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
Besides their possible effects on the development of inflammatory bowel disease(IBD),some environmental factors can modulate the clinical course of both ulcerative colitis(UC) and Crohn's disease(CD).This review i...Besides their possible effects on the development of inflammatory bowel disease(IBD),some environmental factors can modulate the clinical course of both ulcerative colitis(UC) and Crohn's disease(CD).This review is mainly devoted to describing the current knowledge of the impact of some of these factors on the outcome of IBD,with special emphasis on smoking and diet.Although the impact of smoking on the susceptibility to develop CD and UC is firmly established,its influence on the clinical course of both diseases is still debatable.In CD,active smoking is a risk factor for postoperative recurrence.Beyond this clinical setting,smoking cessation seems to be advantageous in those CD patients who were smokers at disease diagnosis,while smoking resumption may be of benefit in ex-smokers with resistant UC.The role of dietary habits on the development of IBD is far from being well established.Also,food intolerances are very frequent,but usually inconsistent among IBD patients,and therefore no general dietary recommendations can be made in these patients.In general,IBD patients should eat a diet as varied as possible.Regarding the possible therapeutic role of some dietary components in IBD,lessons should be drawn from the investigation of the primary therapeutic effect of enteral nutrition in CD.Low-fat diets seem to be particularly useful.Also,some lipid sources,such as olive oil,medium-chain triglycerides,and perhaps omega-3 fatty acids,might have a therapeutic effect.Fermentable fiber may have a role in preventing relapses in inactive UC.展开更多
Objectives:Metastatic spread to the lung is one of the leading causes of fatal outcomes in thyroid cancer,but the underlying molecular mechanisms remain unclear.To investigate how exosomal microRNA-17-5p(miR-17-5p)pro...Objectives:Metastatic spread to the lung is one of the leading causes of fatal outcomes in thyroid cancer,but the underlying molecular mechanisms remain unclear.To investigate how exosomal microRNA-17-5p(miR-17-5p)promotes lung metastasis in thyroid cancer within the framework of the“seed and soil”hypothesis.Methods:Serum exosomes from thyroid cancer lung metastasis patients and controls were analyzed for miR-17,which was elevated in metastatic cases.miR-17 was transfected into embryonic lung fibroblasts(MRC-5),and their supernatants were cocultured with thyroid cancer cells(Cal62).Cell proliferation and migration were evaluated using colony formation,Ki67 staining,and Transwell assays.Interleukin-6(IL-6)/interleukin-8(IL-8)levels and nuclear factor kappa-B(NF-κB)/nuclear factor kappa-B repressing factor(NKRF)expression were analysed by enzyme-linked immunosorbent assays(ELISA)and western blot.In vivo models verified the metastatic-promoting effect of miR-17.Results:miR-17-5p was significantly enriched in serum exosomes of metastatic patients.In MRC-5 cells,it suppressed NKRF,NF-κB signaling,and increased secretion of IL-6 and IL-8,enhancing Cal62 proliferation and migration.Animal experiments confirmed its role in promoting tumor growth and lung metastasis.Conclusions:Exosomal miR-17-5p remodels the pulmonary microenvironment into a pro-inflammatory niche,facilitating thyroid cancer colonization and offering a potential therapeutic target.展开更多
The impaired function of periodontal ligament stem cells(PDLSCs)impedes restoration of periodontal tissues.The cGAS-cGAMP-STING pathway is an innate immune pathway that sensing cytosolic double-stranded DNA(dsDNA),but...The impaired function of periodontal ligament stem cells(PDLSCs)impedes restoration of periodontal tissues.The cGAS-cGAMP-STING pathway is an innate immune pathway that sensing cytosolic double-stranded DNA(dsDNA),but its role in regulating the function of PDLSCs is still unclear.In this study,we found that mito-chondrial DNA(mtDNA)was released into the cytoplasm through the mitochondrial permeability transition pore(mPTP)in PDLSCs upon inflammation,which binds to cGAS and activated the STING pathway by promoting the production of cGAMP,and ultimately impaired the osteogenic differentiation of PDLSCs.Additionally,it is first found that inflammation can down-regulate the level of the ATP-binding cassette membrane subfamily member C1(ABCC1,a cGAMP exocellular transporter)and ectonucleotide pyrophosphatase/phosphodiesterase 1(ENPP1,a cGAMP hydrolase),which further aggravated the accumulation of intracellular cGAMP,leading to the persistent activation of the cGAS-STING pathway and thus the impaired the differentiation capacity of PDLSCs.Furthermore,we designed a hydrogel system loaded with a mPTP blocker,an ABCC1 agonist and ENPP1 to promote periodontal tissue regeneration by modulating the production,exocytosis,and clearance of cGAMP.In conclusion,our results highlight the profound effects,and specific mechanisms,of the cGAS-STING pathway on the function of stem cells and propose a new strategy to promote periodontal tissue restoration based on the reestablishment of cGAMP homeostasis.展开更多
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.
