Skeletal muscle injuries caused by trauma,infections,or sports tear are common clinical diseases.Currently,the regeneration and repair of muscle tissue,which is highly heterogeneous,remains a significant challenge.Giv...Skeletal muscle injuries caused by trauma,infections,or sports tear are common clinical diseases.Currently,the regeneration and repair of muscle tissue,which is highly heterogeneous,remains a significant challenge.Given the anisotropic structure,high strength and tensile characteristics of skeletal muscle,this study proposes a treatment strategy for muscle injury that combines materials nano-topological cues and biochemical cues.The approach aims to facilitate muscle injury repair through the use of heterogeneous nanofibers on the surface of the sandwich-like electrospun nanofibrous scaffold and macrophage phenotype transformation.Specifically,the outer layer of the sandwich-like scaffold consists of highly aligned fibers,while the middle layer is a core-shell structured random fibers containing hyaluronic acid,and the fiber matrix is composed of optimized proportions of polycaprolactone and gelatin.Mechanical testing shows that the sandwich-like scaffold combines the excellent tensile strength of the outer aligned fibers with the larger elongation at break and suture retention strength of the inner random fibers.Cell and animal experiments confirmed that the aligned fibers in the outer layers guide the cell adhesion,cytoskeleton and nuclear remodeling,and myogenic differentiation of myoblasts,and hyaluronic acid promotes both myogenic differentiation and macrophage phenotype transformation,ultimately accelerating skeletal muscle regeneration.This sandwich-like nanofibrous scaffold provides a novel cell-free,and factor-free approach for the regeneration of skeletal muscle injuries.展开更多
There is growing evidence that long-term central nervous system(CNS)inflammation exacerbates secondary deterioration of brain structures and functions and is one of the major determinants of disease outcome and progre...There is growing evidence that long-term central nervous system(CNS)inflammation exacerbates secondary deterioration of brain structures and functions and is one of the major determinants of disease outcome and progression.In acute CNS injury,brain microglia are among the first cells to respond and play a critical role in neural repair and regeneration.However,microglial activation can also impede CNS repair and amplify tissue damage,and phenotypic transformation may be responsible for this dual role.Mesenchymal stem cell(MSC)-derived exosomes(Exos)are promising therapeutic agents for the treatment of acute CNS injuries due to their immunomodulatory and regenerative properties.MSC-Exos are nanoscale membrane vesicles that are actively released by cells and are used clinically as circulating biomarkers for disease diagnosis and prognosis.MSC-Exos can be neuroprotective in several acute CNS models,including for stroke and traumatic brain injury,showing great clinical potential.This review summarized the classification of acute CNS injury disorders and discussed the prominent role of microglial activation in acute CNS inflammation and the specific role of MSC-Exos in regulating pro-inflammatory microglia in neuroinflammatory repair following acute CNS injury.Finally,this review explored the potential mechanisms and factors associated with MSCExos in modulating the phenotypic balance of microglia,focusing on the interplay between CNS inflammation,the brain,and injury aspects,with an emphasis on potential strategies and therapeutic interventions for improving functional recovery from early CNS inflammation caused by acute CNS injury.展开更多
AIM：To report a phenotypic variant pedigree of lattice corneal dystrophy（LCD）associated with two mutations,R124C and A546 D,in the transforming growth factor betainduced gene（TGFBI）.METHODS：A detailed ocular exa...AIM：To report a phenotypic variant pedigree of lattice corneal dystrophy（LCD）associated with two mutations,R124C and A546 D,in the transforming growth factor betainduced gene（TGFBI）.METHODS：A detailed ocular examination was taken for all participants of a LCD family. Peripheral blood leukocytes from each participant were extracted to obtain the DNA. Polymerase chain reaction（PCR）of all seventeen exons of TGFBI gene was performed. The products were sequenced and analyzed. Histological examination was carried out after a penetrating keratoplasty from the right eye of proband. RESULTS：Genetic analysis showed that the proband and all 6 affected individuals harbored both a heterozygous CGC to TGC mutation at codon 124 and a heterozygous GCC to GAC mutation at codon 546 of TGFBI. None of the 100 control subjects and unaffected family members was positive for these two mutations. Ocular examination displayed multiple refractile lattice-like opacities in anterior stroma of the central cornea and small granular deposits in the peripheral cornea. The deposits were stained positively with Congo red indicating be amyloid in nature and situated mainly in the anterior and middle stroma. CONCLUSION：We observed a novel LCD family which carried two pathogenic mutations（R124C and A546D）in the TGFBI gene. The phenotypic features were apparently different from those associated with corresponding single mutations. The result reveals that although the definite mutation is the most important genetic cause of the disease,some different modifier alleles may influence the phenotype.展开更多
