Periodontitis is a complex chronic inflammatory disease.The invasion of pathogens induces the inflammatory microenvironment in periodontitis.Cell behavior changes in response to changes in the microenvironment,which i...Periodontitis is a complex chronic inflammatory disease.The invasion of pathogens induces the inflammatory microenvironment in periodontitis.Cell behavior changes in response to changes in the microenvironment,which in turn alters the local inflammatory microenvironment of the periodontium through factors secreted by cells.It has been confirmed that periodontal ligament stem cells(PDLSCs)are vital in the development of periodontal disease.Moreover,PDLSCs are the most effective cell type to be used for periodontium regeneration.This review focuses on changes in PDLSCs,their basic biological behavior,osteogenic differentiation,and drug effects caused by the inflammatory microenvironment,to provide a better understanding of the influence of these factors on periodontal tissue homeostasis.In addition,we discuss the underlying mechanism in detail behind the reciprocal responses of PDLSCs that affect the microenvironment.展开更多
Oxidative stress,dysbiosis,and immune dysregulation have been confirmed to play pivotal roles in the complex pathogenesis of inflammatory bowel disease(IBD).Herein,we design copper ion-luteolin nanocomplexes(CuL NCs)t...Oxidative stress,dysbiosis,and immune dysregulation have been confirmed to play pivotal roles in the complex pathogenesis of inflammatory bowel disease(IBD).Herein,we design copper ion-luteolin nanocomplexes(CuL NCs)through a metal-polyphenol coordination strategy,which plays a multifaceted role in the amelioration of IBD.The fabricated CuL NCs function as therapeutic agents with exceptional antioxidant and anti-inflammatory capabilities because of their great stability and capacity to scavenge reactive oxygen species(ROS).It can effectively modulate the inflammatory microenvironment including facilitating the efficient reduction of pro-inflammatory cytokine levels,protecting intestinal epithelial cells,promoting mucosal barrier repair and regu-lating intestinal microbiota.In addition,CuL NCs have been found to enhance cellular antioxidant and anti-inflammatory capacities by regulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1(Nrf2/HO-1)oxidative stress pathway and nuclear factor kappa B(NF-κB)signaling pathway,respectively.Notably,CuL NCs demonstrate significant prophylactic and therapeutic efficacy in mouse models with typical IBD,including ulcerative colitis(UC)and Crohn’s disease(CD).This study provides a new approach for building multifaceted therapeutic platforms for natural products to treat IBD.展开更多
Objective: The analgesic effect of Paeonia Lactiflora has been widely accepted in traditional Chinese medicine. But little is known about the potential mechanism. This study aims to elucidate the effective components ...Objective: The analgesic effect of Paeonia Lactiflora has been widely accepted in traditional Chinese medicine. But little is known about the potential mechanism. This study aims to elucidate the effective components and analgesic mechanism based on network pharmacology. Methods: TCMSP was screened to collect the possible active ingredients and their CAS and SMILES was searched in Pubchem and further be used for reverse molecular docking in Swiss Target Prediction database to obtain potential targets. Pain-related molecules were obtained from GeenCards database, and the predicted targets of Paeonia Lactiflora for pain treatment were selected by Wayne diagram. For mechanism analysis, the protein-protein interactions were constructed by String, the GO analysis and KEGG analysis were conducted in DAVID. Results: Through GO analysis and KEGG analysis, we found that the pain related signaling pathways mainly involved in serotonergic synapse, calcium signaling pathway, inflammatory mediator TRP channels. Using network-based systems biology and molecular docking analyses, we predicted that 11 active ingredients in Paeonia Lactiflora has the analgesic effects with 97 potential targets. PRKCA, CASP3, ALOX15, SLC6A4, PRKCG, ALOX5, PRKCB, ALOX12, EGFR, ADRB2, RYR3, RYR1, NOS2, PTAFR, PRKCQ, and PRKCD were involved in the analgesic effects of Paeonia Lactiflora. Conclusion: Paeonia Lactiflora may alleviate pain through inflammatory mediator regulation of TRP channels, Ca2+ signaling pathway and 5-HT receptor. PRKCA, PRKCB, PRKCD,PRKCQ, and PRKCG may be new targets for pain treatment.展开更多