文摘Besides their possible effects on the development of inflammatory bowel disease(IBD),some environmental factors can modulate the clinical course of both ulcerative colitis(UC) and Crohn's disease(CD).This review is mainly devoted to describing the current knowledge of the impact of some of these factors on the outcome of IBD,with special emphasis on smoking and diet.Although the impact of smoking on the susceptibility to develop CD and UC is firmly established,its influence on the clinical course of both diseases is still debatable.In CD,active smoking is a risk factor for postoperative recurrence.Beyond this clinical setting,smoking cessation seems to be advantageous in those CD patients who were smokers at disease diagnosis,while smoking resumption may be of benefit in ex-smokers with resistant UC.The role of dietary habits on the development of IBD is far from being well established.Also,food intolerances are very frequent,but usually inconsistent among IBD patients,and therefore no general dietary recommendations can be made in these patients.In general,IBD patients should eat a diet as varied as possible.Regarding the possible therapeutic role of some dietary components in IBD,lessons should be drawn from the investigation of the primary therapeutic effect of enteral nutrition in CD.Low-fat diets seem to be particularly useful.Also,some lipid sources,such as olive oil,medium-chain triglycerides,and perhaps omega-3 fatty acids,might have a therapeutic effect.Fermentable fiber may have a role in preventing relapses in inactive UC.
基金supported by grants from the National Natural Science Foundation of China(Nos.82173125,81974374)General Support Projects of the Health Commission of Binhai New Area(2023BWKY024)Tianjin Key Medical Discipline Construction Project(TJYXZDXK044A).
文摘Objectives:Metastatic spread to the lung is one of the leading causes of fatal outcomes in thyroid cancer,but the underlying molecular mechanisms remain unclear.To investigate how exosomal microRNA-17-5p(miR-17-5p)promotes lung metastasis in thyroid cancer within the framework of the“seed and soil”hypothesis.Methods:Serum exosomes from thyroid cancer lung metastasis patients and controls were analyzed for miR-17,which was elevated in metastatic cases.miR-17 was transfected into embryonic lung fibroblasts(MRC-5),and their supernatants were cocultured with thyroid cancer cells(Cal62).Cell proliferation and migration were evaluated using colony formation,Ki67 staining,and Transwell assays.Interleukin-6(IL-6)/interleukin-8(IL-8)levels and nuclear factor kappa-B(NF-κB)/nuclear factor kappa-B repressing factor(NKRF)expression were analysed by enzyme-linked immunosorbent assays(ELISA)and western blot.In vivo models verified the metastatic-promoting effect of miR-17.Results:miR-17-5p was significantly enriched in serum exosomes of metastatic patients.In MRC-5 cells,it suppressed NKRF,NF-κB signaling,and increased secretion of IL-6 and IL-8,enhancing Cal62 proliferation and migration.Animal experiments confirmed its role in promoting tumor growth and lung metastasis.Conclusions:Exosomal miR-17-5p remodels the pulmonary microenvironment into a pro-inflammatory niche,facilitating thyroid cancer colonization and offering a potential therapeutic target.
基金the National Natural Science Founda-tion of China(82220108019 to P.Ji and 82201059 to Q.M.Zhai)the Chongqing Postdoctoral Science Special Foundation(2021XM1031 to Q.M.Zhai)+1 种基金China Postdoctoral Science Foundation(2022M720599 to Q.M.Zhai)Haobo medical technology(Shanghai)limited company helped us synthesize the PEGA materials.
文摘The impaired function of periodontal ligament stem cells(PDLSCs)impedes restoration of periodontal tissues.The cGAS-cGAMP-STING pathway is an innate immune pathway that sensing cytosolic double-stranded DNA(dsDNA),but its role in regulating the function of PDLSCs is still unclear.In this study,we found that mito-chondrial DNA(mtDNA)was released into the cytoplasm through the mitochondrial permeability transition pore(mPTP)in PDLSCs upon inflammation,which binds to cGAS and activated the STING pathway by promoting the production of cGAMP,and ultimately impaired the osteogenic differentiation of PDLSCs.Additionally,it is first found that inflammation can down-regulate the level of the ATP-binding cassette membrane subfamily member C1(ABCC1,a cGAMP exocellular transporter)and ectonucleotide pyrophosphatase/phosphodiesterase 1(ENPP1,a cGAMP hydrolase),which further aggravated the accumulation of intracellular cGAMP,leading to the persistent activation of the cGAS-STING pathway and thus the impaired the differentiation capacity of PDLSCs.Furthermore,we designed a hydrogel system loaded with a mPTP blocker,an ABCC1 agonist and ENPP1 to promote periodontal tissue regeneration by modulating the production,exocytosis,and clearance of cGAMP.In conclusion,our results highlight the profound effects,and specific mechanisms,of the cGAS-STING pathway on the function of stem cells and propose a new strategy to promote periodontal tissue restoration based on the reestablishment of cGAMP homeostasis.