Objective: To investigate the bioactive components of Sangqi Qingxuan formula(SQQX), predict the pharmacological targets, and explore the mechanism of hypertensive vascular remodeling(HVR).Methods: Network pharmacolog...Objective: To investigate the bioactive components of Sangqi Qingxuan formula(SQQX), predict the pharmacological targets, and explore the mechanism of hypertensive vascular remodeling(HVR).Methods: Network pharmacology was adopted to predict how SQQX acts in HVR. The effectiveness was assessed by blood pressure measurements and pathological morphology observation based on a spontaneously hypertensive rat model, while the mechanism of SQQX on HVR was validated by immunohistochemistry(IHC) and western blot(WB) according to the results of network pharmacology.Results: There were 130 bioactive components of SQQX and 231 drug targets predicted by the Traditional Chinese Medicine Systems Pharmacology Database. Subsequently, 181 common targets were identified for SQQX against HVR, with TP53, MAPK1, and AKT1 as the core targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses was employed to identify the top 20 enriched functions and the top 20 pathways(P <.01). Finally, the key role of the ERK/MAPK signaling pathway in HVR was determined. The in vivo results suggested that SQQX reduced systolic blood pressure and increased the ratio of thoracic aortic wall thickness to lumen diameter. Additionally, compared with the model group, SQQX increased the expression of smooth muscle 22 alpha(IHC: P <.001;WB:P <.05) and decreased the expression of osteopontin(IHC: P <.001;WB: P <.05), ERK1/2(IHC: P <.001;WB: ERK1 & ERK2, all P <.05), p-ERK1/2(IHC: P <.001;WB: ERK1 & ERK2, all P <.05), and the ratio of pERK1/2 to ERK1/2 protein(IHC: P <.001).Conclusions: SQQX, which has multiple bioactive ingredients and potential targets, is an effective treatment for HVR. The mechanism of antihypertensive and vascular protection may be related to the inhibition of phenotypic transformation of vascular smooth muscle cells and the ERK/MAPK signaling pathway.展开更多
Volatile organic compounds(VOCs)are widespread indoor gaseous pollutants that are associated with vascular diseases.However,due to methodological limitations,the underlying mechanisms of VOC-induced aortic fibrosis re...Volatile organic compounds(VOCs)are widespread indoor gaseous pollutants that are associated with vascular diseases.However,due to methodological limitations,the underlying mechanisms of VOC-induced aortic fibrosis remains unclear.To address this gap,we established a real-world indoor renovation VOC inhalation mouse model and used an innovative ex vivo biosensor assay with endothelial cells to respond to serum derived from VOC exposed mice,exploring the adverse health outcomes of total VOCs on the aorta and its potential mechanisms.The ex vivo biosensor assay confirmed that VOCs triggered phenotypic transformation of aortic smooth muscle cells via epigenetic changes in aortic endothelial cells.Mechanistically,VOCs elevated mitochondrial DNA(mtDNA)methylation by upregulating DNMT1,leading to mtDNA leakage and subsequent activation of the cGAS-STING inflammatory pathway.By integrating real-world indoor VOC exposure with mechanistic cellular analysis,this ex vivo biosensor assay offers a physiologically relevant model to elucidate the systemic vascular toxicity of complex environmental mixtures.Overall,this study revealed the molecular mechanism of indoor VOC-induced aortic fibrosis based on increased mtDNA methylation in aortic endothelial cells,which mediated the phenotypic transformation of aortic smooth muscle cells.mtDNA methylation may serve as a potential target for preventing aortic fibrosis or alleviating symptoms in affected patients.Our study highlights the urgent need for improved VOC monitoring in indoor environments and provides strategies for more precise environmental risk assessments.展开更多
基金supported by the National Natural Science Foundation of China(32401132,82172394,U22A20280)the China Postdoctoral Science Foundation(2022TQ0224,2024M752224)+1 种基金the 1·3·5 project for disciplines of excellence,West China Hospital,Sichuan University(No.ZYGD23033,2023HXBH008)the Open project of Guangxi Key Laboratory of the Rehabilitation and Reconstruction for Oral and Maxillofacial Research(GXKLOMRR2401)。