Rheumatoid arthritis(RA)is a chronic inflammatory disease characterized by synovitis and destruction of cartilage,promoted by sustained inflammation.However,current treatments remain unsatisfactory due to lacking of s...Rheumatoid arthritis(RA)is a chronic inflammatory disease characterized by synovitis and destruction of cartilage,promoted by sustained inflammation.However,current treatments remain unsatisfactory due to lacking of selective and effective strategies for alleviating inflammatory environments in RA joint.Inspired by neutrophil chemotaxis for inflammatory region,we therefore developed neutrophil-derived exosomes functionalized with sub-5 nm ultrasmall Prussian blue nanoparticles(uPB-Exo)via click chemistry,inheriting neutrophil-targeted biological molecules and owning excellent anti-inflammatory properties.uPB-Exo can selectively accumulate in activated fibroblast-like synoviocytes,subsequently neutralizing pro-inflammatory factors,scavenging reactive oxygen species,and alleviating inflammatory stress.In addition,uPB-Exo effectively targeted to inflammatory synovitis,penetrated deeply into the cartilage and real-time visualized inflamed joint through MRI system,leading to precise diagnosis of RA in vivo with high sensitivity and specificity.Particularly,uPB-Exo induced a cascade of anti-inflammatory events via Th17/Treg cell balance regulation,thereby significantly ameliorating joint damage.Therefore,nanoenzyme functionalized exosomes hold the great potential for enhanced treatment of RA in clinic.展开更多
Tendinopathy is a common musculoskeletal disorder which results in chronic pain and reduced performance.The therapeutic effect of stem cell derived-small extracellular vesicles(sEVs)for tendinopathy has been validated...Tendinopathy is a common musculoskeletal disorder which results in chronic pain and reduced performance.The therapeutic effect of stem cell derived-small extracellular vesicles(sEVs)for tendinopathy has been validated in recent years.However,whether large extracellular vesicles(lEVs),another subset of extracellular vesicles,possesses the ability for the improvement of tendinopathy remains unknown.Here,we showed that lEVs secreted from iPSC-derived MSCs(iMSC-lEVs)significantly mitigated pain derived from tendinopathy in rats.Immuno-histochemical analysis showed that iMSC-lEVs regulated the heterogeneity of infiltrated macrophages and several inflammatory cytokines in rat tendon tissue.Meanwhile,in vitro experiments revealed that the M1 pro-inflammatory macrophages were repolarized towards M2 anti-inflammatory macrophages by iMSC-lEVs,and this effect was mediated by regulating p38 MAPK pathway.Moreover,liquid chromatography-tandem mass spectrometry analysis identified 2208 proteins encapsulated in iMSC-lEVs,including 134 new-found proteins beyond current Vesiclepedia database.By bioinformatics and Western blot analyses,we showed that DUSP2 and DUSP3,the negative regulator of p38 phosphorylation,were enriched in iMSC-lEVs and could be transported to macrophages.Further,the immunomodulatory effect of iMSC-lEVs on macrophages was validated in explant tendon tissue from tendinopathy patients.Taken together,our results demonstrate that iMSC-lEVs could reduce inflammation in tendinopathy by regulating macrophage heterogeneity,which is mediated via the p38 MAPK pathway by delivery of DUSP2 and DUSP3,and might be a promising candidate for tendinopathy therapy.展开更多
Stem cell-based therapy has been used to treat ischaemic heart diseases for two decades.However,optimal cell types and transplantation methods remain unclear.This study evaluated the therapeutic effects of human umbil...Stem cell-based therapy has been used to treat ischaemic heart diseases for two decades.However,optimal cell types and transplantation methods remain unclear.This study evaluated the therapeutic effects of human umbilical cord mesenchymal stem cell(hUCMSC)sheet on myocardial infarction(MI).Methods:hUCMSCs expressing luciferase were generated by lentiviral transduction for in vivo bio-luminescent imaging tracking of cells.We applied a temperature-responsive cell culture surface-based method to form the hUCMSC sheet.Cell retention was evaluated using an in vivo bio-luminescent imaging tracking system.Unbiased transcriptional profiling of infarcted hearts and further