The Experts below are selected from a list of 7752 Experts worldwide ranked by ideXlab platform
Pércio S. Gulko - One of the best experts on this subject based on the ideXlab platform.
-
antioxidant carbon nanoparticles inhibit fibroblast like Synoviocyte invasiveness and reduce disease severity in a rat model of rheumatoid arthritis
Antioxidants, 2020Co-Authors: Mark R Tanner, Teresina Laragione, Redwan Huq, William K A Sikkema, Lizanne G Nilewski, Nejla Yosef, Cody Schmitt, Carlos Perfecto Floressuarez, Arielle Raugh, Pércio S. GulkoAbstract:Reactive oxygen species have been involved in the pathogenesis of rheumatoid arthritis (RA). Our goal was to determine the effects of selectively scavenging superoxide (O2•−) and hydroxyl radicals with antioxidant nanoparticles, called poly(ethylene glycol)-functionalized hydrophilic carbon clusters (PEG-HCCs), on the pathogenic functions of Fibroblast-Like Synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and on the progression of an animal model of RA. We used human FLS from patients with RA to determine PEG-HCC internalization and effects on FLS cytotoxicity, invasiveness, proliferation, and production of proteases. We used the pristane-induced arthritis (PIA) rat model of RA to assess the benefits of PEG-HCCs on reducing disease severity. PEG-HCCs were internalized by RA-FLS, reduced their intracellular O2•−, and reduced multiple measures of their pathogenicity in vitro, including proliferation and invasion. In PIA, PEG-HCCs caused a 65% reduction in disease severity, as measured by a standardized scoring system of paw inflammation and caused a significant reduction in bone and tissue damage, and circulating rheumatoid factor. PEG-HCCs did not induce lymphopenia during PIA. Our study demonstrated a role for O2•− and hydroxyl radicals in the pathogenesis of a rat model of RA and showed efficacy of PEG-HCCs in treating a rat model of RA.
-
fri0066 gastrin releasing peptide and its receptor increase arthritis fibroblast like Synoviocyte invasiveness over the pi3k akt pathway
Annals of the Rheumatic Diseases, 2017Co-Authors: M Farinon, Pércio S. Gulko, Vanessa Schuck Clarimundo, R T Pedό, Von Teixeira, C Nor, Ricardo Machado Xavier, Paulo G V OliveiraAbstract:Background Rheumatoid arthritis (RA) is an autoimmune disease where the chronic inflammation and subsequent cartilage and bone erosion lead to joint destruction. The Fibroblast-Like Synoviocytes (FLS) have a central role in disease pathogenesis and in vitro FLS invasiveness correlates with articular damage in RA patients. Gastrin-releasing peptide (GRP) plays an important role in the immune and inflammatory response. GRP is found in synovial fluid of RA patients and its receptor (GRPR) is found in synovial membrane of murine arthritis. RC-3095 in an antagonist of GRPR. Objectives To evaluate the role of GRP and GRPR on invasive behavior of mice FLS and to evaluate the GRP-induced signaling on PI3K/AKT pathway. Methods FLS were isolated from joints of DBA/1J mice with collagen-induced arthritis. Expression of GRPR in FLS was investigated by immunocytochemistry and western blot (WB). Proliferation of FLS treated with GRP (0.1 μM – 10 μM) (n=3) and RC-3095 (0.05 μM – 10 μM) (n=4) was assessed by Sulforhodamine B assay in 24h, 48h and 72h. Invasion assay with FLS was performed using a Matrigel-coated transwell system over 24h in two different experimental arms: first, FLS were treated with GRP (10 μM), RC-3095 (1 μM) or GRP+RC-3095 (GRP 10 μM and RC-3095 1 μM) (n=6) and after, FLS were treated with GRP (10 μM), Ly294002 (10 μM), or GRP+Ly294002 (GRP 10 μM and Ly294002 10 μM) (n=4). Akt phosphorylation was assessed by WB. Results GRPR protein was detected in FLS both by immunocytochemistry and WB. GRP and RC-3095 treatments did not affect FLS proliferation. Exposure to GRP increased FLS invasion (5356±1027) by nearly two-fold compared with untreated cells (2845±532) (p Conclusions Our group demonstrated for the first time GRPR expression in FLS and that GRP are able to activate FLS invasion through AKT pathway. Finally, our results suggest that GRP/GRPR pathway could be relevant in the development of FLS-targeted therapy for RA. References Scott TL et al. Lancet 376;9746:1094–108. Bottini N, Firestein GS. Nat Rev Rheumatol 2013;9:24–33. Grimsholm O et al. Arthritis Res Ther 2005;7:R416–26. Oliveira PG et al. Arthritis Rheum 2011;63:2956–2965. Acknowledgements FIPE-HCPA, CAPES, CNPq. Disclosure of Interest None declared
-
kca1 1 inhibition attenuates fibroblast like Synoviocyte invasiveness and ameliorates disease in rat models of rheumatoid arthritis
