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Triptolide Inhibits Expression of Inflammatory Cytokines and Proliferation of Fibroblast-like Synoviocytes Induced by IL-6/sIL-6R-Mediated JAK2/STAT3 Signaling Pathway 被引量:15
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作者 Jian-jing LIN Ke TAO +4 位作者 Nan GAO Hui ZENG De-li WANG Jun YANG Jian WENG 《Current Medical Science》 SCIE CAS 2021年第1期133-139,共7页
Triptolide,a component of the Chinese herb Tripterygium wilfordii Hook F,has been proved to be effective in the treatment of rheumatoid arthritis(RA).However,its underlying mechanisms on RA have not yet been well esta... Triptolide,a component of the Chinese herb Tripterygium wilfordii Hook F,has been proved to be effective in the treatment of rheumatoid arthritis(RA).However,its underlying mechanisms on RA have not yet been well established.We observed the inhibitory effect of triptolide on the expression of inflammatory cytokines and proliferation of fibroblast-like synoviocytes(FLS)induced by the complex of interleukin-6(IL-6)and the soluble form of the IL-6 receptor(sIL-6R).Furthermore,to clarify the underlying mechanisms,we treated FLS with the Janus-activated kinase 2(JAK2)inhibitor/signal transducer and activator of transcription 3(STAT3)activation blocker AZD1480.In this study,immunohistochemical staining was used to identify vimentin(+)and CD68(−)in FLS.The FLS proliferation was measured by cell proliferation assay,and the cell cycles were analyzed by flow cytometry.Furthermore,ELISA was used to detect the expression of the inflammatory factors in culture solution.The expression levels of p-JAK2,JAK2,p-STAT3 and STAT3 were investigated through Western blotting analysis.The results showed that IL-6/sIL-6R significantly increased the cell proliferation and expression of inflammatory cytokines,including IL-6,interleukin-1β(IL-1β)and vascular endothelial growth factor(VEGF).Triptolide or AZD1480 inhibited the cell proliferation and inflammatory cytokine expression in IL-6/sIL-6R-stimulated FLS by suppressing JAK2/STAT3.The study suggested that the physiological effects of triptolide on RA were due to its contribution to the inhibition of the inflammatory cytokine expression and FLS proliferation by suppressing the JAK2/STAT3 signaling pathway.It may provide an innovative insight into the effect of triptolide in preventing RA pathogenesis. 展开更多
关键词 TRIPTOLIDE inflammatory cytokines PROLIFERATION fibroblast-like synoviocytes JAK2/STAT3
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Protective effects of Dioscin on TNF-α-induced collagen-induced arthritis rat fibroblast-like synoviocytes involves in regulating the LTB4/BLT pathway
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作者 ZHIPING WEI YAJUN LIU +6 位作者 MEIWEN YANG MENGDI LI KEXIN LI LUXI ZHENG HUIQIONG GUO FENFANG HONG SHULONG YANG 《BIOCELL》 SCIE 2021年第4期1005-1012,共8页
Background and Objective:LTB4 has been shown to be involved in rheumatoid arthritis(RA)pathogenesis.The effect of Dioscin(Dio)on the LTB4 pathway of RA have not been reported yet.This study aimed at further exploring ... Background and Objective:LTB4 has been shown to be involved in rheumatoid arthritis(RA)pathogenesis.The effect of Dioscin(Dio)on the LTB4 pathway of RA have not been reported yet.This study aimed at further exploring whether Dioscin’s effects on TNF-αinduced collagen-induced arthritis(CIA)rat fibroblast-like synoviocytes(FLS)connected with the LTB4 and its receptor pathway.Materials&Methods:In this experiment,control group,TNF-αgroup,and different concentrations of Dioscin groups were established.Cell viability was evaluated using MTT assay.The levels of LTB4 in the samples of above groups were measured using ELISA.The mRNA expression levels of LTA4H,BLT1,and BLT2 were detected by quantitative real time PCR,while the expression level of LTA4H proteins were detected using western blot.The distribution of LTA4H was assessed by immunofluorescence assay.Results:the LTB4 level of TNF-αgroup in sample supernatant was higher than both control group and Dioscin groups with decreased LTB4 levels(p<0.05).Compared with the control group,the expression of LTA4H was significantly increased in TNF-αgroup(p<0.05),whereas LTA4H expressions were significantly decreased in all Dioscin groups when compared to TNF-αgroup(p<0.05).The mRNA expressions of BLT1 and BLT2 were markedly higher in TNF-αgroup than those in control group while Dioscin treatment significantly inhibited the increased expressions of BLT1 and BLT2 induced by TNF-α(p<0.05).Conclusions:These results firstly demonstrate that the protective effect of Dioscin on TNF-αinduced FLS may involve in its reducing LTB4 production by down-regulating LTA4H expression,and may inhibit its downstream pathway by decreasing LTB4 receptors levels.This findings suggest that dioscin produces a potential therapeutic effects for RA via its influencing LTA4H/LTB4/BLT pathway. 展开更多