immunohistochemical assessment of monocyte and macrophage subtypes were used to determine the mechanisms underlying the therapeutic effects of the hUCMSC sheet.Echocardiography and pathological analyses of heart sections were performed to evaluate cardiac function,angiogenesis and left ventricular remodelling.Results:When transplanted to the infarcted mouse hearts,hUCMSC sheet significantly improved the retention and survival compared with cell suspension.At the early stage of MI,hUCMSC sheet modulated inflammation by decreasing Mcp1-positive monocytes and CD68-positive macrophages and increasing Cx3cr1-positive non-classical macrophages,preserving the cardiomyocytes from acute injury.Moreover,the extracellular matrix produced by hUCMSC sheet then served as bioactive scaffold for the host cells to graft and generate new epicardial tissue,providing mechanical support and routes for revascularsation.These effects of hUCMSC sheet treatment significantly improved the cardiac function at days 7 and 28 post-MI.Conclusions:hUCMSC sheet formation dramatically improved the biological functions of hUCMSCs,mitigating adverse post-MI remodelling by modulating the inflammatory response and providing bioactive scaffold upon transplantation into the heart.Translational perspective:Due to its excellent availability as well as superior local cellular retention and survival,allogenic transplantation of hUCMSC sheets can more effectively acquire the biological functions of hUCMSCs,such as modulating inflammation and enhancing angiogenesis.Moreover,the hUCMSC sheet method allows the transfer of an intact extracellular matrix without introducing exogenous or synthetic biomaterial,further improving its clinical applicability.展开更多
基金supported by the Jilin Provincial Department of Finance(No.jcsz2020304-9)the Guangzhou Medical University Student Innovation Ability Improvement Program(No.(2022)66-113),China。
文摘Periodontitis is a complex chronic inflammatory disease.The invasion of pathogens induces the inflammatory microenvironment in periodontitis.Cell behavior changes in response to changes in the microenvironment,which in turn alters the local inflammatory microenvironment of the periodontium through factors secreted by cells.It has been confirmed that periodontal ligament stem cells(PDLSCs)are vital in the development of periodontal disease.Moreover,PDLSCs are the most effective cell type to be used for periodontium regeneration.This review focuses on changes in PDLSCs,their basic biological behavior,osteogenic differentiation,and drug effects caused by the inflammatory microenvironment,to provide a better understanding of the influence of these factors on periodontal tissue homeostasis.In addition,we discuss the underlying mechanism in detail behind the reciprocal responses of PDLSCs that affect the microenvironment.
基金supported by the National Natural Science Foundation of China(Grants 82200610)the Natural Science Foundation of Hubei Province(2024AFB109)the Basic and Clinical Cooperative Research and Promotion Program of Anhui Medical University(2021xkjT027).
文摘Oxidative stress,dysbiosis,and immune dysregulation have been confirmed to play pivotal roles in the complex pathogenesis of inflammatory bowel disease(IBD).Herein,we design copper ion-luteolin nanocomplexes(CuL NCs)through a metal-polyphenol coordination strategy,which plays a multifaceted role in the amelioration of IBD.The fabricated CuL NCs function as therapeutic agents with exceptional antioxidant and anti-inflammatory capabilities because of their great stability and capacity to scavenge reactive oxygen species(ROS).It can effectively modulate the inflammatory microenvironment including facilitating the efficient reduction of pro-inflammatory cytokine levels,protecting intestinal epithelial cells,promoting mucosal barrier repair and regu-lating intestinal microbiota.In addition,CuL NCs have been found to enhance cellular antioxidant and anti-inflammatory capacities by regulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1(Nrf2/HO-1)oxidative stress pathway and nuclear factor kappa B(NF-κB)signaling pathway,respectively.Notably,CuL NCs demonstrate significant prophylactic and therapeutic efficacy in mouse models with typical IBD,including ulcerative colitis(UC)and Crohn’s disease(CD).This study provides a new approach for building multifaceted therapeutic platforms for natural products to treat IBD.
