasticity.Notably,extracellular RNAs(exRNAs),specifically double-stranded RNAs(dsRNAs),were increased in the sciatic nerve,serum,and hippocampus after CCI.The co-localization of dsRNA with TLR3 was also increased in hippocampal neurons.And the administration of poly(I:C),a dsRNA analog,elevated the levels of dsRNAs and TLR3 in the hippocampus,exacerbating hippocampus-dependent memory.In additon,the dsRNA/TLR3 inhibitor improved cognitive function after CCI.Together,our findings suggested that exRNAs,particularly dsRNAs,that were present in the condition of chronic neuropathic pain,activated TLR3,initiated downstream inflammatory and apoptotic signaling,caused damage to synaptic plasticity,and contributed to the etiology of cognitive impairment after chronic neuropathic pain.
基金This study was supported by grants from the Zhejiang Provincial Natural Science Foundation of China(No.LQ17H010004 and No.LQ16H040002)the National Natural Science Foundation of China(No.81772054 and No.81701379)+1 种基金the Zhejiang Medicines Health Science and Technology Program(No.2016KYB189)the Wenzhou Science and Technology Bureau Program(No.Y20170179).
文摘Background:Pulmonary fibrosis is a respiratory disease caused by the proliferation of fibroblasts and accumulation of the extracellular matrix(ECM).It is known that the lung ECM is mainly composed of a three-dimensional fiber mesh filled with various high-molecular-weight proteins.However,the small-molecular-weight proteins in the lung ECM and their differences between normal and fibrotic lung ECM are largely unknown.Methods::Healthy adult male Sprague-Dawley rats(Rattus norvegicus)weighing about 150 to 200 g were randomly divided into three groups using random number table:A,B,and C and each group contained five rats.The rats in Group A were administered a single intragastric(i.g.)dose of 500μL of saline as control,and those in Groups B and C were administered a single i.g.dose of paraquat(PQ)dissolved in 500μL of saline(20 mg/kg).After 2 weeks,the lungs of rats in Group B were harvested for histological observation,preparation of de-cellularized lung scaffolds,and proteomic analysis for small-molecular-weight proteins,and similar procedures were performed on Group C and A after 4 weeks.The differentially expressed small-molecular-weight proteins(DESMPs)between different groups and the subcellular locations were analyzed.Results::Of the 1626 small-molecular-weight proteins identified,1047 were quantifiable.There were 97 up-regulated and 45 downregulated proteins in B vs.A,274 up-regulated and 31 down-regulated proteins in C vs.A,and 237 up-regulated and 28 downregulated proteins identified in C vs.B.Both the up-regulated and down-regulated proteins in the three comparisons were mainly distributed in single-organism processes and cellular processes within biological process,cell and organelle within cellular component,and binding within molecular function.Further,more up-regulated than down-regulated proteins were identified in most sub-cellular locations.The interactions of DESMPs identified in extracellular location in all comparisons showed that serum albumin(Alb)harbored the highest degree of node(25),followed by prolyl 4-hydroxylase beta polypeptide(12),integrinβ1(10),apolipoprotein A1(9),and fibrinogen gamma chain(9).Conclusions::Numerous PQ-induced DESMPs were identified in de-cellularized lungs of rats by high throughput proteomics analysis.The DESMPs between the control and treatment groups showed diversity in molecular functions,biological processes,and pathways.In addition,the interactions of extracellular DESMPs suggested that the extracellular proteins Alb,Itgb1,Apoa1,P4hb,and Fgg in ECM could be potentially used as biomarker candidates for pulmonary fibrosis.These results provided useful information and new insights regarding pulmonary fibrosis.
