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1.  Ursodeoxycholic Acid Ameliorates Pain Severity and Cartilage Degeneration in Monosodium Iodoacetate-Induced Osteoarthritis in Rats 
Immune Network  2014;14(1):45-53.
Osteoarthritis (OA) is a degenerative joint disease characterized by a progressive loss of cartilage. And, increased oxidative stress plays a relevant role in the pathogenesis of OA. Ursodeoxycholic acid (UDCA) is a used drug for liver diseases known for its free radical-scavenging property. The objectives of this study were to investigate the in vivo effects of UDCA on pain severity and cartilage degeneration using an experimental OA model and to explore its mode of actions. OA was induced in rats by intra-articular injection of monosodium iodoacetate (MIA) to the knee. Oral administration UDCA was initiated on the day of MIA injection. Limb nociception was assessed by measuring the paw withdrawal latency and threshold. Samples were analyzed macroscopically and histologically. Immunohistochemistry was used to investigate the expression of interleukin-1β (IL-1β), IL-6, nitrotyrosine and inducible nitric oxide synthase (iNOS) in knee joints. UDCA showed an antinociceptive property and attenuated cartilage degeneration. OA rats given oral UDCA significantly exhibited a decreased number of osteoclasts in subchondral bone legion compared with the vehicle-treated OA group. UDCA reduced the expression of IL-1β, IL-6, nitrotyrosine and iNOS in articular cartilage. UDCA treatment significantly attenuated the mRNA expression of matrix metalloproteinase-3 (MMP-3), -13, and ADAMTS5 in IL-1β-stimulated human OA chondrocytes. These results show the inhibitory effects of UDCA on pain production and cartilage degeneration in experimentally induced OA. The chondroprotective properties of UDCA were achieved by suppressing oxidative damage and inhibiting catabolic factors that are implicated in the pathogenesis of cartilage damage in OA.
doi:10.4110/in.2014.14.1.45
PMCID: PMC3942507  PMID: 24605080
Ursodeoxycholic acid (UDCA); Monosodium iodoacetate (MIA); Osteoarthritis; Oxidative stress
2.  Grape Seed Proanthocyanidin Extract–Mediated Regulation of STAT3 Proteins Contributes to Treg Differentiation and Attenuates Inflammation in a Murine Model of Obesity-Associated Arthritis 
PLoS ONE  2013;8(11):e78843.
Grape seed proanthocyanidin extract (GSPE) is a natural flavonoid that exerts anti-inflammatory properties. Obesity is an inflammatory condition and inflammatory cells and their secretion of pro-inflammatory molecules contribute to the pathogenesis of obesity. Rheumatoid arthritis (RA) is a chronic autoimmune disease that is characterized by inflammation of joints lined by synovium. Previously, we demonstrated that obesity augmented arthritis severity in collagen induced arthritis (CIA), a murine model of human RA. Here, we investigated whether oral administration of GSPE showed antiobesity and anti-arthritic effects in high-fat diet-induced obese (DIO) mice and in obese CIA mice, respectively. The pathophysiologic mechanisms by which GSPE attenuates weight gain and arthritis severity in vivo were also investigated. In DIO mice, GSPE administration significantly inhibited weight gain, reduced fat infiltration in liver and improved serum lipid profiles. The antiobesity effect of GSPE was associated with increased populations of regulatory T (Treg) cells and those of decreased Th17 cells. Decrease of Th17 cells was associated with significant inhibition of their key transcriptional factors, pSTAT3Tyr705 and pSTAT3Ser727. On the contrary, GSPE-induced Treg induction was associated with enhanced pSTAT5 expression. To identify the anti-arthritis effects of GSPE, GSPE was given orally for 7 weeks after type II collagen immunization. GSPE treatment significantly attenuated the development of autoimmune arthritis in obese CIA model. In line with DIO mice, GSPE administration decreased Th17 cells and reciprocally increased Treg cells by regulating STAT proteins in autoimmune arthritis model. The expressions of pro-inflammatory cytokines and nitrotyrosine in synovium were significantly inhibited by GSPE treatment. Taken together, GSPE functions as a reciprocal regulator of T cell differentiation – suppression of Th17 cells and induction of Tregs in both DIO and obese CIA mice. GSPE may act as a therapeutic agent to treat immunologic diseases related with enhanced STAT3 activity such as metabolic disorders and autoimmune diseases.