文摘Skeletal muscle injuries caused by trauma,infections,or sports tear are common clinical diseases.Currently,the regeneration and repair of muscle tissue,which is highly heterogeneous,remains a significant challenge.Given the anisotropic structure,high strength and tensile characteristics of skeletal muscle,this study proposes a treatment strategy for muscle injury that combines materials nano-topological cues and biochemical cues.The approach aims to facilitate muscle injury repair through the use of heterogeneous nanofibers on the surface of the sandwich-like electrospun nanofibrous scaffold and macrophage phenotype transformation.Specifically,the outer layer of the sandwich-like scaffold consists of highly aligned fibers,while the middle layer is a core-shell structured random fibers containing hyaluronic acid,and the fiber matrix is composed of optimized proportions of polycaprolactone and gelatin.Mechanical testing shows that the sandwich-like scaffold combines the excellent tensile strength of the outer aligned fibers with the larger elongation at break and suture retention strength of the inner random fibers.Cell and animal experiments confirmed that the aligned fibers in the outer layers guide the cell adhesion,cytoskeleton and nuclear remodeling,and myogenic differentiation of myoblasts,and hyaluronic acid promotes both myogenic differentiation and macrophage phenotype transformation,ultimately accelerating skeletal muscle regeneration.This sandwich-like nanofibrous scaffold provides a novel cell-free,and factor-free approach for the regeneration of skeletal muscle injuries.
文摘There is growing evidence that long-term central nervous system(CNS)inflammation exacerbates secondary deterioration of brain structures and functions and is one of the major determinants of disease outcome and progression.In acute CNS injury,brain microglia are among the first cells to respond and play a critical role in neural repair and regeneration.However,microglial activation can also impede CNS repair and amplify tissue damage,and phenotypic transformation may be responsible for this dual role.Mesenchymal stem cell(MSC)-derived exosomes(Exos)are promising therapeutic agents for the treatment of acute CNS injuries due to their immunomodulatory and regenerative properties.MSC-Exos are nanoscale membrane vesicles that are actively released by cells and are used clinically as circulating biomarkers for disease diagnosis and prognosis.MSC-Exos can be neuroprotective in several acute CNS models,including for stroke and traumatic brain injury,showing great clinical potential.This review summarized the classification of acute CNS injury disorders and discussed the prominent role of microglial activation in acute CNS inflammation and the specific role of MSC-Exos in regulating pro-inflammatory microglia in neuroinflammatory repair following acute CNS injury.Finally,this review explored the potential mechanisms and factors associated with MSCExos in modulating the phenotypic balance of microglia,focusing on the interplay between CNS inflammation,the brain,and injury aspects,with an emphasis on potential strategies and therapeutic interventions for improving functional recovery from early CNS inflammation caused by acute CNS injury.
基金Supported by the Ph.D.Programs Foundation of Heilongjiang Province(No.LBH-Q13126)the Research Foundation of the First Affiliated Hospital,Harbin Medical University(No.2011BS017)
文摘AIM：To report a phenotypic variant pedigree of lattice corneal dystrophy（LCD）associated with two mutations,R124C and A546 D,in the transforming growth factor betainduced gene（TGFBI）.METHODS：A detailed ocular examination was taken for all participants of a LCD family. Peripheral blood leukocytes from each participant were extracted to obtain the DNA. Polymerase chain reaction（PCR）of all seventeen exons of TGFBI gene was performed. The products were sequenced and analyzed. Histological examination was carried out after a penetrating keratoplasty from the right eye of proband. RESULTS：Genetic analysis showed that the proband and all 6 affected individuals harbored both a heterozygous CGC to TGC mutation at codon 124 and a heterozygous GCC to GAC mutation at codon 546 of TGFBI. None of the 100 control subjects and unaffected family members was positive for these two mutations. Ocular examination displayed multiple refractile lattice-like opacities in anterior stroma of the central cornea and small granular deposits in the peripheral cornea. The deposits were stained positively with Congo red indicating be amyloid in nature and situated mainly in the anterior and middle stroma. CONCLUSION：We observed a novel LCD family which carried two pathogenic mutations（R124C and A546D）in the TGFBI gene. The phenotypic features were apparently different from those associated with corresponding single mutations. The result reveals that although the definite mutation is the most important genetic cause of the disease,some different modifier alleles may influence the phenotype.
