Wan-Hee Yoo

Epigallocatechin-3-gallate suppresses TNF-α -induced production of MMP-1 and -3 in rheumatoid arthritis synovial fibroblasts

Rheumatoid arthritis (RA) synovial fibroblasts produce matrix metaloproteinases (MMPs), which destruct cartilage and bone in RA joint. Tumor necrosis factor-α (TNF-α) is one of the most important mediator leading to MMP production in RA synovial fibroblasts. Here we show that epigallocatechin-3-Gallate (EGCG) suppresses TNF-α-induced production of MMP-1 and MMP-3 in RA synovial fibroblasts, which was accompanied by inhibition of mitogen activated protein kinase (MAPK) and activator protein-1 (AP-1) pathways. EGCG treatment resulted in dose-dependent inhibition of TNF-α-induced production of MMP-1 and MMP-3 at the protein and mRNA levels in RA synovial fibroblast. EGCG treatment also inhibited TNF-α-induced phosphorylation of MAPKs, such as ERK1/2, p38, JNK. Electrophoretic mobility shift assay revealed that EGCG inhibits binding of AP-1 proteins to its response elements in synovial fibroblast treated. Thus, EGCG may play a role in regulating inflammation and bone destruction in RA patients.

Autophagy induction and CHOP under-expression promotes survival of fibroblasts from rheumatoid arthritis patients under endoplasmic reticulum stress

IntroductionSynovial fibroblasts from rheumatoid arthritis show resistance to apoptotic stimuli, indicating they may be difficult to treat. To clearly understand these mechanisms of resistance, rheumatoid and osteoarthritis synovial fibroblasts (RASF and OASF) were exposed to endoplasmic reticulum (ER) stress such as thapsigargin, Ca2+-ATPase inhibitor.MethodsFibroblasts were assessed microscopically for cell viability by trypan blue exclusion and for autophagic cells by LC-3II formation. Caspase-3 activity was measured as aminomethyl-coumarin (AMC) liberated from AC-DEVD-AMC. Immunoblotting was performed to compare protein expression in OASF and RASF.ResultsER stress caused cell death in OASF but not in RASF. Thapsigargin, a Ca2+-ATPase inhibitor, did not change the expression of GRP78, an ER chaperone in OASF and RASF, but induced another ER stress protein, CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) differently, showing high levels in OASF and low levels in RASF. Thapsigargin increased the autophagy response in RASF, with autophagosome formation, beclin expression, and LC3-II conversion. Transfection with beclin siRNA inhibited autophagy and increased the susceptibility to ER stress-induced cell death. On the other hand, CHOP siRNA increased autophagy and improved cell survival, especially in RASF, indicating that CHOP is involved in regulation of autophagy and cell death, but that low expression of CHOP protects RASF from apoptosis.ConclusionsAutophagy induction and CHOP under-expression increases cell resistance against ER stress-induced cell death in fibroblasts from rheumatoid arthritis patients.

Adult respiratory distress syndrome in systemic lupus erythematosus: causes and prognostic factors: a single center, retrospective study