doi:10.1371/journal.pone.0078843
PMCID: PMC3818494  PMID: 24223854
3.  In vivo action of IL-27: reciprocal regulation of Th17 and Treg cells in collagen-induced arthritis 
Interleukin (IL)-27 is a novel cytokine of the IL-6/IL-12 family that has been reported to be involved in the pathogenesis of autoimmune diseases and has a pivotal role as both a pro- and anti-inflammatory cytokine. We investigated the in vivo effects of IL-27 on arthritis severity in a murine collagen-induced arthritis (CIA) model and its mechanism of action regarding control of regulatory T (Tregs) and IL-17-producing T helper 17 (Th17) cells. IL-27-Fc-treated CIA mice showed a lower severity of arthritis. IL-17 expression in the spleens was significantly decreased in IL-27-Fc-treated CIA mice compared with that in the CIA model. The Th17 population was decreased in the spleens of IL-27-Fc-treated CIA mice, whereas the CD4+CD25+Foxp3+ Treg population increased. In vitro studies revealed that IL-27 inhibited IL-17 production in murine CD4+ T cells, and the effect was associated with retinoic acid-related orphan receptor γT and signal transducer and activator of transcription 3 inhibition. In contrast, fluorescein isothiocyanate-labeled forkhead box P3 (Foxp3) and IL-10 were profoundly augmented by IL-27 treatment. Regarding the suppressive capacity of Treg cells, the proportions of CTLA-4+ (cytotoxic T-lymphocyte antigen 4), PD-1+ (programmed cell death protein 1) and GITR+ (glucocorticoid-induced tumor necrosis factor receptor) Tregs increased in the spleens of IL-27-Fc-treated CIA mice. Furthermore, in vitro differentiated Treg cells with IL-27 exerted a more suppressive capacity on T-cell proliferation. We found that IL-27 acts as a reciprocal regulator of the Th17 and Treg populations in CD4+ cells isolated from healthy human peripheral blood mononuclear cells (PBMCs), as well as from humans with rheumatoid arthritis (RA) PBMCs. Our study suggests that IL-27 has the potential to ameliorate overwhelming inflammation in patients with RA through a reciprocal regulation of Th17 and Treg cells.
doi:10.1038/emm.2013.89
PMCID: PMC3809362  PMID: 24091748
collagen-induced arthritis; interleukin-27; interleukin-17-producing T cells; regulatory T cells; rheumatoid arthritis
4.  Compressive Neuropathy of the Posterior Tibial Nerve at the Lower Calf Caused by a Ruptured Intramuscular Baker Cyst 
Annals of Rehabilitation Medicine  2013;37(4):577-581.
Baker cyst is an enlargement of the gastrocnemius-semimembranosus bursa. Neuropathy can occur due to either direct compression from the cyst itself or indirectly after cyst rupture. We report a unique case of a 49-year-old man with left sole pain and paresthesia who was diagnosed with posterior tibial neuropathy at the lower calf area, which was found to be caused by a ruptured Baker cyst. The patient's symptoms resembled those of lumbosacral radiculopathy and tarsal tunnel syndrome. Posterior tibial neuropathy from direct pressure of ruptured Baker cyst at the calf level has not been previously reported. Ruptured Baker cyst with resultant compression of the posterior tibial nerve at the lower leg should be included in the differential diagnosis of patients who complain of calf and sole pain. Electrodiagnostic examination and imaging studies such as ultrasonography or magnetic resonance imaging should be considered in the differential diagnosis of isolated paresthesia of the lower leg.
doi:10.5535/arm.2013.37.4.577
PMCID: PMC3764355  PMID: 24020041
Tibial neuropathy; Nerve compression syndromes; Popliteal cyst
5.  Curcumin Attenuates Acute Graft-versus-Host Disease Severity via In Vivo Regulations on Th1, Th17 and Regulatory T Cells 
PLoS ONE  2013;8(6):e67171.
Background
In this study we examined the in vivo and in vitro effects and mechanisms of action of curcumin on the development of acute graft-versus-host disease (GVHD) using a murine model.