关键词 Rheumatoid arthritis DIOSCIN fibroblast-like synoviocytes Leukotriene B4 LTA4 hydrolase Leukotriene B4 receptor
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Nuciferine alleviates collagen-induced arthritic in rats by inhibiting the proliferation and invasion of human arthritis-derived fibroblast-like synoviocytes and rectifying Th17/Treg imbalance
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作者 WANG Hao GENG Xiaolong +7 位作者 AI Fangbin YU Zhilun ZHANG Yan ZHANG Beibei LV Cheng GAO Ruiyang YUE Bei DOU Wei 《Chinese Journal of Natural Medicines》 SCIE CAS CSCD 2024年第4期341-355,共15页
Rheumatoid arthritis(RA)is a chronic autoimmune disorder marked by persistent synovial inflammation and joint degradation,posing challenges in the development of effective treatments.Nuciferine,an alkaloid found in lo... Rheumatoid arthritis(RA)is a chronic autoimmune disorder marked by persistent synovial inflammation and joint degradation,posing challenges in the development of effective treatments.Nuciferine,an alkaloid found in lotus leaf,has shown promising anti-inflammatory and anti-tumor effects,yet its efficacy in RA treatment remains unexplored.This study investigated the antiproliferative effects of nuciferine on the MH7A cell line,a human RA-derived fibroblast-like synoviocyte,revealing its ability to inhibit cell proliferation,promote apoptosis,induce apoptosis,and cause G1/S phase arrest.Additionally,nuciferine significantly reduced the migration and invasion capabilities of MH7A cells.The therapeutic potential of nuciferine was further evaluated in a collagen-induced arthritis(CIA)rat model,where it markedly alleviated joint swelling,synovial hyperplasia,cartilage injury,and inflammatory infiltration.Nuciferine also improved collagen-induced bone erosion,decreased pro-inflammatory cytokines and serum immunoglobulins(IgG,IgG1,IgG2a),and restored the balance between T helper(Th)17 and regulatory T cells in the spleen of CIA rats.These results indicate that nuciferine may offer therapeutic advantages for RA by decreasing the proliferation and invasiveness of FLS cells and correcting the Th17/Treg cell imbalance in CIA rats. 展开更多
关键词 Rheumatoid arthritis Collagen-induced arthritis fibroblast-like synoviocyte Immune imbalance NUCIFERINE
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GRK2 mediated degradation of SAV1 initiates hyperplasia of fibroblast-like synoviocytes in rheumatoid arthritis
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作者 Paipai Guo Ji Jiang +12 位作者 Rui Chu Feng He Mingli Ge Ruhong Fang Qiuyun Guan Huijuan Cheng Chunru Jiang Tiantian Su Zhenduo Zhu Hao Liu Wei Wei Shihao Zhang Qingtong Wang 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2024年第3期1222-1240,共19页
Hyperplasia and migration of fibroblast-like synoviocytes(FLSs)are the key drivers in the pathogenesis of rheumatoid arthritis(RA)and joint destruction.Abundant Yes-associated protein(YAP),which is a powerful transcri... Hyperplasia and migration of fibroblast-like synoviocytes(FLSs)are the key drivers in the pathogenesis of rheumatoid arthritis(RA)and joint destruction.Abundant Yes-associated protein(YAP),which is a powerful transcription co-activator for proliferative genes,was observed in the nucleus of inflammatory FLSs with unknown upstream mechanisms.Using Gene Expression Omnibus database analysis,it was found that Salvador homolog-1(SAV1),the pivotal negative regulator of the Hippo-YAP pathway,was slightly downregulated in RA synovium.However,SAV1 protein expression is extremely reduced.Subsequently,it was revealed that SAV1 is phosphorylated,ubiquitinated,and degraded by interacting with an important serine-threonine kinase,G protein-coupled receptor(GPCR)kinase 2(GRK2),which was predominately upregulated by GPCR activation induced by ligands such as prostaglandin E2(PGE2)in RA.This process further contributes to the decreased phosphorylation,nuclear translocation,and transcriptional potency of YAP,and leads to aberrant FLSs proliferation.Genetic depletion of GRK2 or inhibition of GRK2 by paroxetine rescued SAV1 expression and restored YAP phosphorylation and finally inhibited RA FLSs proliferation and migration.Similarly,paroxetine treatment effectively reduced the abnormal proliferation of FLSs in a rat model of collagen-induced arthritis which was accompanied by a significant improvement in clinical manifestations.Collectively,these results elucidate the significance of GRK2 regulation of Hippo-YAP signaling in FLSs proliferation and migration and the potential application of GRK2 inhibition in the treatment of FLSs-driven joint destruction in RA. 展开更多