Arthritis & Rheumatism, 2015Co-Authors: Mark R Tanner, Teresina Laragione, Pércio S. Gulko, Redwan Huq, Rajeev B Tajhya, Liang Sun, Fatima S Khan, Frank T Horrigan, Christine BeetonAbstract:Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disease that preferentially targets diarthrodial joints (1, 2). It is characterized by extensive synovial hyperplasia and cartilage and bone damage, leading to disability. While the etiology of RA is not fully understood, it involves the activation of endothelial and synovial cells, as well as the activation and recruitment of immune cells to the synovium. Fibroblast-Like Synoviocytes (FLS) are prominent in the RA pannus where they secrete proteases that degrade collagen, cytokines and chemokines that induce the accumulation and activation of inflammatory cells, and growth factors that induce angiogenesis (3, 4). Importantly, FLS from patients with RA (RA-FLS) are highly invasive and can migrate from affected to healthy joints (5). Their ex vivo invasive properties tightly correlate with histological and radiographic damage in RA and its experimental models (6, 7); this damage itself being correlated with disease severity and an increased risk of disability, deformities, and premature death (8). Thus, reducing the pathogenic properties of RA-FLS represents an attractive target for the treatment of RA, particularly since no RA therapies have been developed to specifically target these cells. We have previously identified the KCa1.1 channel (BK, maxi-K, Slo1, KCNMA1) as the major potassium channel expressed by RA-FLS (9). Inhibiting the function of this channel in RA-FLS through blocking its pore-forming α subunit ex vivo perturbs the calcium homeostasis of the cells and inhibits their proliferation, migration, and invasiveness, as well as their production of proteases, chemokines, and growth factors (9). These results suggest KCa1.1 channels as important regulators of the destructive phenotype of RA-FLS and as therapeutic target for RA by attenuating these pathogenic functions. We tested this possibility in the current study, using experimental arthritis in rats. We first demonstrated that functional KCa1.1 are the major potassium channels at the plasma membrane of FLS from rats with the pristane-induced arthritis (PIA) model of RA and are expressed in larger numbers by PIA-FLS when compared to FLS from healthy animals. Blocking KCa1.1 inhibited the proliferation of PIA-FLS and reduced their ability to produce the matrix metalloproteinase (MMP) pro-MMP-2. Importantly, blocking KCa1.1 or reducing its expression reduced the invasiveness of PIA-FLS. In contrast, opening native KCa1.1 or over-expression of the channel enhanced the invasiveness of PIA-FLS and of healthy rat FLS. Treatment of rats at onset of clinical signs in two models of RA with a KCa1.1-specific blocker reduced disease severity, synovial inflammation, cartilage and bone damage, and inhibited the ex vivo invasiveness of FLS.
-
Vol 10 No 4
2013Co-Authors: Teresina Laragione, Pércio S. Gulko, Max Brenner, Open AccessAbstract:Research article Cia5d regulates a new Fibroblast-Like Synoviocyte invasion-associated gene expression signatur
-
liver x receptor regulates rheumatoid arthritis fibroblast like Synoviocyte invasiveness matrix metalloproteinase 2 activation interleukin 6 and cxcl10
Molecular Medicine, 2012Co-Authors: Teresina Laragione, Pércio S. GulkoAbstract:Fibroblast-Like Synoviocyte (FLS) invasiveness correlates with articular damage in rheumatoid arthritis (RA), yet little is known about its regulation. In this study we aimed to determine the role of the nuclear receptor liver X receptor (LXR) in FLS invasion. FLS were isolated from synovial tissues obtained from RA patients and from DA rats with pristane-induced arthritis. Invasion was tested on Matrigel-coated chambers in the presence of the LXR agonist T0901317, or control vehicle. FLS were cultured in the presence or absence of T0901317, and supernatants were used to quantify matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-3, interleukin-6 (IL-6), tumor necrosis factor-α and C-X-C motif chemokine ligand 10 (CXCL10). Nuclear factor-κB (NF-κB) (p65) and Akt activation, actin cytoskeleton, cell morphology and lamellipodia formation were also determined. The LXR agonist T0901317 significantly reduced DA FLS invasion by 99% (P ≤ 0.001), and RA FLS invasion by 96% (P ≤ 0.001), compared with control. T0901317-induced suppression of invasion was associated with reduced production of activated MMP-2, IL-6 and CXCL10 by RA FLS, and with reduction of actin filament reorganization and reduced polarized formation of lamellipodia. T0901317 also prevented both IL-1β-induced and IL-6-induced FLS invasion. NF-κB (p65) and Akt activation were not significantly affected by T0901317. This is the first description of a role for LXR in the regulation of FLS invasion and in processes and pathways implicated both in invasion as well as in inflammatory responses. These findings provide a new rationale for considering LXR agonists as therapeutic agents aimed at reducing both inflammation and FLS-mediated invasion and destruction in RA.