Methodology/Principal Findings
Mixed lymphocyte reactions were used to determine the in vitro effects of curcumin. Treatment with curcumin attenuated alloreactive T cell proliferation and inhibited the production of interferon (IFN)-γ and interleukin (IL)-17. In a murine acute GVHD model, transplantation of curcumin-treated allogeneic splenocytes into irradiated recipient mice significantly reduced the clinical severity scores of acute GVHD manifested in the liver, skin, colon and lung as compared with animals receiving vehicle-treated splenocytes. c-Fos and c-Jun expression levels in the skin and intestine, which are major target organs, were analyzed using immunohistochemical staining. Expression of both proteins was reduced in epithelial tissues of skin and intestine from curcumin-treated GVHD animals. The IFN-γ-expressing CD4+ splenocytes and IFN-γ-expressing lymph node cells were dramatically decreased in curcumin-treated mice. In contrast, CD4+Foxp3+ splenocytes were increased in the curcumin-treated acute GVHD animals. Flow cytometric analysis revealed that animals transplanted with curcumin-treated allogeneic splenocytes showed increased populations of CD4+ regulatory T cells (Tregs) as well as CD8+ Treg cells, compared to animals administered vehicle-treated splenocytes. Curcumin-treated acute GVHD animals could have a change in B cell subpopulations.
Conclusion/Significance
In the present study, we investigated the efficacy and mechanism of action of curcumin treatment against acute GVHD. The acute GVHD mice administered with curcumin-treated splenocytes showed significantly reduced severity of acute GVHD. Curcumin exerted in vivo preventive effects on acute GVHD by reciprocal regulation of T helper 1 (Th1) and Treg (both CD4+ and CD8+ Treg) cell lineages as well as B cell homeostasis.
doi:10.1371/journal.pone.0067171
PMCID: PMC3688629  PMID: 23840617
6.  Temporal differential effects of proinflammatory cytokines on osteoclastogenesis 
Bone destruction and inflammation are closely linked. Cytokines play an important role in inflammatory bone destruction by upregulating the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL). The direct role of cytokines that act in a non-RANKL-dependent manner has yet to be elucidated. The aim of this study was to investigate the direct osteoclastogenic properties of inflammatory cytokines at different time-points of osteoclastogenesis. Mouse bone marrow macrophages were stimulated with the macrophage colony-stimulating factor (M-CSF) and various concentrations of RANKL. Inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-17 and IL-23, were added to the culture system of osteoclastogenesis. Two time-points of cytokine treatment were set. The ‘early’ effect of each cytokine was investigated at the time of first RANKL treatment, whereas the ‘late’ effect was investigated 48 h after the first RANKL challenge. Osteoclast differentiation and function were assessed using an osteoclast marker [tartrate-resistant acid phosphatase (TRAP)] and by visualization of pit formation. A permissive level of RANKL was required for cytokine-associated osteoclastogenesis in all experiments. In the M-CSF/RANKL monocellular culture system, IL-1β enhanced and IL-6 decreased osteoclast formation in a dose-dependent manner, regardless of temporal differences. Other cytokines showed various responses according to the phase of osteoclast maturation and the concentration of each cytokine and RANKL. Furthermore, luciferase assays showed that both IL-1β and RANKL activated the NF-κB signaling pathway. Collectively, our data revealed that targeting IL-1β may be a promising strategy to inhibit inflammation-associated bone destruction and osteoporosis.
doi:10.3892/ijmm.2013.1269
PMCID: PMC3621814  PMID: 23403591
inflammation; osteoclast; receptor activator nuclear factor-κB ligand; interleukin-1β; interleukin-6; nuclear factor-κB
7.  Periarticular Osteoporosis Is a Prominent Feature in Early Rheumatoid Arthritis: Estimation Using Shaft to Periarticular Bone Mineral Density Ratio 
Journal of Korean Medical Science  2013;28(2):287-294.
We aimed to quantify periarticular osteoporosis and investigate its significance in 45 patients with rheumatoid arthritis (RA) and 106 controls. Dual-energy X-ray absorptiometry (DXA) was used to determine the ratio of shaft to periarticular bone mineral density (BMD) as an index of periarticular demineralization. Periarticular osteoporosis was measured by conventional radiography. The BMDs of shaft and periarticular regions in eight designated areas on proximal phalanges were quantified. Clinical variables were examined to identify risk factors for periarticular osteoporosis. The assessment of periarticular osteoporosis on X-ray images reached a moderate degree of interobserver agreement among four physicians (ĸ = 0.47). For BMD quantification, we designed three types of mathematical formulae: the ratio of shaft to periarticular BMD, the mean of the ratios, and the ratio of the sums. These ratios were significantly higher in the patients with early RA (disease duration ≤ 3 yr) than in controls (P < 0.01). The findings were not as distinctive in patients with established RA. Body mass index, cumulative dose of corticosteroid, and C-terminal telopeptide were correlated with BMD ratios. Conclusively, DXA-assisted localized quantification and BMD ratio calculations are feasible for assessing periarticular demineralization. Periarticular osteoporosis is a relatively distinctive feature of early RA.