To determine the causes and prognostic factors of Adult Respiratory Distress Syndrome (ARDS) in patients with systemic lupus erythematosus (SLE). Methods: Among 544 Korean SLE patients, who were followed in the Lupus Clinic of the Catholic Medical Center from 1993 to 1997, patients diagnosed as ARDS were examined retrospectively. During the study period, non-SLE patients with ARDS were investigated and then compared to SLE patients with ARDS in terms of clinical variables. Results: Nineteen patients with SLE were revealed to have a history of ARDS (3.5%) and 13 (68.4%) of 19 patients died. Death related to ARDS was found in 34.2% of all deaths (n = 38) from SLE during the study period. The frequency and causes of ARDS were as follows; 9 sepsis or bacteremia (47.4%), 2 miliary tuberculosis (10.5%), 2 invasive pulmonary aspergillosis (10.5%), 2 acute pulmonary alveolar hemorrhage syndrome (10.5%), 1 acute lupus pneumonitis (5.3%), 1 massive hemorrhage due to placenta previa (5.3%), 1 aspiration pneumonitis (5.3%), 1 disseminated intravascular coagulation associated with systemic vasculitis (5.3%). The main organisms in sepsis were gram negative bacilli (61.5%) The median steroid dose administered 1 month before ARDS was significantly higher in patients (n = 13) with infectious ARDS compared to those (n = 6) with ARDS due to other causes (P = 0.038). Comparison of the laboratory and clinical variables between the survivors (n = 6) and the deceased (n = 13) showed that the survivors had lower SLAM indices at presentation (P = 0.004) and APACHE (Acute Physiology, Age, Chronic Health Evaluation) III scores within 24 h after diagnosis of ARDS (P = 0.024) than the deceased. The APACHE III scores correlated well with the SLAM indices (r = 0.615, P = 0.007). Non-SLE patients with ARDS during the study period were selected for comparison to SLE patients with ARDS. Age at the onset of ARDS was younger in SLE (n = 19) compared to non-SLE (n = 190) (P < 0.001). Duration from ARDS onset to death was shorter in SLE patients (P < 0.001). The mortality from ARDS tended to be higher in SLE patients (P = NS). The first-day APACHE III score was significantly higher in deceased SLE patients (n = 13) compared to deceased non-SLE patients (n = 105) (P = 0.001). Conclusions: ARDS was a common premortem event of SLE and showed a high fatality rate in SLE. The most common cause of ARDS in Korean patients with SLE was sepsis by gram negative bacilli. ARDS in SLE developed at a younger age, and progressed more rapidly compared to ARDS in general. The SLAM index and APACHE III score could be useful to predict the prognosis of ARDS in SLE.

Prevalence of insulin resistance and metabolic syndrome in patients with gouty arthritis

The study was performed to confirm the high prevalence of metabolic syndrome in gouty patients and to define the relationship between insulin resistance and gouty arthritis. We recruited 83 patients with gouty arthritis and checked clinical factors according to the diagnostic criteria of metabolic syndrome from the ATP III guidelines and WHO Asia-Pacific obesity criteria recommendations. We also assessed the clinical characteristics of subjects and homeostasis model assessment of insulin resistance (HOMA-IR) and compared with previous study groups as controls. The prevalence of metabolic syndrome in patients with gout was 30.1% according to ATP III criteria and 50.6% with WHO Asia-Pacific adjustment and is significantly higher than the previous control study groups (ATP III: 5.2, 10.6%, WHO Asia-Pacific adjustment: 9.8, 13.9%). The mean value of HOMA-IR in patients with gout was 2.63xa0±xa01.36 and is significantly higher than control study (1.91xa0±xa01.01, Pxa0<xa00.05). There were significant correlations between 24-h urinary uric acid excretion and waist circumference (r2xa0=xa00.225, Pxa0=xa00.049), fasting insulin (r2xa0=xa00.241, Pxa0=xa00.035), and insulin resistance (HOMA-IR) (r2xa0=xa00.271, Pxa0=xa00.017). There were significant correlations between insulin resistance and waist circumference (r2xa0=xa00.341, Pxa0<xa00.01), BMI (r2xa0=xa00.390, Pxa0<xa00.01). The value of HOMA-IR (insulin resistance) and the prevalence of metabolic syndrome in patients with gout are significantly higher than normal healthy control groups. The hyperuricemia in gout might be caused by the increased adiposity associated with insulin resistance.