Teresina Laragione - One of the best experts on this subject based on the ideXlab platform.
-
antioxidant carbon nanoparticles inhibit fibroblast like Synoviocyte invasiveness and reduce disease severity in a rat model of rheumatoid arthritis
Antioxidants, 2020Co-Authors: Mark R Tanner, Teresina Laragione, Redwan Huq, William K A Sikkema, Lizanne G Nilewski, Nejla Yosef, Cody Schmitt, Carlos Perfecto Floressuarez, Arielle Raugh, Pércio S. GulkoAbstract:Reactive oxygen species have been involved in the pathogenesis of rheumatoid arthritis (RA). Our goal was to determine the effects of selectively scavenging superoxide (O2•−) and hydroxyl radicals with antioxidant nanoparticles, called poly(ethylene glycol)-functionalized hydrophilic carbon clusters (PEG-HCCs), on the pathogenic functions of Fibroblast-Like Synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and on the progression of an animal model of RA. We used human FLS from patients with RA to determine PEG-HCC internalization and effects on FLS cytotoxicity, invasiveness, proliferation, and production of proteases. We used the pristane-induced arthritis (PIA) rat model of RA to assess the benefits of PEG-HCCs on reducing disease severity. PEG-HCCs were internalized by RA-FLS, reduced their intracellular O2•−, and reduced multiple measures of their pathogenicity in vitro, including proliferation and invasion. In PIA, PEG-HCCs caused a 65% reduction in disease severity, as measured by a standardized scoring system of paw inflammation and caused a significant reduction in bone and tissue damage, and circulating rheumatoid factor. PEG-HCCs did not induce lymphopenia during PIA. Our study demonstrated a role for O2•− and hydroxyl radicals in the pathogenesis of a rat model of RA and showed efficacy of PEG-HCCs in treating a rat model of RA.
-
Suppression and resolution of autoimmune arthritis by rhesus θ-defensin-1, an immunomodulatory macrocyclic peptide.
PLOS ONE, 2017Co-Authors: Justin B. Schaal, Teresina Laragione, Prasad Tongaonkar, Akshay Subramanian, Reshma J. Patel, Kevin D. Roberts, Katie Trinh, Patti Tran, Dat Q Tran, Dmitriy MinondAbstract:θ-defensins constitute a family of macrocyclic peptides expressed exclusively in Old World monkeys. The peptides are pleiotropic effectors of innate immunity, possessing broad spectrum antimicrobial activities and immunoregulatory properties. Here we report that rhesus θ-defensin 1 (RTD-1) is highly effective in arresting and reversing joint disease in a rodent model of rheumatoid arthritis (RA). Parenteral RTD-1 treatment of DA/OlaHsd rats with established pristane-induced arthritis (PIA) rapidly suppressed joint disease progression, restored limb mobility, and preserved normal joint architecture. RTD-1 significantly reduced joint IL-1β levels compared with controls. RTD-1 dose-dependently inhibited Fibroblast-Like Synoviocyte (FLS) invasiveness and FLS IL-6 production. Consistent with the inhibition of FLS invasiveness, RTD-1 was a potent inhibitor of arthritogenic proteases including ADAMs 17 and 10 which activate TNFα, and inhibited matrix metalloproteases, and cathepsin K. RTD-1 was non-toxic, non-immunogenic, and effective when administered as infrequently as once every five days. Thus θ-defensins, which are absent in humans, have potential as retroevolutionary biologics for the treatment of RA.
