Fibroblast growth factor(FGF)7,a member of FGF family,is initially found to be secreted from mesenchymal cells to repair epithelial tissues.However,its functions in the nervous system are largely unknown.The present s...Fibroblast growth factor(FGF)7,a member of FGF family,is initially found to be secreted from mesenchymal cells to repair epithelial tissues.However,its functions in the nervous system are largely unknown.The present study showed that FGF7 was a neuromodulator localized in the large dense-core vesicles(LDCVs)in nociceptive neurons.FGF7 was mainly expressed in small-diameter neurons of the dorsal root ganglion and could be transported to the dorsal spinal cord.Interestingly,FGF7 was mostly stored in LDCVs that did not contain neuropeptide substance P.Electrophysiological recordings in the spinal cord slice showed that buffer-applied FGF7 increased the amplitude of excitatory post-synaptic current evoked by stimulating the sensory afferent fibers.Behavior tests showed that intrathecally applied FGF7 potentiated the formalin-induced acute nociceptive response.Moreover,both acute and inflammatory nociceptive responses were significantly reduced in Fgf7-deficient mice.These results suggest that FGF7 exerts an excitatory modulation of nociceptive afferent transmission.展开更多
In a recent publication in Cell,Hsu and colleagues describe a novel kind of extracellular vesicle that is involved in the resolution of inflammation.Such large_ageing_neutrophil-derived,vesicles(LAND-Vs)that express C...In a recent publication in Cell,Hsu and colleagues describe a novel kind of extracellular vesicle that is involved in the resolution of inflammation.Such large_ageing_neutrophil-derived,vesicles(LAND-Vs)that express CD55^(+) and CD47^(+) are protected against efferocytosis and exhibit anti-inflammatory functions by inhibiting the complement activation.These findings reveal an important functional switch of neutrophils throughout the course of inflammation and identify a novel class of EVs that mediate neutrophil action beyond their limited lifespan,which may open new modes of therapeutic interference in various inflammatory conditions.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
Two triblock polymers, tetraaniline-block-poly（N-isopropyl acrylamide）-block-poly（hydroxyethyl acrylate） （TA-b-PNIPAM-b-PHEA） and TA-b-PHEA-b-PNIPAM, were synthesized with unambiguous structure by a two step met...Two triblock polymers, tetraaniline-block-poly（N-isopropyl acrylamide）-block-poly（hydroxyethyl acrylate） （TA-b-PNIPAM-b-PHEA） and TA-b-PHEA-b-PNIPAM, were synthesized with unambiguous structure by a two step method. The difference of these two diblock polymers is the connection order of carboxyl group to block, e.g., carboxyl group to PNIPAM block for PNIPAM-b-PHEA and to PHEA block for PHEA-b-PNIPAM. Secondly, block tetraaniline was linked to the diblock polymer through amidation to yield the corresponding triblock copolymer. Both of them have almost the identical chemical compositions. The only difference is the connection order of each block in the triblock polymers. When they were self-assembled at 45℃ in a suitable solution, both of their aggregates have spherical shape with slight defects on their surface with the average diameter of about 400 nm. However, when their aggregate dispersion was cooled down to 20 ℃, only TA-b-PHEA-b-PNIPAM＇s morphology changed, forming worm-like aggregates with the diameter of about 100-200 nm transformed from spherical ag- gregates. Both amphiphilic property and position of each block in this triblock copolymer are very essential for this morphology transformation. Since the worm-like aggregates presented here by our group have hollow structure in- side, its controlled release properties for doxorubicin were evaluated. Drug release experiment indicated that along with the temperature changes, the rearrangement of the intermediate layer structure caused morphology change in aggregate, thus accelerating the speed of drug release.展开更多
A number of transmembrane receptors are targeted to the nucleus and convincingly localized therein.However,what remains a conundrum is how these cell-surface receptors end up in the nucleus.In this study,we reported t...A number of transmembrane receptors are targeted to the nucleus and convincingly localized therein.However,what remains a conundrum is how these cell-surface receptors end up in the nucleus.In this study,we reported that the transmembrane receptor phosphorylated TrkA was located in a series of carrier vesicles,including ring-like vesicles near the plasma membrane,large core vesicles and small dense core vesicles around the nuclei,as well as in the nucleus in human glioma cell line U251 using immunocytochemistry and immunofluorescence staining.Meanwhile,we also showed that small dense core vesicles budded from large core vesicles,and interacted with the nuclear envelope.Accordingly,our results suggested that such a series of membrane compartments might be involved in the pathway of nuclear translocation of the transmembrane receptor TrkA.展开更多
基金This work was supported by the National Natural Science Foundation of China(31130066)the Strategic Priority Research Program(B)of Chinese Academy of Sciences(XDB01020300).