基金the National Natural Science Foundation of China (Grant No. 81874404).
文摘Objective: The analgesic effect of Paeonia Lactiflora has been widely accepted in traditional Chinese medicine. But little is known about the potential mechanism. This study aims to elucidate the effective components and analgesic mechanism based on network pharmacology. Methods: TCMSP was screened to collect the possible active ingredients and their CAS and SMILES was searched in Pubchem and further be used for reverse molecular docking in Swiss Target Prediction database to obtain potential targets. Pain-related molecules were obtained from GeenCards database, and the predicted targets of Paeonia Lactiflora for pain treatment were selected by Wayne diagram. For mechanism analysis, the protein-protein interactions were constructed by String, the GO analysis and KEGG analysis were conducted in DAVID. Results: Through GO analysis and KEGG analysis, we found that the pain related signaling pathways mainly involved in serotonergic synapse, calcium signaling pathway, inflammatory mediator TRP channels. Using network-based systems biology and molecular docking analyses, we predicted that 11 active ingredients in Paeonia Lactiflora has the analgesic effects with 97 potential targets. PRKCA, CASP3, ALOX15, SLC6A4, PRKCG, ALOX5, PRKCB, ALOX12, EGFR, ADRB2, RYR3, RYR1, NOS2, PTAFR, PRKCQ, and PRKCD were involved in the analgesic effects of Paeonia Lactiflora. Conclusion: Paeonia Lactiflora may alleviate pain through inflammatory mediator regulation of TRP channels, Ca2+ signaling pathway and 5-HT receptor. PRKCA, PRKCB, PRKCD,PRKCQ, and PRKCG may be new targets for pain treatment.
基金Key Program of NSFC(81730067)Major Project of NSFC(81991514)+5 种基金Fundamental Research Funds for the Central Universities(14380493,14380494)National Science Foundation of China(Grant No 82002370,31800806,82000069)China Postdoctoral Science Foundation(Grant No 2019M661806)Natural science foundation of Jiangsu province(Grant No BK20200117,BK20200314),Jiangsu postdoctoral research support project(Grant No 2021K059A)Nanjing University Innovation Program for PhD candidates(CXYJ21-62)Jiangsu Provincial Key Medical Center Foundation,Jiangsu Provincial Medical Outstanding Talent Foundation,Jiangsu Provincial Medical Youth Talent Foundation,Jiangsu Provincial Key Medical Talent Foundation,Program of Innovation and Entrepreneurship of Jiangsu Province.
文摘Rheumatoid arthritis(RA)is a chronic inflammatory disease characterized by synovitis and destruction of cartilage,promoted by sustained inflammation.However,current treatments remain unsatisfactory due to lacking of selective and effective strategies for alleviating inflammatory environments in RA joint.Inspired by neutrophil chemotaxis for inflammatory region,we therefore developed neutrophil-derived exosomes functionalized with sub-5 nm ultrasmall Prussian blue nanoparticles(uPB-Exo)via click chemistry,inheriting neutrophil-targeted biological molecules and owning excellent anti-inflammatory properties.uPB-Exo can selectively accumulate in activated fibroblast-like synoviocytes,subsequently neutralizing pro-inflammatory factors,scavenging reactive oxygen species,and alleviating inflammatory stress.In addition,uPB-Exo effectively targeted to inflammatory synovitis,penetrated deeply into the cartilage and real-time visualized inflamed joint through MRI system,leading to precise diagnosis of RA in vivo with high sensitivity and specificity.Particularly,uPB-Exo induced a cascade of anti-inflammatory events via Th17/Treg cell balance regulation,thereby significantly ameliorating joint damage.Therefore,nanoenzyme functionalized exosomes hold the great potential for enhanced treatment of RA in clinic.
基金National Natural Science Foundation of China(Grant No.81870972,82072550)Science and Technology Commission of Shanghai Municipality(Grant No.21DZ2201300).