-
kca1 1 inhibition attenuates fibroblast like Synoviocyte invasiveness and ameliorates disease in rat models of rheumatoid arthritis
Arthritis & Rheumatism, 2015Co-Authors: Mark R Tanner, Teresina Laragione, Pércio S. Gulko, Redwan Huq, Rajeev B Tajhya, Liang Sun, Fatima S Khan, Frank T Horrigan, Christine BeetonAbstract:Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disease that preferentially targets diarthrodial joints (1, 2). It is characterized by extensive synovial hyperplasia and cartilage and bone damage, leading to disability. While the etiology of RA is not fully understood, it involves the activation of endothelial and synovial cells, as well as the activation and recruitment of immune cells to the synovium. Fibroblast-Like Synoviocytes (FLS) are prominent in the RA pannus where they secrete proteases that degrade collagen, cytokines and chemokines that induce the accumulation and activation of inflammatory cells, and growth factors that induce angiogenesis (3, 4). Importantly, FLS from patients with RA (RA-FLS) are highly invasive and can migrate from affected to healthy joints (5). Their ex vivo invasive properties tightly correlate with histological and radiographic damage in RA and its experimental models (6, 7); this damage itself being correlated with disease severity and an increased risk of disability, deformities, and premature death (8). Thus, reducing the pathogenic properties of RA-FLS represents an attractive target for the treatment of RA, particularly since no RA therapies have been developed to specifically target these cells. We have previously identified the KCa1.1 channel (BK, maxi-K, Slo1, KCNMA1) as the major potassium channel expressed by RA-FLS (9). Inhibiting the function of this channel in RA-FLS through blocking its pore-forming α subunit ex vivo perturbs the calcium homeostasis of the cells and inhibits their proliferation, migration, and invasiveness, as well as their production of proteases, chemokines, and growth factors (9). These results suggest KCa1.1 channels as important regulators of the destructive phenotype of RA-FLS and as therapeutic target for RA by attenuating these pathogenic functions. We tested this possibility in the current study, using experimental arthritis in rats. We first demonstrated that functional KCa1.1 are the major potassium channels at the plasma membrane of FLS from rats with the pristane-induced arthritis (PIA) model of RA and are expressed in larger numbers by PIA-FLS when compared to FLS from healthy animals. Blocking KCa1.1 inhibited the proliferation of PIA-FLS and reduced their ability to produce the matrix metalloproteinase (MMP) pro-MMP-2. Importantly, blocking KCa1.1 or reducing its expression reduced the invasiveness of PIA-FLS. In contrast, opening native KCa1.1 or over-expression of the channel enhanced the invasiveness of PIA-FLS and of healthy rat FLS. Treatment of rats at onset of clinical signs in two models of RA with a KCa1.1-specific blocker reduced disease severity, synovial inflammation, cartilage and bone damage, and inhibited the ex vivo invasiveness of FLS.
-
Vol 10 No 4
2013Co-Authors: Teresina Laragione, Pércio S. Gulko, Max Brenner, Open AccessAbstract:Research article Cia5d regulates a new Fibroblast-Like Synoviocyte invasion-associated gene expression signatur
-
liver x receptor regulates rheumatoid arthritis fibroblast like Synoviocyte invasiveness matrix metalloproteinase 2 activation interleukin 6 and cxcl10
Molecular Medicine, 2012Co-Authors: Teresina Laragione, Pércio S. GulkoAbstract:Fibroblast-Like Synoviocyte (FLS) invasiveness correlates with articular damage in rheumatoid arthritis (RA), yet little is known about its regulation. In this study we aimed to determine the role of the nuclear receptor liver X receptor (LXR) in FLS invasion. FLS were isolated from synovial tissues obtained from RA patients and from DA rats with pristane-induced arthritis. Invasion was tested on Matrigel-coated chambers in the presence of the LXR agonist T0901317, or control vehicle. FLS were cultured in the presence or absence of T0901317, and supernatants were used to quantify matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-3, interleukin-6 (IL-6), tumor necrosis factor-α and C-X-C motif chemokine ligand 10 (CXCL10). Nuclear factor-κB (NF-κB) (p65) and Akt activation, actin cytoskeleton, cell morphology and lamellipodia formation were also determined. The LXR agonist T0901317 significantly reduced DA FLS invasion by 99% (P ≤ 0.001), and RA FLS invasion by 96% (P ≤ 0.001), compared with control. T0901317-induced suppression of invasion was associated with reduced production of activated MMP-2, IL-6 and CXCL10 by RA FLS, and with reduction of actin filament reorganization and reduced polarized formation of lamellipodia. T0901317 also prevented both IL-1β-induced and IL-6-induced FLS invasion. NF-κB (p65) and Akt activation were not significantly affected by T0901317. This is the first description of a role for LXR in the regulation of FLS invasion and in processes and pathways implicated both in invasion as well as in inflammatory responses. These findings provide a new rationale for considering LXR agonists as therapeutic agents aimed at reducing both inflammation and FLS-mediated invasion and destruction in RA.
Yanqing Liu - One of the best experts on this subject based on the ideXlab platform.