关键词 Rheumatoid arthritis fibroblast-like synoviocytes G protein-coupled receptor kinase 2 Salvador homolog-1 Yes-associated protein
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Tetrandrine inhibits migration and invasion of rheumatoid arthritis fibroblast-like synoviocytes through down-regulating the expressions of Rac1, Cdc42, and Rho A GTPases and activation of the PI3K/Akt and JNK signaling pathways 被引量:18
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作者 LV Qi ZHU Xian-Yang +2 位作者 XIA Yu-Feng DAI Yue WEI Zhi-Feng 《Chinese Journal of Natural Medicines》 SCIE CAS CSCD 2015年第11期831-841,共11页
Tetrandrine (Tet), the main active constituent of Stephania tetrandra root, has been demonstrated to alleviate adjuvant-induced arthritis in rats. The present study was designed to investigate the effects of Tet on ... Tetrandrine (Tet), the main active constituent of Stephania tetrandra root, has been demonstrated to alleviate adjuvant-induced arthritis in rats. The present study was designed to investigate the effects of Tet on the migration and invasion of rheumatoid arthritis fibroblast-like synovioeytes (RA-FLS) and explore the underlying mechanisms. By using cultures of primary FLS isolated from synoviums of RA patients and cell line MH7A, Tet (0.3, 1 μmol L-1) was proven to significantly impede migration and invasion of RA-FLS, but not cell proliferation. Tet also greatly reduced the activation and expressions of matrix degrading enzymes MMP-2/9, the expression of F-actin and the activation of FAK, which controlled the morphologic changes in migration process of FLS. To identify the key signaling pathways by which Tet exerts anti-migration effect, the specific inhibitors of multiple signaling pathways LY294002, Triciribine, SP600125, U0126, SB203580, and PDTC (against PI3K, Akt, JNK, ERK, p38 MAPK and NF-kB-p65, respectively) were used. Among them, LY294002, Triciribine, and SP600125 were shown to obviously inhibit the migration of MH7A cells. Consistently, Tet was able to down-regulate the activation of Akt and JNK as demonstrated by Western blotting assay. Moreover, Tet could reduce the expressions of migration-related proteins Rho GTPases Rac 1, Cdc42, and RhoA in MH7A cells. In conclusion, Tet can impede the migration and invasion of RA-FLS, which provides a plausible explanation for its protective effect on RA. The underlying mechanisms involve the reduction of the expressions of Racl, Cdc42, and RhoA, inhibition of the activation of Akt and JNK, and subsequent down-regulation of activation and/or expressions of MMP-2/9, F-actin, and FAK. 展开更多
关键词 TETRANDRINE Rheumatoid arthritis fibroblast-like synoviocytes Migration Invasion
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Therapeutic effect of neohesperidin on TNF-α-stimulated human rheumatoid arthritis fibroblast-like synoviocytes 被引量:15
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作者 WANG Xiao-He DAI Ce +3 位作者 WANG Jun LIU Rui LI Lei YIN Zong-Sheng 《Chinese Journal of Natural Medicines》 SCIE CAS CSCD 2021年第10期741-749,共9页
During the pathogensis of rheumatoid arthritis(RA),activated RA fibroblast-like synoviocytes(RA-FLSs)combines similar proliferative features as tumor and inflammatory features as osteoarthritis,which eventually leads ... During the pathogensis of rheumatoid arthritis(RA),activated RA fibroblast-like synoviocytes(RA-FLSs)combines similar proliferative features as tumor and inflammatory features as osteoarthritis,which eventually leads to joint erosion.Therefore,it is imperative to research and develop new compounds,which can effectively inhibit abnormal activation of RA-FLSs and retard RA progression.Neohesperidin(Neo)is a major active component of flavonoid compounds with anti-inflammation and anti-oxidant properties.In this study,the anti-inflammation,anti-migration,anti-invasion,anti-oxidant and apoptosis-induced effects of Neo on RAFLSs were explored to investigate the underlying mechanism.The results suggested that Neo decreased the levels of interleukin IL-1β,IL-6,IL-8,TNF-α,MMP-3,MMP-9 and MMP-13 in FLSs.Moreover,Neo blocked the activation of the MAPK signaling pathway.Furthermore,treatment with Neo induced the apoptosis of FLSs,and inhibited the migration of FLSs.It was also found that Neo reduced the accumulation of reactive oxygen species(ROS)induced by TNF-α.Taken together,our results highlighted that Neo may act as a potential and promising therapeutic drug for the management of RA. 展开更多