文摘Tendinopathy is a common musculoskeletal disorder which results in chronic pain and reduced performance.The therapeutic effect of stem cell derived-small extracellular vesicles(sEVs)for tendinopathy has been validated in recent years.However,whether large extracellular vesicles(lEVs),another subset of extracellular vesicles,possesses the ability for the improvement of tendinopathy remains unknown.Here,we showed that lEVs secreted from iPSC-derived MSCs(iMSC-lEVs)significantly mitigated pain derived from tendinopathy in rats.Immuno-histochemical analysis showed that iMSC-lEVs regulated the heterogeneity of infiltrated macrophages and several inflammatory cytokines in rat tendon tissue.Meanwhile,in vitro experiments revealed that the M1 pro-inflammatory macrophages were repolarized towards M2 anti-inflammatory macrophages by iMSC-lEVs,and this effect was mediated by regulating p38 MAPK pathway.Moreover,liquid chromatography-tandem mass spectrometry analysis identified 2208 proteins encapsulated in iMSC-lEVs,including 134 new-found proteins beyond current Vesiclepedia database.By bioinformatics and Western blot analyses,we showed that DUSP2 and DUSP3,the negative regulator of p38 phosphorylation,were enriched in iMSC-lEVs and could be transported to macrophages.Further,the immunomodulatory effect of iMSC-lEVs on macrophages was validated in explant tendon tissue from tendinopathy patients.Taken together,our results demonstrate that iMSC-lEVs could reduce inflammation in tendinopathy by regulating macrophage heterogeneity,which is mediated via the p38 MAPK pathway by delivery of DUSP2 and DUSP3,and might be a promising candidate for tendinopathy therapy.
基金This work was supported by the Peking University Third Hospital Key Clinical Foundation[grant numbers BYSY2015007,BYSY2018039 and BYSYDL2019016 to Y.L.]the capital health research and development of special[grant number 2020-2-4096 to Y.L.]+1 种基金the Beijing Natural Science Foundation[grant number Z190013 to F.L.]the National Natural Science Foundation of China[grant number 81970205 to F.L.].
文摘Stem cell-based therapy has been used to treat ischaemic heart diseases for two decades.However,optimal cell types and transplantation methods remain unclear.This study evaluated the therapeutic effects of human umbilical cord mesenchymal stem cell(hUCMSC)sheet on myocardial infarction(MI).Methods:hUCMSCs expressing luciferase were generated by lentiviral transduction for in vivo bio-luminescent imaging tracking of cells.We applied a temperature-responsive cell culture surface-based method to form the hUCMSC sheet.Cell retention was evaluated using an in vivo bio-luminescent imaging tracking system.Unbiased transcriptional profiling of infarcted hearts and further immunohistochemical assessment of monocyte and macrophage subtypes were used to determine the mechanisms underlying the therapeutic effects of the hUCMSC sheet.Echocardiography and pathological analyses of heart sections were performed to evaluate cardiac function,angiogenesis and left ventricular remodelling.Results:When transplanted to the infarcted mouse hearts,hUCMSC sheet significantly improved the retention and survival compared with cell suspension.At the early stage of MI,hUCMSC sheet modulated inflammation by decreasing Mcp1-positive monocytes and CD68-positive macrophages and increasing Cx3cr1-positive non-classical macrophages,preserving the cardiomyocytes from acute injury.Moreover,the extracellular matrix produced by hUCMSC sheet then served as bioactive scaffold for the host cells to graft and generate new epicardial tissue,providing mechanical support and routes for revascularsation.These effects of hUCMSC sheet treatment significantly improved the cardiac function at days 7 and 28 post-MI.Conclusions:hUCMSC sheet formation dramatically improved the biological functions of hUCMSCs,mitigating adverse post-MI remodelling by modulating the inflammatory response and providing bioactive scaffold upon transplantation into the heart.Translational perspective:Due to its excellent availability as well as superior local cellular retention and survival,allogenic transplantation of hUCMSC sheets can more effectively acquire the biological functions of hUCMSCs,such as modulating inflammation and enhancing angiogenesis.Moreover,the hUCMSC sheet method allows the transfer of an intact extracellular matrix without introducing exogenous or synthetic biomaterial,further improving its clinical applicability.