-
long non coding rna pvt1 knockdown suppresses fibroblast like Synoviocyte inflammation and induces apoptosis in rheumatoid arthritis through demethylation of sirt6
Journal of Biological Engineering, 2019Co-Authors: Dan Liu, Chunwang Zhang, Wei Zhou, Wei Tan, Yuxuan Fang, Yu Zhang, Yanqing LiuAbstract:As a type of chronic autoimmune joint disease, rheumatoid arthritis (RA) is a disorder, characterized by a variety of physical symptoms as well as RA Fibroblast-Like Synoviocyte (RA-FLS) proliferation. More recently, long non-coding RNAs (lncRNAs) have been implicated in the progression of various diseases including the progression of RA. Hence, the aim of the current study was to investigate the role by which the lncRNA, plasmacytoma variant translocation 1 (PVT1), influences RA-FLSs and its ability to modulate the methylation of sirtuin 6 (sirt6). RA rat models were initially established to determine the expression of PVT1 and sirt6 in synovial tissues and RA-FLSs. Elevation or depletion of PVT1 or sirt6 was achieved by means of transformation with plasmids in order to investigate their effects on RA-FLS proliferation, inflammation and apoptosis. The localization of PVT1 and its binding ability to the sirt6 promoter region were also explored in an attempt to elucidate the correlation between PVT1 and sirt6 methylation. High expression of PVT1 and low expression of sirt6 were detected in the synovial tissues and RA-FLSs of the rat models. RA-FLSs treated with sh-PVT1 or oe-sirt6 exhibited suppressed cell proliferation, inflammation and induced apoptosis. PVT1 was predominately localized in the nucleus while evidence was obtained indicating that it could bind to the sirt6 promoter to induce sirt6 methylation, thus inhibiting sirt6 transcription. PVT1 knockdown was observed to restore sirt6 expression through decreasing sirt6 methylation, thereby alleviating RA. The key findings of the study provide evidence suggesting that, PVT1 knockdown is able to restrain RA progression by inhibiting sirt6 methylation to restore its expression.
-
anti invasive effects of celastrol in hypoxia induced fibroblast like Synoviocyte through suppressing of hif 1α cxcr4 signaling pathway
International Immunopharmacology, 2013Co-Authors: Dan Liu, Yu Zhang, Yayun Qian, Yaodong Zhu, Shiyu Guo, Masataka Sunagawa, Tadashi Hisamitsu, Yanqing LiuAbstract:Rheumatoid arthritis (RA) joints are in a hypoxic condition. Hypoxia-induced migration and invasion of Fibroblast-Like Synoviocytes (FLSs) are considered to play a critical role in the pathogenesis of RA. Among the key genes upregulated by hypoxia-inducible factor-1α (HIF-1α), CXC chemokine receptor 4 (CXCR4) plays an important role in FLS migration and invasion. Our previous studies have shown that celastrol exerts anti-arthritic effects by inhibiting FLS migration and invasion under normoxic conditions. However, the effect and molecular mechanisms underlying the effect of celastrol on hypoxia-induced FLS migration and invasion are poorly understood. In the present study, we assessed the effect of celastrol on hypoxia-induced FLS migration and invasion. Results showed that celastrol suppressed hypoxia-induced FLS migration and invasion. In addition, we also found that celastrol inhibited hypoxia-induced CXCR4 expression at both the mRNA and the protein levels in RA-FLSs. Meanwhile, it is revealed that celastrol inhibited the transcriptional activity of CXCR4 under hypoxic conditions by suppressing the binding activity of HIF-1α in the CXCR4 promoter, and blocked hypoxia-induced accumulation of nuclear HIF-1α. Furthermore, treatment with HIF-1α inhibitor reduced the hypoxia-induced expression and transcriptional activity of CXCR4. In conclusion, our results indicate that celastrol inhibits hypoxia-induced migration and invasion via suppression of HIF-1α mediated CXCR4 expression in FLSs under hypoxic conditions. These results provide a strong rationale for further testing and validation of the use of celastrol as a new alternative for using in the treatment of RA.
-
celastrol inhibits lipopolysaccharide stimulated rheumatoid fibroblast like Synoviocyte invasion through suppression of tlr4 nf κb mediated matrix metalloproteinase 9 expression
PLOS ONE, 2013Co-Authors: Dan Liu, Yu Zhang, Yayun Qian, Shiyu Guo, Masataka Sunagawa, Tadashi Hisamitsu, Hua Zhang, Yanqing LiuAbstract:Invasion of Fibroblast-Like Synoviocytes (FLSs) is critical in the pathogenesis of rheumatoid arthritis (RA). The metalloproteinases (MMPs) and activator of Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway play a critical role in RA-FLS invasion induced by lipopolysaccharide (LPS). The present study aimed to explore the anti-invasive activity of celastrol on LPS-stimulated human RA-FLSs, and to elucidate the mechanism involved. We investigated the effect of celastrol on LPS-induced FLS migration and invasion as well as MMP expression and explored the upstream signal transduction. Results showed that celastrol suppressed LPS-stimulated FLS migration and invasion by inhibiting MMP-9 expression and activity. Furthermore, our results revealed that celastrol inhibited the transcriptional activity of MMP-9 by suppressing the binding activity of NF-κB in the MMP-9 promoter, and suppressed the TLR4/MyD88/NF-κB pathway. Administration of celastrol (0.5 mg/kg and 1 mg/kg, intraperitoneally) daily for 3 weeks in a collagen-induced arthritis rat model markedly alleviated the clinical signs, synovial hyperplasia and inflammatory cell infiltration of joints. In conclusion, celastrol might inhibit FLS migration and invasion induced by LPS by suppressing TLR4/NF-κB-mediated MMP-9 expression, providing a theoretical foundation for the clinical treatment of RA with celastrol.
