Periodontitis is a widespread oral disease characterized by continuous inflammation of the periodontal tissue and an irreversible alveolar bone loss, which eventually leads to tooth loss. Four-octyl itaconate(4-OI) is...Periodontitis is a widespread oral disease characterized by continuous inflammation of the periodontal tissue and an irreversible alveolar bone loss, which eventually leads to tooth loss. Four-octyl itaconate(4-OI) is a cell-permeable itaconate derivative and has been recognized as a promising therapeutic target for the treatment of inflammatory diseases. Here, we explored, for the first time,the protective effect of 4-OI on inhibiting periodontal destruction, ameliorating local inflammation, and the underlying mechanism in periodontitis. Here we showed that 4-OI treatment ameliorates inflammation induced by lipopolysaccharide in the periodontal microenvironment. 4-OI can also significantly alleviate inflammation and alveolar bone loss via Nrf2 activation as observed on samples from experimental periodontitis in the C57BL/6 mice. This was further confirmed as silencing Nrf2 blocked the antioxidant effect of 4-OI by downregulating the expression of downstream antioxidant enzymes. Additionally, molecular docking simulation indicated the possible mechanism under Nrf2 activation. Also, in Nrf2-/-mice, 4-OI treatment did not protect against alveolar bone dysfunction due to induced periodontitis, which underlined the importance of the Nrf2 in 4-OI mediated periodontitis treatment.Our results indicated that 4-OI attenuates inflammation and oxidative stress via disassociation of KEAP1-Nrf2 and activation of Nrf2 signaling cascade. Taken together, local administration of 4-OI offers clinical potential to inhibit periodontal destruction,ameliorate local inflammation for more predictable periodontitis.展开更多
Extracellular vesicles(EVs)derived from mesenchymal stem cells(MSCs)have emerged as a new mode of intercellular crosstalk and are responsible for many of the thera-peutic effects of MSCs.To promote the application of ...Extracellular vesicles(EVs)derived from mesenchymal stem cells(MSCs)have emerged as a new mode of intercellular crosstalk and are responsible for many of the thera-peutic effects of MSCs.To promote the application of MSC-EVs,recent studies have focused on the manipulation of MSCs to improve the production of EVs and EV-mediated activities.The current paper details an optimization method using non-invasive low-intensity pulsed ul-trasound(LIPUS)as the stimulation for improving oral MSC-EV production and effectiveness.Stem cells from apical papilla(SCAP),a type of oral mesenchymal stem cell,displayed inten-sity-dependent pro-osteogenic and anti-inflammatory responses to LIPUS without significant cytotoxicity or apoptosis.The stimuli increased the secretion of EVs by promoting the expres-sion of neutral sphingomyelinases in SCAP.In addition,EVs from LIPUS-induced SCAP exhibited stronger efficacy in promoting the osteogenic differentiation and anti-inflammation of peri-odontal ligament cells in vitro and alleviating oral inflammatory bone loss in vivo.In addition,LIPUS stimulation affected the physical characteristics and miRNA cargo of SCAP-EVs.Further investigations indicated that miR-935 is an important mediator of the pro-osteogenic and anti-inflammatory capabilities of LIPUS-induced SCAP-EVs.Taken together,these findings demonstrate that LIPUS is a simple and effective physical method to optimize SCAP-EV produc-tion and efficacy.展开更多
基金supported by the National Natural Science Foundation of China (31971282 and 32071362)2019 Chongqing Graduate Tutor Team Construction Project (dstd201903)Scientific and Technological Research Program of Chongqing Municipal Education Commission (KJQN201900415)。
文摘Periodontitis is a widespread oral disease characterized by continuous inflammation of the periodontal tissue and an irreversible alveolar bone loss, which eventually leads to tooth loss. Four-octyl itaconate(4-OI) is a cell-permeable itaconate derivative and has been recognized as a promising therapeutic target for the treatment of inflammatory diseases. Here, we explored, for the first time,the protective effect of 4-OI on inhibiting periodontal destruction, ameliorating local inflammation, and the underlying mechanism in periodontitis. Here we showed that 4-OI treatment ameliorates inflammation induced by lipopolysaccharide in the periodontal microenvironment. 4-OI can also significantly alleviate inflammation and alveolar bone loss via Nrf2 activation as observed on samples from experimental periodontitis in the C57BL/6 mice. This was further confirmed as silencing Nrf2 blocked the antioxidant effect of 4-OI by downregulating the expression of downstream antioxidant enzymes. Additionally, molecular docking simulation indicated the possible mechanism under Nrf2 activation. Also, in Nrf2-/-mice, 4-OI treatment did not protect against alveolar bone dysfunction due to induced periodontitis, which underlined the importance of the Nrf2 in 4-OI mediated periodontitis treatment.Our results indicated that 4-OI attenuates inflammation and oxidative stress via disassociation of KEAP1-Nrf2 and activation of Nrf2 signaling cascade. Taken together, local administration of 4-OI offers clinical potential to inhibit periodontal destruction,ameliorate local inflammation for more predictable periodontitis.
基金supported by the National Natural Science Foundation of China(No.81771082,81800985,82170968,31971282)the 2019 Chongqing Graduate Tutor Team Construction Project(No.dstd201903),Chinathe Natural Science Foundation of Chongqing(No.cstc2019jcyj-msxmX0851),China.
文摘Extracellular vesicles(EVs)derived from mesenchymal stem cells(MSCs)have emerged as a new mode of intercellular crosstalk and are responsible for many of the thera-peutic effects of MSCs.To promote the application of MSC-EVs,recent studies have focused on the manipulation of MSCs to improve the production of EVs and EV-mediated activities.The current paper details an optimization method using non-invasive low-intensity pulsed ul-trasound(LIPUS)as the stimulation for improving oral MSC-EV production and effectiveness.Stem cells from apical papilla(SCAP),a type of oral mesenchymal stem cell,displayed inten-sity-dependent pro-osteogenic and anti-inflammatory responses to LIPUS without significant cytotoxicity or apoptosis.The stimuli increased the secretion of EVs by promoting the expres-sion of neutral sphingomyelinases in SCAP.In addition,EVs from LIPUS-induced SCAP exhibited stronger efficacy in promoting the osteogenic differentiation and anti-inflammation of peri-odontal ligament cells in vitro and alleviating oral inflammatory bone loss in vivo.In addition,LIPUS stimulation affected the physical characteristics and miRNA cargo of SCAP-EVs.Further investigations indicated that miR-935 is an important mediator of the pro-osteogenic and anti-inflammatory capabilities of LIPUS-induced SCAP-EVs.Taken together,these findings demonstrate that LIPUS is a simple and effective physical method to optimize SCAP-EV produc-tion and efficacy.