doi:10.3346/jkms.2013.28.2.287
PMCID: PMC3565142  PMID: 23399828
Bone Density; Arthrits; Rheumatoid; Periarticular Osteopenia
8.  Regression of syndesmophyte after bone marrow transplantation for acute myeloid leukemia in a patient with ankylosing spondylitis: a case report 
Introduction
Disease progression of ankylosing spondylitis has been considered irreversible. However, we report a case of spontaneous regression of syndesmophyte development following allogeneic peripheral blood stem cell transplantation in a patient with acute myeloid leukemia, who was also diagnosed as having ankylosing spondylitis. To the best of our knowledge, this is the first case report presenting the partial radiologic regression of syndesmophytes.
Case presentation
A 39-year-old man with active ankylosing spondylitis achieved clinical remission and partial radiological regression of cervical spine syndesmophytes following a peripheral blood stem cell transplantation for acute myeloid leukemia. Our patient received an allogeneic peripheral blood stem cell transplantation following a pre-transplantation conditioning regimen of total body irradiation and cyclophosphamide. The donor was a human leukocyte antigen-matched 29-year-old man. Our patient has remained asymptomatic and has received no medication for ankylosing spondylitis for nearly three years.
Conclusions
Several explanations are proposed for the regression of syndesmophytes and clinical improvement in active ankylosing spondylitis observed in our patient, including changes in bone remodeling and immune reconstitution following stem cell transplantation, the effect of immunosuppressive agents, or fluctuation in the natural course of ankylosing spondylitis although further studies are required. The regression of syndesmophytes in ankylosing spondylitis in this case raises the possibility that stem cell transplantation might contribute to the development of a novel therapeutic strategy for treatment of the disease.
doi:10.1186/1752-1947-6-250
PMCID: PMC3459693  PMID: 22909092
9.  Measurement of Interleukin-33 (IL-33) and IL-33 Receptors (sST2 and ST2L) in Patients with Rheumatoid Arthritis 
Journal of Korean Medical Science  2011;26(9):1132-1139.
The interleukin-33 (IL-33)/ST2 pathway has emerged as an intercellular signaling system that participates in antigen-allergen response, autoimmunity and fibrosis. It has been suggested that IL-33/ST2 signaling has been involved in the pathogenesis of rheumatoid arthritis (RA), because IL-33 and its receptor have been specifically mapped to RA synovium. The aim of this study was to determine the levels of IL-33 and sST2 in sera and synovial fluids in patients with RA. The serum level of IL-33 was significantly higher in patients with RA (294.9 ± 464.0 pg/mL) than in healthy controls (96.0 ± 236.9 pg/mL, P = 0.002). The synovial fluid level of IL-33 was significantly higher in RA patients than in osteoarthritis patients. The level of serum sST2 was higher in RA patients than in healthy controls (P = 0.042). A significant relationship was found between the levels of IL-33 and IL-1β (r = 0.311, P = 0.005), and IL-33 and IL-6 (r = 0.264, P = 0.017) in 81 RA patients. The levels of IL-33, sST2 and C-reactive protein decreased after conventional disease-modifying antirheumatic drugs treatment in 10 patients with treatment-naïve RA. Conclusively, IL-33 is involved in the pathogenesis of RA and may reflect the degree of inflammation in patients with RA.
doi:10.3346/jkms.2011.26.9.1132
PMCID: PMC3172648  PMID: 21935266
Interleukin-33; sST2, ST2L; Arthritis, Rheumatoid
10.  Engagement of Toll-Like Receptor 3 Induces Vascular Endothelial Growth Factor and Interleukin-8 in Human Rheumatoid Synovial Fibroblasts 
Background/Aims
Angiogenesis, which is a critical step in the initiation and progression of rheumatoid arthritis (RA), involves pro-angiogenic factors, including interleukin (IL)-8 and vascular endothelial growth factor (VEGF). We investigated the role of Toll-like receptor 3 (TLR3) in the regulation of pro-angiogenic factors in RA fibroblast-like synoviocytes (FLS).