Quercetin Inhibits IL-1β-Induced Proliferation and Production of MMPs, COX-2, and PGE2 by Rheumatoid Synovial Fibroblast

This study was aimed to determine the effects of quercetin on the interleukin-1β (IL-1β)-induced proliferation of rheumatoid synovial fibroblasts (RASFs) and production of matrix metalloproteinases (MMPs), cyclooxygenase (COX), and prostaglandin E2 (PGE2) by RASFs. The proliferation and apoptosis of RASFs was evaluated with CCK-8 reagent and flow cytometry in the presence of IL-1with CCK-8 reagquercetin. The expression of MMPs, IL-1β enhanced the expression of MMP-1, MMP-3, tissue inhibitor of metalloproteinase (TIMP)-1, COXs, PGE2, and intracellular mitogen-activated protein kinase (MAPK) signalings including phosphorylated extracellular signal-regulated kinase (p-ERK), p-p38, phosphorylated c-Jun N-terminal kinase (p-JNK), and nuclear factor kB (NF-kB) were examined by immunoblotting or semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) in conditions as described above. Quercetin inhibits unstimulated and IL-1β-induced proliferation of RASFs and MMP-1, 3, COX-2 messenger ribonucleic acid and protein expression, PGE2 production induced with IL-1β. Quercetin also inhibits the phosphorylation of ERK-1/2, p38, JNK and activation of NF-kB by IL-1ed. These results indicate that quercetin inhibits synovial fibroblasts proliferation and MMPs, COX-2, and PGE2 production, which involved joint destruction in rheumatoid arthritis (RA), and suggest that it might be a new therapeutic agent for management of RA.

Successful treatment of steroid and cyclophosphamide-resistant diffuse scleroderma-associated interstitial lung disease with rituximab

Scleroderma (SSc) is a multisystem disorder characterized by fibrosis and collagen deposition in the dermis, but affects multiple organ systems, leading to esophageal dysmotility, renal failure, and interstitial lung disease (ILD). ILD is common manifestation of diffuse type of SSc and may be life threatening, and require aggressive therapy with cytotoxic agents. Although high-dose steroid and cyclophosphamide are most commonly used therapy for SSc-associated ILD, the efficacy is questionable in some cases and more effective and less toxic therapies are needed. Rituximab (RTX) is a chimeric mAb against human CD20 that depletes peripheral B cells and introduced for systemic rheumatic diseases. However, there were no enough evidences for SSc-associated ILD. We report herein a case of 47-year-old female with diffuse type of SSc with steroid and cyclophosphamide-resistant ILD that was successfully treated with RTX. Thus, we suggested that RTX could be an efficacious therapeutic modality for severe, conventional treatment-resistant SSc-associated ILD.

Effects of Ficus carica paste on loperamide-induced constipation in rats.

OBJECTIVEnConstipation is one of the most common gastrointestinal complaints worldwide. This study examined the effects of fig (Ficus carica L.) paste for the treatment of loperamide-induced constipation in a rat model.nnnMETHODSnAnimals were divided into one normal control group and four experimental groups (0, 1, 6, and 30 g/kg). Loperamide (2 mg/kg, twice per day) was injected intraperitoneally to induce constipation in the four experimental groups. Fig paste was administered for 4 weeks to assess its anti-constipation effects.nnnRESULTSnFecal pellet number, weight and water content were increased in the fig-treated groups as compared to the control group. Reductions in body weight and increased intestinal transit length were observed in the fig-treated groups. Fecal pellet number was reduced in the distal colons of the fig-treated rats. Exercise and ileum tension increased in the experimental groups as compared to the control group. According to histological analyses, the thickness of the distal colon and areas of crypt epithelial cells that produce mucin were increased in the fig-treated groups in a dose-dependent manner.nnnCONCLUSIONnConstipation was decreased when fig fruit was fed to rats. Specifically, fecal number, weight, and water content, as well as histological parameters such as thickness and mucin areas in the distal colon were improved. Fig treatment may be a useful therapeutic and preventive strategy for chronic constipation.

Use of complementary and alternative medicine by rheumatoid arthritis patients in Korea.