文摘Fibroblast growth factor(FGF)7,a member of FGF family,is initially found to be secreted from mesenchymal cells to repair epithelial tissues.However,its functions in the nervous system are largely unknown.The present study showed that FGF7 was a neuromodulator localized in the large dense-core vesicles(LDCVs)in nociceptive neurons.FGF7 was mainly expressed in small-diameter neurons of the dorsal root ganglion and could be transported to the dorsal spinal cord.Interestingly,FGF7 was mostly stored in LDCVs that did not contain neuropeptide substance P.Electrophysiological recordings in the spinal cord slice showed that buffer-applied FGF7 increased the amplitude of excitatory post-synaptic current evoked by stimulating the sensory afferent fibers.Behavior tests showed that intrathecally applied FGF7 potentiated the formalin-induced acute nociceptive response.Moreover,both acute and inflammatory nociceptive responses were significantly reduced in Fgf7-deficient mice.These results suggest that FGF7 exerts an excitatory modulation of nociceptive afferent transmission.
基金funded by institutional funds from the Georg-Speyer-Haus,the LOEWE Center Frankfurt Cancer Institute(FCl)funded by the Hessen State Ministry for Higher Education,Research and the Arts,as well as grants from the Deutsche Forschungsgemeinschaft(FOR2438:Gr1916/11-1,SFB1292-Project ID:318346496-TP16,SFB1479-Project ID:441891347-P02,GRK2336)the German Federal Ministry of Education and Research(BMBF+1 种基金01KD2206Q/SATURN3)the European Research Council(Advanced Grant PLASTICAN-101021078).
文摘In a recent publication in Cell,Hsu and colleagues describe a novel kind of extracellular vesicle that is involved in the resolution of inflammation.Such large_ageing_neutrophil-derived,vesicles(LAND-Vs)that express CD55^(+) and CD47^(+) are protected against efferocytosis and exhibit anti-inflammatory functions by inhibiting the complement activation.These findings reveal an important functional switch of neutrophils throughout the course of inflammation and identify a novel class of EVs that mediate neutrophil action beyond their limited lifespan,which may open new modes of therapeutic interference in various inflammatory conditions.
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 study was supported by the National Natural Science Foundation of China （No. 50903096）.
文摘Two triblock polymers, tetraaniline-block-poly（N-isopropyl acrylamide）-block-poly（hydroxyethyl acrylate） （TA-b-PNIPAM-b-PHEA） and TA-b-PHEA-b-PNIPAM, were synthesized with unambiguous structure by a two step method. The difference of these two diblock polymers is the connection order of carboxyl group to block, e.g., carboxyl group to PNIPAM block for PNIPAM-b-PHEA and to PHEA block for PHEA-b-PNIPAM. Secondly, block tetraaniline was linked to the diblock polymer through amidation to yield the corresponding triblock copolymer. Both of them have almost the identical chemical compositions. The only difference is the connection order of each block in the triblock polymers. When they were self-assembled at 45℃ in a suitable solution, both of their aggregates have spherical shape with slight defects on their surface with the average diameter of about 400 nm. However, when their aggregate dispersion was cooled down to 20 ℃, only TA-b-PHEA-b-PNIPAM＇s morphology changed, forming worm-like aggregates with the diameter of about 100-200 nm transformed from spherical ag- gregates. Both amphiphilic property and position of each block in this triblock copolymer are very essential for this morphology transformation. Since the worm-like aggregates presented here by our group have hollow structure in- side, its controlled release properties for doxorubicin were evaluated. Drug release experiment indicated that along with the temperature changes, the rearrangement of the intermediate layer structure caused morphology change in aggregate, thus accelerating the speed of drug release.
基金the National Natural Science Foundation of China(Grant Nos.30270639,30570894 and 30570981)the Doctoral Research Foundation of the Jiangsu University,China(Grant No.02JDG028)
文摘A number of transmembrane receptors are targeted to the nucleus and convincingly localized therein.However,what remains a conundrum is how these cell-surface receptors end up in the nucleus.In this study,we reported that the transmembrane receptor phosphorylated TrkA was located in a series of carrier vesicles,including ring-like vesicles near the plasma membrane,large core vesicles and small dense core vesicles around the nuclei,as well as in the nucleus in human glioma cell line U251 using immunocytochemistry and immunofluorescence staining.Meanwhile,we also showed that small dense core vesicles budded from large core vesicles,and interacted with the nuclear envelope.Accordingly,our results suggested that such a series of membrane compartments might be involved in the pathway of nuclear translocation of the transmembrane receptor TrkA.