关键词 NEOHESPERIDIN Rheumatoid-arthritis fibroblast-like synoviocytes INflAMMATORY Oxidative stress MAPK
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uPAR promotes tumor-like biologic behaviors of fibroblast-like synoviocytes through PI3K/Akt signaling pathway in patients with rheumatoid arthritis 被引量:12
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作者 Yan Liu Yun Feng Pan +10 位作者 You-qiu Xue Lin-kai Fang Xing-hua Guo Xin Guo Meng Liu Bi-yao Mo Meng-ru Yang Fang Liu Yun-ting Wu Nancy Olsen Song Guo Zheng 《Cellular & Molecular Immunology》 SCIE CAS CSCD 2018年第2期171-181,共11页
Urokinase-type plasminogen activator receptor(uPAR),is a multifunctional receptor on cell surface,widely present in endothelial cells,fibroblasts,and a variety of malignant cells.Current studies have suggested that uP... Urokinase-type plasminogen activator receptor(uPAR),is a multifunctional receptor on cell surface,widely present in endothelial cells,fibroblasts,and a variety of malignant cells.Current studies have suggested that uPAR overexpressed on synovial tissues or in synovial fluid or plasma in patients with rheumatoid arthritis(RA).However,there are limited researches regarding the role of uPAR on fibroblast-like synoviocytes of rheumatoid arthritis(RA-FLSs)and its underlying mechanisms.Here,our studies show that the expression of uPAR protein was significantly higher in fibroblast-like synoviocytes(FLSs)from RA than those from osteoarthritis or traumatic injury patients.uPAR gene silencing significantly inhibited RA-FLSs cell proliferation,restrained cell transformation from the G0/G1 phase to S phase,aggravated cell apoptosis,interfered with RA-FLSs cell migration and invasion,and reduced activation of the PI3K/Akt signaling pathway,which may be associated withβ1-integrin.Cell supernatants from uPAR gene-silenced RA-FLSs markedly inhibited the migration and tubule formation ability of the HUVECs(a human endothelial cell line).Therefore,we demonstrate that uPAR changes the biological characteristics of RA-FLSs,and affects neoangiogenesis of synovial tissues in patients with RA.All of these may be associated with theβ1-integrin/PI3K/Akt signaling pathway.These results imply that targeting uPAR and its downstream signal pathway may provide therapeutic effects in RA. 展开更多
关键词 ANGIOGENESIS cell viability fibroblast-like synoviocytes rheumatoid arthritis UPAR
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Activation of human fibroblast-like synoviocytes by uric acid crystals in rheumatoid arthritis 被引量:5
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作者 Da P Chen Chun K Wong +2 位作者 Lai S Tam Edmund K Li Christopher WK Lam 《Cellular & Molecular Immunology》 SCIE CAS CSCD 2011年第6期469-478,共10页
Hyperuricemia-mediated uric acid crystal formation may cause joint inflammation and provoke the destruction of joints through the activation of inflammasome-mediated innate immune responses.However,the immunopathologi... Hyperuricemia-mediated uric acid crystal formation may cause joint inflammation and provoke the destruction of joints through the activation of inflammasome-mediated innate immune responses.However,the immunopathological effects and underlying intracellular regulatory mechanisms of uric acid crystal-mediated activation of fibroblast-like synoviocytes(FLS)in rheumatoid arthritis(RA)have not been elucidated.Therefore,we investigated the in vitro effects of monosodium urate crystals,alone or in combination with the inflammatory cytokines tumor-necrosis factor(TNF)-a or interleukin(IL)-1b,on the activation of human FLS from RA patients and normal control subjects and the underlying intracellular signaling mechanisms of treatment with these crystals.Monosodium urate crystals were able to significantly increase the release of the inflammatory cytokine IL-6,the chemokine CXCL8 