-
celastrol inhibits interleukin 17a stimulated rheumatoid fibroblast like Synoviocyte migration and invasion through suppression of nf κb mediated matrix metalloproteinase 9 expression
International Immunopharmacology, 2012Co-Authors: Yu Zhang, Dan Liu, Yayun Qian, Shiyu Guo, Masataka Sunagawa, Tadashi Hisamitsu, Hua Zhang, Yanqing LiuAbstract:Interleukin-17A (IL-17A)-induced migration and invasion of Fibroblast-Like Synoviocytes (FLSs) is critical for the pathogenesis of rheumatoid arthritis (RA). More than 30% of RA patients are resistant to available therapies, despite the introduction of novel biologic agents. Therefore, it is necessary to develop new anti-arthritic agents. Recent studies have demonstrated that celastrol has anti-arthritic activity in an adjuvant-induced arthritis (AIA) model. However, the effect and molecular mechanisms of celastrol on the migration and invasion of RA-FLSs are not yet understood. Results showed that treatment of RA-FLSs with celastrol suppressed the IL-17A-induced migration and invasion abilities of the cells. In addition, celastrol inhibited IL-17A-induced matrix metalloproteinase (MMP)-9 mRNA and protein expression, and the proteolytic activity of MMP-9 in RA-FLSs. Furthermore, our results revealed that celastrol inhibited the transcriptional activity of MMP-9 by suppression of the binding activity of nuclear factor-κB (NF-κB) in the MMP-9 promoter, and inhibited IκBα phosphorylation and nuclear translocation of NF-κB. In conclusion, celastrol can inhibit IL-17A-induced migration and invasion by suppressing NF-κB-mediated MMP-9 expression in RA-FLSs. These results provide a strong rationale for further testing and validation of celastrol as an adjunct with conventional drugs for the treatment of RA in humans.
Dan Liu - One of the best experts on this subject based on the ideXlab platform.
-
long non coding rna pvt1 knockdown suppresses fibroblast like Synoviocyte inflammation and induces apoptosis in rheumatoid arthritis through demethylation of sirt6
Journal of Biological Engineering, 2019Co-Authors: Dan Liu, Chunwang Zhang, Wei Zhou, Wei Tan, Yuxuan Fang, Yu Zhang, Yanqing LiuAbstract:As a type of chronic autoimmune joint disease, rheumatoid arthritis (RA) is a disorder, characterized by a variety of physical symptoms as well as RA Fibroblast-Like Synoviocyte (RA-FLS) proliferation. More recently, long non-coding RNAs (lncRNAs) have been implicated in the progression of various diseases including the progression of RA. Hence, the aim of the current study was to investigate the role by which the lncRNA, plasmacytoma variant translocation 1 (PVT1), influences RA-FLSs and its ability to modulate the methylation of sirtuin 6 (sirt6). RA rat models were initially established to determine the expression of PVT1 and sirt6 in synovial tissues and RA-FLSs. Elevation or depletion of PVT1 or sirt6 was achieved by means of transformation with plasmids in order to investigate their effects on RA-FLS proliferation, inflammation and apoptosis. The localization of PVT1 and its binding ability to the sirt6 promoter region were also explored in an attempt to elucidate the correlation between PVT1 and sirt6 methylation. High expression of PVT1 and low expression of sirt6 were detected in the synovial tissues and RA-FLSs of the rat models. RA-FLSs treated with sh-PVT1 or oe-sirt6 exhibited suppressed cell proliferation, inflammation and induced apoptosis. PVT1 was predominately localized in the nucleus while evidence was obtained indicating that it could bind to the sirt6 promoter to induce sirt6 methylation, thus inhibiting sirt6 transcription. PVT1 knockdown was observed to restore sirt6 expression through decreasing sirt6 methylation, thereby alleviating RA. The key findings of the study provide evidence suggesting that, PVT1 knockdown is able to restrain RA progression by inhibiting sirt6 methylation to restore its expression.