Methods
FLS were isolated from RA synovial tissues and stimulated with the TLR3 ligand, poly (I:C). The levels of VEGF and IL-8 in the culture supernatants were measured using enzyme-linked immunosorbent assays, and the mRNA levels were assessed by semiquantitative reverse transcription-polymerase chain reaction. The expression patterns of VEGF and IL-8 in the RA synovium and osteoarthritis (OA) synovium were compared using immunohistochemistry.
Results
The expression levels of TLR3, VEGF, and IL-8 were significantly higher in the RA synovium than in the OA synovium. VEGF and IL-8 production were increased in the culture supernatants of RA FLS stimulated with poly (I:C), and the genes for these proteins were up-regulated at the transcriptional level after poly (I:C) treatment. Treatment with inhibitors of nuclear factor-kappaB (NF-κB), i.e., pyrrolidine dithiocarbamate and parthenolide, abrogated the stimulatory effect of poly (I:C) on the production of VEGF and IL-8 in RA FLS.
Conclusions
Our results suggest that the activation of TLR3 in RA FLS promotes the production of proangiogenic factors, in a process that is mediated by the NF-κB signaling pathway. Therefore, targeting the TLR3 pathway may be a promising approach to preventing pathologic angiogenesis in RA.
doi:10.3904/kjim.2010.25.4.429
PMCID: PMC2997973  PMID: 21179282
Toll-like receptor 3; Arthritis, rheumatoid; Vascular endothelial growth factor; Interleukin-8; Synovial fibroblast
11.  Hemorrhagic pericarditis with cardiac tamponade after percutaneous coronary intervention associated with the use of abciximab 
Glycoprotein (GP) IIb/IIIa inhibitors, such as abciximab, are used as adjunctive therapy for percutaneous coronary intervention (PCI) in high-risk non-ST-elevation myocardial infarction (NSTEMI) and in ST-elevation myocardial infarction (STEMI), although their effects when used for STEMI are less clear. As the use of GP IIb/IIIa inhibitors becomes more widespread, determining the risks associated with them becomes more important. The major risks associated with the use of GP IIb/IIIa inhibitors are the potential for major bleeding and thrombocytopenia. This is the first reported case in Korea of hemorrhagic pericarditis resulting in cardiac tamponade associated with the use of abciximab, a commonly used GP Ilb/IIa inhibitor, following PCI.
doi:10.3904/kjim.2008.23.3.156
PMCID: PMC2686964  PMID: 18787370
Abciximab; Pericarditis
12.  The Association Between Current Helicobacter pylori Infection and Coronary Artery Disease 
Background
The role of Helicobacter pylori (H. pylori) in the pathogenesis of coronary artery disease (CAD) is still controversial, and the relation between current H. pylori infection and CAD has not been fully examined. This study evaluated the relation between H. pylori infection as confirmed by gastroduodenoscopic biopsy and CAD.
Methods
We determined the presence of H. pylori infections, via gastroduodenoscopy, in 88 patients of the normal coronary angiographic group and also in 175 patients of the CAD group, and the latter patients had more than 50% coronary stenosis angiographically demonstrated. We excluded those patients with a history of previous H. pylori eradication and/or malignancy. A small piece of tissue from the antrum, which was obtained by gastroduodenoscopic biopsy, was stained by Warthin-starry silver stain. We defined a negative staining result that there was no stained tissue in the sample and the stained tissue was also positive for H. pylori infection.
Results
There was no significant difference, except for gender, age, smoking and high density lipoprotein cholesterol (HDL-c), of the demographic and laboratory characteristics between the groups. Twenty seven (30.7%) patients of the normal control group and 71 (40.6%) patients of the CAD group were positive of H. pylori infection, yet there was no statistical difference. We angiographically followed up the 80 patients of the CAD group who were treated by percutaneous coronary intervention (PCI) at 6 to 9 months after their primary intervention. Twenty two (37.9%) of the 58 patients of the H. pylori negative group and 10 (45.5%) of the 22 patients of the H. pylori positive group were treated with reintervention, but reintervention was also not significantly different between the group with H. pylori infection and the group without the infection.
Conclusions
These data indicated that H. pylori infection had a modest influence on CAD and progressive atheroma, but the showed a tendency to increase. Further studies are needed to evaluate the relationship between H. pylori infection and CAD.
doi:10.3904/kjim.2007.22.3.152
PMCID: PMC2687700  PMID: 17939331
Helicobacter pylori; Coronary artery disease

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