and the matrix metalloproteinase(MMP)-1 from both normal and RA-FLS(all P,0.05).Moreover,the additive or synergistic effect on the release of IL-6,CXCL8 and MMP-1 from both normal and RA-FLS was observed following the combined treatment with monosodium urate crystals and TNF-a or IL-1b.Further experiments showed that the release of the measured inflammatory cytokine,chemokine and MMP-1 stimulated by monosodium urate crystals were differentially regulated by the intracellular activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase pathways but not the p38 mitogen-activated protein kinase pathway.Our results therefore provide a new insight into the uric acid crystal-activated immunopathological mechanisms mediated by distinct intracellular signal transduction pathways leading to joint inflammation in RA. 展开更多
关键词 CYTOKINES fibroblast-like synoviocytes rheumatoid arthritis signal transduction uric acid
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Activity of fibroblast-like synoviocytes in rheumatoid arthritis was impaired by dickkopf-1 targeting siRNA 被引量:4
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作者 Yan-Ying Liu Shi-Yao Wang +7 位作者 Ying-Ni Li Wen-Jie Bian Lin-Qi Zhang Yu-Hui Li Li Long Xia Liu Xue-Wu Zhang Zhan-Guo Li 《Chinese Medical Journal》 SCIE CAS CSCD 2020年第6期679-686,共8页
Background:Fibroblast-like synoviocytes(FLSs),resident mesenchymal cells of synovial joints,play an important role in the pathogenesis of rheumatoid arthritis(RA).Dickkopf-1(DKK-1)has been proposed to be a master regu... Background:Fibroblast-like synoviocytes(FLSs),resident mesenchymal cells of synovial joints,play an important role in the pathogenesis of rheumatoid arthritis(RA).Dickkopf-1(DKK-1)has been proposed to be a master regulator of bone remodeling in inflammatory arthritis.Here,potential impairation on the activity of FLSs derived from RA to small interfering RNAs(siRNAs)targeting DKK-1 was investigated.Methods:siRNAs targeting DKK-1 were transfected into FLSs of patients with RA.Interleukin(IL)-1β,IL-6,IL-8,matrix metalloproteinase(MMP)2,MMP3,MMP9,transforming growth factor(TGF)-pi,TGF-β2 and monocyte chemoattractant protein(MCP)-1 levels in the cell culture supernatant were detected by enzyme-linked immunosorbent assay(ELISA).Invasion assay and 3H incorporation assay were utilized to investigate the effects of siRNAs targeting DKK-1 on FLSs invasion and cell proliferation,respectively.Western blotting was performed to analyze the expression of nuclear factor(NF)-kB,interleukin-1 receptor-associared kinase(IRAK)1,extracellular regulated protein kinases(ERK)1,Jun N-terminal kinase(JNK)and p-catenin in FLSs.Results:DKK-1 targeting siRNAs inhibited the expression of DKK-1 in FLSs(P<0.01).siRNAs induced a significant reduction of the levels of IL-6,IL-8,MMP2,MMP3 and MMP9 in FLSs compared to the control group(P<0.05).DKK-1 targeting siRNAs inhibited the proliferation and invasion of FLSs(P<0.05).Important molecules of pro-inflammatory signaling in FLSs,including IRAKI and ERK1,were decreased by the inhibition of DKK-1 in FLSs.In contrast,β-catenin,a pivotal downstream molecule of the Wnt signaling pathway was increased.Conclusions:By inhibiting DKK-1,we were able to inhibit the proliferation,invasion and pro-inflammatory cytokine secretion of FLSs derived from RA,which was mediated by the ERK or the IRAK-1 signaling pathway.These data indicate the application of DKK-1 silencing could be a potential therapeutic approach to RA. 展开更多
关键词 DICKKOPF-1 fibroblast-like synoviocytes RHEUMATOID ARTHRITIS small interfering RNAS
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Targeted inhibition of GRK2 kinase domain by CP-25 to reverse fibroblast-like synoviocytes dysfunction and improve collagen-induced arthritis in rats 被引量:10
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作者 Chenchen Han Yifan Li +10 位作者 Yuwen Zhang Yang Wang Dongqian Cui Tingting Luo Yu Zhang Qian Liu Hao Li Chun Wang Dexiang Xu Yang Ma Wei Wei 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2021年第7期1835-1852,共18页