-
sirt1 inhibits rheumatoid arthritis fibroblast like Synoviocyte aggressiveness and inflammatory response via suppressing nf κb pathway
Bioscience Reports, 2018Co-Authors: Zhongbing Xia, Chunwang Zhang, Yuxuan Fang, Ying Liu, Fanru Meng, Dan LiuAbstract:Rheumatoid arthritis (RA) is an autoimmune disease of the joints characterized by synovial hyperplasia and chronic inflammation. Fibroblast-Like Synoviocytes (FLS) play a central role in RA initiation, progression, and perpetuation. Prior studies showed that sirtuin 1 (SIRT1), a deacetylase participating in a broad range of transcriptional and metabolic regulations, may impact cell proliferation and inflammatory responses. However, the role of SIRT1 in RA-FLS was unclear. Here, we explored the effects of SIRT1 on the aggressiveness and inflammatory responses of cultured RA-FLS. SIRT1 expression was significantly lower in synovial tissues and FLS from RA patients than from healthy controls. Overexpression of SIRT1 significantly inhibited RA-FLS proliferation, migration, and invasion. SIRT1 overexpression also significantly increased RA-FLS apoptosis and caspase-3 and -8 activity. Focusing on inflammatory phenotypes, we found SIRT1 significantly reduced RA-FLS secretion of TNF-α, IL-6, IL-8, and IL-1β. Mechanistic studies further revealed SIRT1 suppressed NF-κB pathway by reducing p65 protein expression, phosphorylation, and acetylation in RA-FLS. Our results suggest SIRT1 is a key regulator in RA pathogenesis by suppressing aggressive phenotypes and inflammatory response of FLS. Enhancing SIRT1 expression or function in FLS could be therapeutic beneficial for RA by inhibiting synovial hyperplasia and inflammation.
-
rheumatoid arthritis fibroblast like Synoviocyte suppression mediated by pten involves survivin gene silencing
Scientific Reports, 2017Co-Authors: Danna Chen, Dongdong Liu, Dan Liu, Anping Peng, Li Lin, Fudong Luo, Lin Chen, Xianzhang Huang, Junhua ZhuangAbstract:Survivin is a proto-oncogene biomarker known for its anti-apoptotic and cell cycle regulating properties induced by the activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway. In the context of non-cancer pathology, such as rheumatoid arthritis (RA), survivin has emerged as a feature associated with severe joint damage and poor treatment response. Phosphatase and tensin homolog (PTEN) is a phosphatase antagonizing all classes of PI3K. The interplay between survivin oncogenic mechanisms and proliferation suppression networks in RA has remained largely elusive. This study investigated the effect of PTEN on survivin gene expression in rheumatiod arthritis Fibroblast-Like Synoviocyte (RA-FLS). We showed for the first time that the suppression of RA-FLS was mediated by PTEN involving survivin silencing. Considering that survivin suppressants are currently available in clinical trials and clinical use, their effects in RA-FLS support a probably RA therapy to clinical practice.
-
anti invasive effects of celastrol in hypoxia induced fibroblast like Synoviocyte through suppressing of hif 1α cxcr4 signaling pathway
International Immunopharmacology, 2013Co-Authors: Dan Liu, Yu Zhang, Yayun Qian, Yaodong Zhu, Shiyu Guo, Masataka Sunagawa, Tadashi Hisamitsu, Yanqing LiuAbstract:Rheumatoid arthritis (RA) joints are in a hypoxic condition. Hypoxia-induced migration and invasion of Fibroblast-Like Synoviocytes (FLSs) are considered to play a critical role in the pathogenesis of RA. Among the key genes upregulated by hypoxia-inducible factor-1α (HIF-1α), CXC chemokine receptor 4 (CXCR4) plays an important role in FLS migration and invasion. Our previous studies have shown that celastrol exerts anti-arthritic effects by inhibiting FLS migration and invasion under normoxic conditions. However, the effect and molecular mechanisms underlying the effect of celastrol on hypoxia-induced FLS migration and invasion are poorly understood. In the present study, we assessed the effect of celastrol on hypoxia-induced FLS migration and invasion. Results showed that celastrol suppressed hypoxia-induced FLS migration and invasion. In addition, we also found that celastrol inhibited hypoxia-induced CXCR4 expression at both the mRNA and the protein levels in RA-FLSs. Meanwhile, it is revealed that celastrol inhibited the transcriptional activity of CXCR4 under hypoxic conditions by suppressing the binding activity of HIF-1α in the CXCR4 promoter, and blocked hypoxia-induced accumulation of nuclear HIF-1α. Furthermore, treatment with HIF-1α inhibitor reduced the hypoxia-induced expression and transcriptional activity of CXCR4. In conclusion, our results indicate that celastrol inhibits hypoxia-induced migration and invasion via suppression of HIF-1α mediated CXCR4 expression in FLSs under hypoxic conditions. These results provide a strong rationale for further testing and validation of the use of celastrol as a new alternative for using in the treatment of RA.