This study measured the prevalence of use of complementary and alternative medicine (CAM) in Korean patients with rheumatoid arthritis (RA). A trained nurse conducted 20-min questionnaire-based interviews at the hospitals when each patient visited as an outpatient. The questionnaire included questions on demographic information, clinical information, and the use of CAM. Of the 153 respondents, 125 (82%) had used CAM; 37% of those who used CAM had started taking CAM products following suggestions from family members and other relatives. In users of CAM, 35% considered that it improved the symptoms of RA, and 14% felt it was effective in achieving psychological relaxation. We categorized treatment into six CAM categories used by the respondents: 84.0% of patients used traditional Oriental medical treatments, 70.4% used plant- and animal-derived over-the-counter health care products, and 13.6% used manual therapies. Most RA patients (64%) would like to try a new type of CAM. About half of the respondents (48%) expected to receive information about CAM from their general practitioner even if most (72%) did not discuss their use of CAM with their doctor. Most of the RA patients in this study used CAM, and half reported beneficial effects. Despite the presence of adverse side effects, patients tended to use CAM without discussing it with their main physicians, suggesting that physicians should be actively involved in the prescription and use of CAM.

Review : Decreased tumour necrosis factor-beta production in TNFB*2 homozygote: an important predisposing factor of lupus nephritis in Koreans

Low TNF production and its association with TNF gene restriction fragment length polymorphism (RFLP) was demonstrated in (NZW/NZB) F1 mice. However, little is known about the significance of TNF production in association with TNF gene polymorphism in human SLE. This study was designed to evaluate the role of TNF production of peripheral blood mononuclear cells (PBMC) and its association with TNFB gene polymorphism in SLE, particularly lupus nephritis. TNFB gene polymorphism was defined by PCR-NcoI RFLP. TNF productions of phytohemagglutinin (PHA)- stimulated PBMC and T cells were examined by bioassay using L929 cell line and ELISA. The PBMC stimulated by PHA from patients with SLE (n = 60) tended to secrete less amounts of TNF by bioassay (1032±184pg/ml vs 1524±224pg/ml, P=0.094), and TNF-β by ELISA (P = 0.0082) than that from normal controls (n = 38). The low TNF-α producer was more frequent in nephritis than non-nephritis (34.4% vs 7.1% respectively, P<0.01). TNF-β also revealed similar results (53.1% vs 21.4%, P<0.05). In SLE, mean production of TNF-β was decreased in TNFB*2 homozygote ( n=18) than that in TNFB*1 homozygote (n = 9) (1126.3±145 pg/ml) vs 642 ± 118.4 pg/ml, respectively, P = 0.021), whereas TNF-α production showed little difference between the two groups (710.1 ± 56.4 vs 542.4 ± 71.1 pg/ml, respectively, P = 0.149). Our results demonstrate that decreased TNF production of PBMC, which was significantly associated with TNFB*2 homozygosity, could be an important predisposing factor of lupus nephritis in Koreans.

Combination treatment with leflunomide and methotrexate for patients with active rheumatoid arthritis

Objective: To determine the efficacy and safety of the combination of leflunomide and methotrexate for the treatment of patients with active rheumatoid arthritis (RA) in an open, non‐comparative, multicentre trial. Methods: Seventy‐four patients with active RA were enrolled to receive concomitantly leflunomide (no loading dose, 10u2005mg/day) and methotrexate (starting at 7.5u2005mg/week and titrating up to 15u2005mg/week) for 20 weeks. The primary end‐point was a 20% improvement in the American College of Rheumatology (ACR) criteria at 20 weeks. Safety measures included evaluation of adverse events at each visit and laboratory data, including haematology and liver function tests. Intention‐to‐treat analyses were conducted. Results: Sixty‐five patients completed 20 weeks of treatment, and 71.6% were responders based on the ACR20 criteria. After 20 weeks, the mean changes were −16.3 for tender joint count, −12.0 for swollen joint count, −44.0 for physician global assessment, −34.3 for patient global assessment, −22.7 for erythrocyte sedimentation rate, and −0.65 for the Health Assessment Questionnaire score. Adverse events occurred in 40.5% of the patients, and were considered serious in four patients who discontinued therapy. Abnormal liver function was noted for 16 patients (21.6%). Two of these patients were withdrawn from the study; after discontinuing the medication, their liver function recovered fully. Conclusion: The combination of leflunomide and methotrexate was effective and well tolerated in the treatment of active RA patients. This combination may be a useful option as an initial treatment for active RA before starting biological agents.