Rheumatoid arthritis(RA)is an autoimmune disease and is mainly characterized by abnormal proliferation of fibroblast-like synoviocytes(FLS).The up-regulated cellular membrane expression of G protein coupled receptor k... Rheumatoid arthritis(RA)is an autoimmune disease and is mainly characterized by abnormal proliferation of fibroblast-like synoviocytes(FLS).The up-regulated cellular membrane expression of G protein coupled receptor kinase 2(GRK2)of FLS plays a critical role in RA progression,the increase of GRK2 translocation activity promotes dysfunctional prostaglandin E4 receptor(EP4)signaling and FLS abnormal proliferation.Recently,although our group found that paeoniflorin-6’-O-benzene sulfonate(CP-25),a novel compound,could reverse FLS dysfunction via GRK2,little is known as to how GRK2 translocation activity is suppressed.Our findings revealed that GRK2 expression up-regulated and EP4 expression down-regulated in synovial tissues of RA patients and collagen-induced arthritis(CIA)rats,and prostaglandin E2(PGE2)level increased in arthritis.CP-25 could down-regulate GRK2 expression,up-regulate EP4 expression,and improve synovitis of CIA rats.CP-25 and GRK2 inhibitors(paroxetine or GSK180736 A)inhibited the abnormal proliferation of FLS in RA patients and CIA rats by down-regulating GRK2 translocation to EP4 receptor.The results of microscale thermophoresis(MST),cellular thermal shift assay,and inhibition of kinase activity assay indicated that CP-25 could directly target GRK2,increase the protein stability of GRK2 in cells,and inhibit GRK2 kinase activity.The docking of CP-25 and GRK2 suggested that the kinase domain of GRK2 might be an important active pocket for CP-25.G201,K220,K230,A321,and D335 in kinase domain of GRK2 might form hydrogen bonds with CP-25.Site-directed mutagenesis and co-immunoprecipitation assay further revealed that CP-25 down-regulated the interaction of GRK2 and EP4 via controlling the key amino acid residue of Ala321 of GRK2.Our data demonstrate that FLS proliferation is regulated by GRK2 translocation to EP4.Targeted inhibition of GRK2 kinase domain by CP-25 improves FLS function and represents an innovative drug for the treatment of RA by targeting GRK2. 展开更多
关键词 CP-25 Rheumatoid arthritis fibroblast-like synoviocyte MH7A G protein coupled receptor kinase 2 Prostaglandin E4 receptor
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Madecassoside impedes invasion of rheumatoid fibroblast-like synoviocyte from adjuvant arthritis rats via inhibition of NF-κB-mediated matrix metalloproteinase-13 expression 被引量:10
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作者 YU Wei-Guang SHEN Yong +2 位作者 WU Jian-Zhong GAO Yan-Bing ZHANG Li-Xing 《Chinese Journal of Natural Medicines》 SCIE CAS CSCD 2018年第5期330-338,共9页
Fibroblast-like synoviocytes(FLS) play a pivotal role in Rheumatoid arthritis(RA) pathogenesis through aggressive migration and invasion. Madecassoside(Madec), a triterpenoid saponin present in Centella asiatica herbs... Fibroblast-like synoviocytes(FLS) play a pivotal role in Rheumatoid arthritis(RA) pathogenesis through aggressive migration and invasion. Madecassoside(Madec), a triterpenoid saponin present in Centella asiatica herbs, has a potent anti-inflammatory effect. In the present study, Madec exerted an obvious therapeutic effect in reversing the histological lesions in adjuvant-induced arthritis(AIA) rats. To recognize the anti-rheumatoid potentials of Madec, we further investigated whether Madec interfered with FLS invasion and metalloproteinase(MMP) expression. In cultures of primary FLS isolated from the AIA rats, Madec(10 and 30 μmol·L–1) was proven to considerably inhibit migration and invasion of FLS induced by interleukin 1β(IL-1β), but exhibiting no obvious effect on cell proliferation. Madec repressed IL-1β-triggered FLS invasion by prohibiting the expression of MMP-13. Additionally, Madec suppressed MMP-13 transcription via inhibiting the MMP-13 promoter-binding activity of NF-κB. Our results further showed that Madec down-regulated the translocation and phosphorylation of NF-κB as demonstrated by Western blotting and immunofluorescence assays. In conclusion, our results suggest that Madec exerts anti-RA activity via inhibiting the NF-κB/MMP-13 pathway. 展开更多
关键词 RHEUMATOID ARTHRITIS fibroblast-like synoviocytes MADECASSOSIDE Adjuvant-induced ARTHRITIS Matrix metalloproteinase-13 INVASION
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改良组织块法分离培养佐剂性关节炎兔成纤维样滑膜细胞 被引量:1
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作者 陈芳 陈利峰 +2 位作者 刘琴 王丽平 张宜 《实验动物与比较医学》 CAS 2016年第4期280-284,共5页
目的 通过改良组织块细胞培养法,建立一种简单、可行的佐剂性关节炎兔成纤维样滑膜细胞(FLS)体外培养方法并观察细胞生物学特性.方法 通过注射弗氏完全佐剂建立关节炎模型,无菌条件下取佐剂性关节炎兔膝关节滑膜组织,剔净后剪成碎块,... 目的 通过改良组织块细胞培养法,建立一种简单、可行的佐剂性关节炎兔成纤维样滑膜细胞(FLS)体外培养方法并观察细胞生物学特性.方法 通过注射弗氏完全佐剂建立关节炎模型,无菌条件下取佐剂性关节炎兔膝关节滑膜组织,剔净后剪成碎块,用灭菌滤纸吸掉组织上附着的水分,碎片接种于培养皿,观察细胞生长状况及形态特征.取第3代对数期细胞,用噻唑蓝(MTT)法绘制其生长曲线,并用免疫荧光法检测波形蛋白的表达情况.结果 体外培养的佐剂性关节炎兔FLS形态为长梭形纤维样,符合FLS的生长特征,免疫荧光检测显强表达波形蛋白.结论 改良组织块法可以分离培养出兔佐剂性关节炎成纤样维滑膜细胞,方法简便,成功率高,满足实验要求. 展开更多