基金supported by the National Natural Science Foundation of China (81774105)。
文摘Objective: To investigate the bioactive components of Sangqi Qingxuan formula(SQQX), predict the pharmacological targets, and explore the mechanism of hypertensive vascular remodeling(HVR).Methods: Network pharmacology was adopted to predict how SQQX acts in HVR. The effectiveness was assessed by blood pressure measurements and pathological morphology observation based on a spontaneously hypertensive rat model, while the mechanism of SQQX on HVR was validated by immunohistochemistry(IHC) and western blot(WB) according to the results of network pharmacology.Results: There were 130 bioactive components of SQQX and 231 drug targets predicted by the Traditional Chinese Medicine Systems Pharmacology Database. Subsequently, 181 common targets were identified for SQQX against HVR, with TP53, MAPK1, and AKT1 as the core targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses was employed to identify the top 20 enriched functions and the top 20 pathways(P <.01). Finally, the key role of the ERK/MAPK signaling pathway in HVR was determined. The in vivo results suggested that SQQX reduced systolic blood pressure and increased the ratio of thoracic aortic wall thickness to lumen diameter. Additionally, compared with the model group, SQQX increased the expression of smooth muscle 22 alpha(IHC: P <.001;WB:P <.05) and decreased the expression of osteopontin(IHC: P <.001;WB: P <.05), ERK1/2(IHC: P <.001;WB: ERK1 & ERK2, all P <.05), p-ERK1/2(IHC: P <.001;WB: ERK1 & ERK2, all P <.05), and the ratio of pERK1/2 to ERK1/2 protein(IHC: P <.001).Conclusions: SQQX, which has multiple bioactive ingredients and potential targets, is an effective treatment for HVR. The mechanism of antihypertensive and vascular protection may be related to the inhibition of phenotypic transformation of vascular smooth muscle cells and the ERK/MAPK signaling pathway.
基金supported by the National Natural Science Foundation of China(92043202,91673074,82241086,and 82273669).
文摘Volatile organic compounds(VOCs)are widespread indoor gaseous pollutants that are associated with vascular diseases.However,due to methodological limitations,the underlying mechanisms of VOC-induced aortic fibrosis remains unclear.To address this gap,we established a real-world indoor renovation VOC inhalation mouse model and used an innovative ex vivo biosensor assay with endothelial cells to respond to serum derived from VOC exposed mice,exploring the adverse health outcomes of total VOCs on the aorta and its potential mechanisms.The ex vivo biosensor assay confirmed that VOCs triggered phenotypic transformation of aortic smooth muscle cells via epigenetic changes in aortic endothelial cells.Mechanistically,VOCs elevated mitochondrial DNA(mtDNA)methylation by upregulating DNMT1,leading to mtDNA leakage and subsequent activation of the cGAS-STING inflammatory pathway.By integrating real-world indoor VOC exposure with mechanistic cellular analysis,this ex vivo biosensor assay offers a physiologically relevant model to elucidate the systemic vascular toxicity of complex environmental mixtures.Overall,this study revealed the molecular mechanism of indoor VOC-induced aortic fibrosis based on increased mtDNA methylation in aortic endothelial cells,which mediated the phenotypic transformation of aortic smooth muscle cells.mtDNA methylation may serve as a potential target for preventing aortic fibrosis or alleviating symptoms in affected patients.Our study highlights the urgent need for improved VOC monitoring in indoor environments and provides strategies for more precise environmental risk assessments.