-
celastrol inhibits lipopolysaccharide stimulated rheumatoid fibroblast like Synoviocyte invasion through suppression of tlr4 nf κb mediated matrix metalloproteinase 9 expression
PLOS ONE, 2013Co-Authors: Dan Liu, Yu Zhang, Yayun Qian, Shiyu Guo, Masataka Sunagawa, Tadashi Hisamitsu, Hua Zhang, Yanqing LiuAbstract:Invasion of Fibroblast-Like Synoviocytes (FLSs) is critical in the pathogenesis of rheumatoid arthritis (RA). The metalloproteinases (MMPs) and activator of Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway play a critical role in RA-FLS invasion induced by lipopolysaccharide (LPS). The present study aimed to explore the anti-invasive activity of celastrol on LPS-stimulated human RA-FLSs, and to elucidate the mechanism involved. We investigated the effect of celastrol on LPS-induced FLS migration and invasion as well as MMP expression and explored the upstream signal transduction. Results showed that celastrol suppressed LPS-stimulated FLS migration and invasion by inhibiting MMP-9 expression and activity. Furthermore, our results revealed that celastrol inhibited the transcriptional activity of MMP-9 by suppressing the binding activity of NF-κB in the MMP-9 promoter, and suppressed the TLR4/MyD88/NF-κB pathway. Administration of celastrol (0.5 mg/kg and 1 mg/kg, intraperitoneally) daily for 3 weeks in a collagen-induced arthritis rat model markedly alleviated the clinical signs, synovial hyperplasia and inflammatory cell infiltration of joints. In conclusion, celastrol might inhibit FLS migration and invasion induced by LPS by suppressing TLR4/NF-κB-mediated MMP-9 expression, providing a theoretical foundation for the clinical treatment of RA with celastrol.
Ikumi Tamai - One of the best experts on this subject based on the ideXlab platform.
-
mechanism of the regulation of organic cation carnitine transporter 1 slc22a4 by rheumatoid arthritis associated transcriptional factor runx1 and inflammatory cytokines
Drug Metabolism and Disposition, 2007Co-Authors: Tomoji Maeda, Keiji Miyazawa, Masamichi Hirayama, Daisuke Kobayashi, Ikumi TamaiAbstract:Recently, it was reported that the organic cation/carnitine transporter 1 (OCTN1, SLC22A4) is associated with chronic inflammatory diseases, such as rheumatoid arthritis (RA) and Crohn's disease. OCTN1 in humans is expressed in synovial tissues of individuals with rheumatoid arthritis. Furthermore octn1 in mice is expressed in inflamed joints with collagen-induced arthritis, a model of human arthritis, but not in the joints of normal mice. OCTN1 should be involved in the inflammatory disease and in the present study, the regulatory mechanism of OCTN1 expression was characterized using the human Fibroblast-Like Synoviocyte cell line MH7A, derived from RA patients. A luciferase-reporter gene assay and gel shift assay demonstrated that RUNX1, which is an essential hematopoietic transcription factor associated with acute myeloid leukemia and is related to RA and Sp1, is involved in the regulation of OCTN1 promoter activity. Inflammatory cytokines such as interleukin-1beta and tumor necrosis factor-alpha increased the expression of OCTN1 mRNA. Furthermore, overexpression of nuclear factor-kappaB (NF-kappaB) activated promoter activity of OCTN1. These results clearly demonstrate that expression of OCTN1 is regulated by various factors, including RUNX1, inflammatory cytokines, and NF-kappaB, all of which are also related to the pathogenesis of RA. Further studies on the physiological substrate(s) of OCTN1 should be done to clarify the roles of OCTN1 in these diseases.
-
Mechanism of the Regulation of Organic Cation/Carnitine Transporter 1 (SLC22A4) by Rheumatoid Arthritis-Associated Transcriptional Factor RUNX1 and Inflammatory Cytokines
Drug Metabolism and Disposition, 2006Co-Authors: Tomoji Maeda, Keiji Miyazawa, Masamichi Hirayama, Daisuke Kobayashi, Ikumi TamaiAbstract:Recently, it was reported that the organic cation/carnitine transporter 1 (OCTN1, SLC22A4) is associated with chronic inflammatory diseases, such as rheumatoid arthritis (RA) and Crohn's disease. OCTN1 in humans is expressed in synovial tissues of individuals with rheumatoid arthritis. Furthermore octn1 in mice is expressed in inflamed joints with collagen-induced arthritis, a model of human arthritis, but not in the joints of normal mice. OCTN1 should be involved in the inflammatory disease and in the present study, the regulatory mechanism of OCTN1 expression was characterized using the human Fibroblast-Like Synoviocyte cell line MH7A, derived from RA patients. A luciferase-reporter gene assay and gel shift assay demonstrated that RUNX1, which is an essential hematopoietic transcription factor associated with acute myeloid leukemia and is related to RA and Sp1, is involved in the regulation of OCTN1 promoter activity. Inflammatory cytokines such as interleukin-1beta and tumor necrosis factor-alpha increased the expression of OCTN1 mRNA. Furthermore, overexpression of nuclear factor-kappaB (NF-kappaB) activated promoter activity of OCTN1. These results clearly demonstrate that expression of OCTN1 is regulated by various factors, including RUNX1, inflammatory cytokines, and NF-kappaB, all of which are also related to the pathogenesis of RA. Further studies on the physiological substrate(s) of OCTN1 should be done to clarify the roles of OCTN1 in these diseases.