关键词 关节炎 成纤维样滑膜细胞(fls) 改良组织块法 fibroblast-like synoviocytes (fls)
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miR-29a对类风湿关节炎成纤维样滑膜细胞增殖和凋亡的影响 被引量:6
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作者 郭雄飞 王挺 汤立新 《基础医学与临床》 CSCD 2020年第1期9-15,共7页
目的探讨miR-29a对类风湿关节炎(RA)成纤维样滑膜细胞(FLS)活力和凋亡的影响。方法分离培养健康人FLS(n-FLS)和RA患者FLS(RA-FLS);Western blot检测n-FLS和RA-FLS中标志物CHI3L1蛋白表达;将miR-29a mimics、si-NFAT5及miR-29a+NFAT5转染... 目的探讨miR-29a对类风湿关节炎(RA)成纤维样滑膜细胞(FLS)活力和凋亡的影响。方法分离培养健康人FLS(n-FLS)和RA患者FLS(RA-FLS);Western blot检测n-FLS和RA-FLS中标志物CHI3L1蛋白表达;将miR-29a mimics、si-NFAT5及miR-29a+NFAT5转染RA-FLSs,转染48 h后,RT-qPCR检测miR-29a和NFAT5 mRNA表达;MTT法及流式细胞计量术分别检测各组细胞活力和凋亡率;Western blot检测p38、p-p38、cleaved-caspase3蛋白表达;通过双荧光报告基因检测系统检测过表达或抑制miR-29a后NFAT5表达,验证miR-29a和NFAT5的靶向关系。结果与n-FLS比较,RA-FLS中CHI3L1蛋白表达明显升高(P<0.05);过表达miR-29a或抑制NFAT5后,RA-FLS细胞活力明显降低,凋亡率明显升高,p-p38表达明显降低,cleaved-caspase3表达明显升高(P<0.05)。miR-29a与野生型NFAT5 3′UTR共转染组RA-FLS的荧光素酶活性明显降低,而anti-miR-29a与野生型NFAT5 3′UTR共转染组荧光素酶活性明显升高(P<0.05);过表达miR-29a可明显下调RA-FLS中NFAT5表达,抑制miR-29a表达可明显上调NFAT5表达(P<0.05);过表达NFAT5可减弱过表达miR-29a对RA-FLS活力和凋亡的影响(P<0.05)。结论 miR-29a可通过靶向NFAT5下调p38MAPK信号通路抑制RA-FLS活力及诱导细胞凋亡。 展开更多
关键词 类风湿关节炎 滑膜样细胞 miR-29a靶基因 活化T细胞核因子5 P38MAPK信号通路
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Fcα受体在类风湿性关节炎人成纤维样滑膜细胞的表达与功能研究
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作者 喻晶 聂李平 +2 位作者 颜存粮 刘小平 桂耀庭 《医学研究杂志》 2012年第6期97-99,共3页
目的探讨Fcα受体在类风湿性关节炎人成纤维样滑膜细胞的表达特征及其功能。方法采用RT-PCR和免疫荧光技术,从基因和蛋白水平检测Fcα受体在类风湿性关节炎人成纤维样滑膜细胞(RA FLS)的表达;采用ELISA方法,检测IgA对RA FLS分泌IL-6的... 目的探讨Fcα受体在类风湿性关节炎人成纤维样滑膜细胞的表达特征及其功能。方法采用RT-PCR和免疫荧光技术,从基因和蛋白水平检测Fcα受体在类风湿性关节炎人成纤维样滑膜细胞(RA FLS)的表达;采用ELISA方法,检测IgA对RA FLS分泌IL-6的影响。结果采用RT-PCR和免疫荧光染色方法,均检测到Fcα受体在RA FLS的表达。sIgA与RAFLS孵育12h后,细胞分泌IL-6的水平明显增高,差异具有显著性(P<0.01)。mIgA与RA FLS孵育12h后,细胞分泌IL-6的量无明显改变(P>0.05)。sIgA+TNF-α同时与RA FLS孵育12h后,细胞分泌IL-6含量明显高于sIgA或TNF-α单一组(P<0.01)。结论 Fcα受体在类风湿性关节炎人成纤维样滑膜细胞存在表达,sIgA增高RA FLS分泌IL-6的水平,并与TNF-α产生协同作用。 展开更多
关键词 人成纤维样滑膜细胞 Fcα受体 IL-6 类风湿性关节炎
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周期性机械拉伸对类风湿关节炎和骨关节炎成纤维样滑膜细胞BMP-2表达的影响 被引量:6
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作者 周薇 吕永钢 +5 位作者 Gurinder K Singh 颜艳 刘万钱 杨宁宁 张非飞 杨力 《医用生物力学》 EI CAS CSCD 2011年第2期121-127,共7页
目的研究周期性拉伸对类风湿关节炎(rheumatoid arthritis,RA)和骨关节炎(osteoarthritis,OA)成纤维样滑膜细胞(fibroblast-like synoviocytes,FLS)中骨形态发生蛋白-2(bone morphogenetic protein-2,BMP-2)表达的影响,探讨力学刺激在... 目的研究周期性拉伸对类风湿关节炎(rheumatoid arthritis,RA)和骨关节炎(osteoarthritis,OA)成纤维样滑膜细胞(fibroblast-like synoviocytes,FLS)中骨形态发生蛋白-2(bone morphogenetic protein-2,BMP-2)表达的影响,探讨力学刺激在不同病理过程中对滑膜组织的作用。方法在正常条件和炎症条件下使用Flex cell 4000周期性力学加载系统,分别对正常、RA、OA来源的人膝关节FLS施加连续2 h和6 h的6%、0.5 Hz的拉应力,比较测定BMP-2 mRNA表达的差异性。结果 2 h的机械拉伸对3种FLS中BMP-2 mRNA的水平均无显著性影响6,h的机械拉伸能够显著升高RA FLS中BMP-2 mRNA的水平。炎症因子(IL-1β)作用2 h对正常FLS无显著影响,作用6 h使其中BMP-2 mRNA的水平显著升高;IL-1β作用2 h和6 h均使RA FLS中BMP-2 mRNA的水平显著升高,但只有作用2 h才使OA FLS中BMP-2 mRNA的水平显著升高,作用6 h对OA FLS中BMP-2 mRNA的水平无显著影响;炎症因子和力学刺激共同作用2 h使正常和RA FLS中BMP-2 mRNA的水平显著升高,作用6 h使正常、RA、OAFLS中BMP-2 mRNA水平均显著升高。结论正常、RA、OA FLS中BMP-2 mRNA对于力学刺激和炎症因子的响应不同,结果提示在RA和OA发病机制中,炎症因子的影响可能比力学刺激更强;力学刺激和IL-1β共同作用6 h后对OA FLS中BMP-2 mRNA产生协同效应,提示两者联合作用对OA病情发展具有一定作用。 展开更多
关键词 周期性拉伸 力学刺激 拉应力 类风湿性关节炎 骨关节炎 成纤维样滑膜细胞 骨形态发生蛋白-2 炎症因子 病理学
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鸦胆子苦醇通过调节细胞骨架力学性质抑制类风湿关节炎成纤维样滑膜细胞的侵袭行为 被引量:3
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作者 余璨 杨力 《医用生物力学》 EI CAS CSCD 北大核心 2016年第5期379-383,共5页
目的研究鸦胆子苦醇对类风湿关节炎(rheumatoid arthritis,RA)成纤维样滑膜细胞(fibroblast-like synoviocytes,FLS)细胞骨架力学性质的调控以及对RA FLS侵袭行为的影响。方法细胞骨架染色法检测鸦胆子苦醇对RA FLS细胞骨架力学性质的调... 目的研究鸦胆子苦醇对类风湿关节炎(rheumatoid arthritis,RA)成纤维样滑膜细胞(fibroblast-like synoviocytes,FLS)细胞骨架力学性质的调控以及对RA FLS侵袭行为的影响。方法细胞骨架染色法检测鸦胆子苦醇对RA FLS细胞骨架力学性质的调控;Transwell小室法检测鸦胆子苦醇对RA FLS细胞骨架的调控和对RA FLS侵袭行为的影响;酶谱和Western blotting法检测鸦胆子苦醇对RA FLS中MMP-2、MMP-3表达的影响。结果通过细胞骨架染色并在显微镜下观察发现,鸦胆子苦醇可显著减少RA FLS伪足数量的产生,通过调节细胞骨架网络的力学性质抑制细胞的运动能力,鸦胆子苦醇可抑制RA FLS的侵袭并能下调MMP-2、MMP-3的表达水平。结论鸦胆子苦醇能调节RA FLS的细胞骨架的力学性质并抑制细胞的侵袭行为,同时鸦胆子苦醇可通过降低MMP-2、MMP-3的表达抑制RA FLS的侵袭。研究结果为进一步开发治疗RA的新药物提供了相应实验依据。 展开更多
关键词 鸦胆子苦醇 力学性质 类风湿关节炎 成纤维样滑膜细胞 细胞侵袭
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独活寄生汤含药血清对佐剂性关节炎大鼠滑膜成纤维细胞增殖和凋亡的影响 被引量:7
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作者 高晓鹏 鲁贵生 《新中医》 CAS 2018年第4期1-5,共5页
目的:探讨独活寄生汤含药血清对佐剂性关节炎大鼠滑膜成纤维细胞(FLS)增殖和凋亡的影响。方法:采用SD大鼠制备独活寄生汤含药血清,弗氏完全佐剂诱导大鼠佐剂性关节炎,分离提取原代滑膜成纤维细胞。滑膜成纤维细胞分为6组,分别是空白组... 目的:探讨独活寄生汤含药血清对佐剂性关节炎大鼠滑膜成纤维细胞(FLS)增殖和凋亡的影响。方法:采用SD大鼠制备独活寄生汤含药血清,弗氏完全佐剂诱导大鼠佐剂性关节炎,分离提取原代滑膜成纤维细胞。滑膜成纤维细胞分为6组,分别是空白组、模型组、甲氨喋呤组、独活寄生汤高、中、低剂量组,每组5个复孔,分别加入相应的药物。CCK8法检测各组细胞增殖率;荧光定量PCR和ELISA分别检测细胞Bax、Bcl-2、caspase3 m RNA和蛋白水平的表达变化。结果:空白组细胞在各时间点未见明显的变化;模型组细胞随时间延长,增殖抑制率升高(P<0.05);甲氨喋呤组和独活寄生汤高、中、低剂量组细胞随干预时间的延长,增殖抑制率降低(P<0.05)。与空白组比较,模型组细胞在各时间点的增殖抑制率均升高(P<0.05);与模型组比较,甲氨喋呤组和独活寄生汤各剂量组细胞在各时间点的增殖抑制率均降低(P<0.05),尤以高剂量组的抑制率更为明显。与空白组比较,模型组细胞Bax、caspase3 m RNA和蛋白水平降低,Bcl-2 m RNA和蛋白水平升高(P<0.05,P<0.01)。与模型组比较,甲氨喋呤组和独活寄生汤中、高剂量组细胞Bax、caspase3 m RNA和蛋白水平升高,Bcl-2 m RNA和蛋白水平降低(P<0.05,P<0.01),高剂量组的作用更为明显。结论:独活寄生汤能抑制佐剂性关节炎大鼠滑膜成纤维细胞的增殖,其作用机制与下调抗凋亡蛋白Bcl-2,上调促凋亡蛋白Bax和caspase3的表达有关。 展开更多
关键词 独活寄生汤 类风湿关节炎(RA) 佐剂性关节炎 滑膜成纤维细胞(fls) 增殖 凋亡
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瑞香素对人类风湿关节炎滑膜成纤维细胞凋亡的影响及其与内质网应激的关系
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作者 敖琴 刘俊 +5 位作者 胡欢 李培霆 秦龙燕 蒙富雪 李龙 曾家顺 《贵州医科大学学报》 CAS 2022年第7期759-765,共7页
目的探讨瑞香素(DAP)对人类风湿关节炎(RA)滑膜成纤维细胞(FLS)凋亡的影响及其与内质网应激(ERS)的关系。方法取对数增长期人RA-FLS细胞,分别用0、10、20、30、40、50、60及70 mg/L DAP处理24 h,采用细胞增殖计数试剂盒(CCK-8)检测RA-FL... 目的探讨瑞香素(DAP)对人类风湿关节炎(RA)滑膜成纤维细胞(FLS)凋亡的影响及其与内质网应激(ERS)的关系。方法取对数增长期人RA-FLS细胞,分别用0、10、20、30、40、50、60及70 mg/L DAP处理24 h,采用细胞增殖计数试剂盒(CCK-8)检测RA-FLS细胞存活率;选择0、20、40及60 mg/L DAP处理RA-FLS细胞,采用流式细胞术检测细胞凋亡率;采用细胞免疫荧光方法检测0和20 mg/L DAP组RA-FLS中蛋白激酶R样内质网激酶(PERK)、磷酰化-PERK(p-PERK)及含半胱氨酸的天冬氨酸蛋白水解酶12(Caspase-12)蛋白表达;采用Western blot方法检测蛋白激酶R样内质网激酶(PERK)、激活转录因子4(ATF4)、葡萄糖调节蛋白78(GRP78)、转录因子C/EBP同源蛋白(CHOP)、含半胱氨酸的天冬氨酸蛋白水解酶12(Caspase-12)及B细胞淋巴瘤/白血病-2(Bcl-2)蛋白表达。结果与0 mg/L DAP组相比,人RA-FLS细胞增殖活性随DAP浓度增加而降低(P<0.05),细胞凋亡率随DAP浓度增加而增大(P<0.05);20 mg/L DAP组人RA-FLS细胞中PERK、GRP78及Caspase-12荧光强度高于0 mg/L DAP组;与0 mg/L DAP组比较,20、40及60 mg/L DAP组人RA-FLS细胞PERK、p-PERK、GRP78、CHOP及Caspase-12蛋白表达均增加(P<0.05),但Bcl-2表达降低(P<0.05)。结论DAP可抑制人RA-FLS细胞增殖并促进细胞凋亡发生,其机制可能与ERS的激活有关。 展开更多
关键词 关节炎 类风湿 细胞增殖 细胞凋亡 瑞香素 内质网应激 滑膜成纤维细胞
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新风胶囊含药血清通过调控环状RNA Cbl原癌基因B(circ-CBLB)影响类风湿关节炎滑膜成纤维细胞增殖和凋亡
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作者 李舒 万磊 +6 位作者 刘健 黄传兵 李方泽 程静 胡赛赛 陈莹莹 朱子衡 《细胞与分子免疫学杂志》 CAS 2024年第9期792-799,共8页
目的探讨新风胶囊(XFC)含药血清通过调控环状RNA Cbl原癌基因B(circ-CBLB)对类风湿关节炎成纤维细胞样滑膜细胞(RA-FLS)增殖、凋亡的影响。方法XFC灌胃大鼠,制备含药血清。人RA-FLS来源于RA患者滑膜组织,用100μL的10 ng/mL肿瘤坏死因子... 目的探讨新风胶囊(XFC)含药血清通过调控环状RNA Cbl原癌基因B(circ-CBLB)对类风湿关节炎成纤维细胞样滑膜细胞(RA-FLS)增殖、凋亡的影响。方法XFC灌胃大鼠,制备含药血清。人RA-FLS来源于RA患者滑膜组织,用100μL的10 ng/mL肿瘤坏死因子α(TNF-α)刺激RA-FLS建立模型。构建pcDNA3.1-circ-CBLB及阴性对照,分别转染至RA-FLS中。实验分为对照组、TNF-α处理的RA-FLS组、XFC处理的RA-FLS组、pcDNA3.1-circ-CBLB-NC转染的RA-FLS组(过表达空转组)、pcDNA3.1-circ-CBLB转染的RA-FLS组(过表达组)、pcDNA3.1-circ-CBLB联合XFC处理的RA-FLS组(过表达给药组)。采用CCK-8法检测细胞活力,采用流式细胞术检测细胞周期与凋亡,采用实时定量PCR检测circ-CBLB表达水平,采用ELISA检测抗炎因子白细胞介素4(IL-4)、IL-10,促炎因子IL-6、TNF-α水平。结果XFC最佳含药血清量为200 mL/L,处理时间为72 h;与同一时间模型组相比,XFC组、过表达组、过表达给药组的细胞活力均下降。与模型组比较,XFC组、过表达组、过表达给药组circ-CBLB表达水平升高、凋亡率升高,S期和G2期细胞比例增加,IL-4、IL-10含量升高,IL-6、TNF-α含量降低。结论XFC处理上调RA-FLS中circ-CBLB表达,提高抗炎因子的水平,降低促炎因子的水平,抑制RA-FLS的细胞活力,提高其凋亡率,延长细胞周期,抑制RA-FLS增殖并促进其凋亡。 展开更多
关键词 新风胶囊(XFC) 环状RNA Cbl原癌基因B(circ-CBLB) 成纤维细胞样滑膜细胞(fls) 细胞增殖 细胞凋亡 细胞因子
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瘀血痹片对大鼠胶原诱导性关节炎的干预作用及抗炎机制 被引量:12
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作者 袁蓓 苏晓慧 +4 位作者 郭婉怡 汪倩 刘春芳 韩岚 林娜 《中国实验方剂学杂志》 CAS CSCD 北大核心 2021年第11期52-62,共11页
目的:观察瘀血痹片对胶原诱导性关节炎(CIA)大鼠的干预作用并探索抗炎相关机制。方法:建立大鼠CIA模型,给药组和阳性药组分别灌胃给予低、中、高剂量瘀血痹片(0.1,0.2,0.4 g·kg^(-1))和甲氨蝶呤(0.4 mg·kg^(-1)),每3 d检测发... 目的:观察瘀血痹片对胶原诱导性关节炎(CIA)大鼠的干预作用并探索抗炎相关机制。方法:建立大鼠CIA模型,给药组和阳性药组分别灌胃给予低、中、高剂量瘀血痹片(0.1,0.2,0.4 g·kg^(-1))和甲氨蝶呤(0.4 mg·kg^(-1)),每3 d检测发病率、机械痛敏阈值及冷刺激痛敏;给药30 d后取材,外周血检测血小板计数(PLT)及纤维蛋白原(FIB)含量;苏木素-伊红染色法分析CIA大鼠关节组织病理变化;免疫组化法(IHC)和蛋白免疫印迹法(Western blot)分别检测CIA大鼠关节组织中白细胞介素(IL)-1β,IL-8,核转录因子-κB(NF-κB)p65,磷酸化NF-κB p65(p-NF-κB p65),大鼠肉瘤(Ras)及Raf-1蛋白表达情况。此外,采用10μg·L^(-1)的肿瘤坏死因子-α(TNF-α)诱导人类类风湿关节炎成纤维样滑膜细胞(RA-FLS),转移小室法检测RA-FLS迁移及侵袭能力。Western blot检测RA-FLS中Ras,Raf-1,p-NF-κB p65蛋白表达水平。结果:与正常组比较,CIA模型组发病率升高,机械痛阈值明显降低(P<0.05,P<0.01),冷刺激反应评分显著增高(P<0.01),外周血中PLT和FIB含量,大鼠关节组织病理评分,RA-FLS迁移和侵袭细胞个数及炎性相关因子的表达水平均显著升高(P<0.01);与模型组比较,瘀血痹片低、中、高剂量组均能降低CIA大鼠发病率,提高其机械痛阈值并降低冷刺激痛敏反应评分(P<0.05,P<0.01);降低CIA大鼠外周血中PLT和FIB含量(P<0.05,P<0.01),改善关节滑膜增生、骨及软骨破坏等病理变化(P<0.05,P<0.01),并抑制RA-FLS的迁移及侵袭。此外,瘀血痹片低、中、高剂量组均能不同程度地著抑制CIA大鼠关节组织中IL^(-1)β,IL-8,Ras,Raf-1和p-NF-κB p65的含量,以及RA-FLS细胞中Ras,Raf-1及p-NF-κB p65等蛋白表达水平(P<0.05,P<0.01)。结论:瘀血痹片具有降低大鼠CIA发病率、关节炎临床症状和改善关节组织病理变化、抑制滑膜生成等作用,并且这一作用可能与其对Ras/Raf-1/NF-κB信号通路的抑制有关。 展开更多
关键词 类风湿关节炎(RA) 瘀血痹片 成纤维样滑膜细胞(fls) 炎症因子 Ras/Raf-1/核转录因子-κB(NF-κB)
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