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ABSTRACT: To investigate the mechanism of the immunosuppressive effect of T-614 [N-(3-formylamino-4-oxo-6-phenoxy-4H-chromen-7-yl)methanesulfonamide], a new antirheumatic drug whose clinical efficacy has been determined for the treatment of patients with rheumatoid arthritis (RA).
RA synovial fibroblast-like cells were cultured with tumor necrosis factor-alpha (TNF-alpha, 10 ng/ml) in the presence or absence of T-614. After incubation, cytokine production was measured by ELISA. Expression of interleukin 6 (IL-6) and IL-8 mRNA was examined by real-time quantitative reverse transcriptase-polymerase chain reaction analysis and TNF-alpha induced nuclear factor-kappaB (NF-kappaB) activation was observed using immunostaining with an antibody against NF-kappaB p65.
T-614 suppressed TNF-alpha induced production of IL-6, IL-8, and monocyte chemoattractant protein 1, and also reduced the accumulation of IL-6 and IL-8 mRNA in a concentration dependent manner. T-614 interfered with the TNF-alpha induced translocation of NF-kappaB to the nucleus from the cytoplasm.
Inhibition of NF-kappaB activation and transcription of proinflammatory cytokines by T-614 contributes to its clinical antirheumatic effect.
The Journal of Rheumatology 01/2002; 28(12):2591-6. · 3.69 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-activated transcriptional factor belonging to the steroid receptor superfamily. It plays a role in both adipocyte differentiation and tumorgenesis. Up-date, the up-regulation of PPAR-gamma expression is a frequent occurrence in a variety of different malignant tumors. In this study, we investigated the expression of PPAR-gamma in human renal cell carcinoma (RCC) tissues, and the role of PPAR-gamma in cell growth in human RCC-derived cell lines. Immunohistochemistry showed a strong immunoreactive expression of PPAR-gamma in all slides from cancer specimens. RT-PCR and Western blot analysis showed 3 RCC cell lines expressed PPAR-gamma mRNA and its protein. MTT assay in 3 RCC cells showed that the synthetic PPAR-gamma agonists thiazolidinedione compounds (pioglitazone and troglitazone) and the endogeneous PPAR-gamma ligand, 15-deoxy-Delta12,14-prostaglandin J(2) (15dPGJ(2)) inhibited the growth of the RCC cells. These results suggest that PPAR-gamma may become a new target in the treatment of RCC.
Biochemical and Biophysical Research Communications 10/2001; 287(3):727-32. · 2.48 Impact Factor
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ABSTRACT: Rheumatoid arthritis (RA) is a chronic polyarticular joint disease associated with massive synovial proliferation, inflammation, and angiogenesis. PPAR-gamma ligands, both 15-deoxy-Delta(12,14)-prostaglandin J2 (15d- PGJ2) and troglitazone (TRO), can inhibit the growth of RA synoviocytes in vitro, and suppress the chronic inflammation of adjuvant-induced arthritis in rats, but the potency of 15d-PGJ2 is higher than TRO. Prostaglandin (PG) E2 plays important roles in joint erosion and synovial inflammation. In the present study, 15d-PGJ2, but not TRO and other prostanoids, suppressed interleukin (IL)-1beta-induced PGE2 synthesis in rheumatoid synovial fibroblasts (RSFs) through the inhibition of cyclooxygenase (COX-2) and cytosolic phospholipase A2 (cPLA2) expression. Furthermore, the inhibition was not affected by pretreatment with anti-PPAR-gamma antibody. It means that this anti-inflammatory effect of 15d-PGJ2 for PG synthesis may be independent of PPAR-gamma and 15d-PGJ2 is a key regulator of negative feedback of the arachidonate cascade on the COX pathway. These findings provide new insight into the feedback mechanism of the arachidonate cascade.
Biochemical and Biophysical Research Communications 06/2001; 283(4):750-5. · 2.48 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and have a dominant regulatory role in adipocyte and monocyte differentiation. PPAR-gamma agonists are also negative regulators of macrophage activation and have modulatory effects on tumorigenesis. In this study we demonstrate that synovial tissue localized expression of PPAR-gamma in patients with rheumatoid arthritis (RA). We detected markedly enhanced expression of PPAR-gamma in macrophages, as well as modestly enhanced expression in the synovial lining layer, fibroblasts, and endothelial cells. Activation of the PPAR-gamma by 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and the synthetic PPAR-gamma ligand (troglitazone) induced RA synoviocyte apoptosis in vitro. Moreover, intraperitoneal administration of these PPAR-gamma ligands ameliorated adjuvant-induced arthritis with suppression of pannus formation and mononuclear cell infiltration in female Lewis rats. Anti-inflammatory effects of 15d-PGJ(2) were more potent than troglitazone. These findings suggest that PPAR-gamma may be an important immunoinflammatory mediator and its ligands, especially 15d-PGJ(2), may be useful in the treatment of RA.
Journal of Clinical Investigation 08/2000; 106(2):189-97. · 15.39 Impact Factor
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ABSTRACT: Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptors superfamily, have an important regulatory role in adipogenesis and inflammation. PPAR-gamma ligands induce terminal differentiation and growth inhibition of human breast cancer cells and prostatic cancer cells. In this study, we demonstrated that PPAR-gamma, but not PPAR-alpha, was expressed in human lung cancer cell lines by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. We also found that the synthetic PPAR-gamma agonist thiazolidinedione compounds (troglitazone) and the endogenous PPAR-gamma ligand, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), inhibited the growth of human lung cancer cells through the induction of apoptosis. However, PPAR-alpha agonist (bezafibrate) and other prostanoids (PGE(2), PGF(2alpha)) did not induce apoptosis. These findings suggest that PPAR-gamma may play an important role in the pathogenesis of lung cancer and that PPAR-gamma agonist may be useful therapeutic agents in the treatment of human lung cancer.
Biochemical and Biophysical Research Communications 05/2000; 270(2):400-5. · 2.48 Impact Factor
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R Yamada,
H Sano,
T Hla,
A Hashiramoto,
Y Kawahito,
S Mukai,
M Kohno,
Y Tsubouchi,
M Inoue,
A Komatsu, K Inoue,
M Kondo
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ABSTRACT: The effects of cyclooxygenase (COX)-2 antisense oligodeoxynucleotide (ODN) in induction of adjuvant-induced arthritis were investigated. Female Lewis rats were injected with Mycobacterium butyricum intradermally at the base of tails to induce arthritis. Synthetic 18 mer phosphorothioate ODNs corresponding to the translation initiation site of rat COX-2 mRNA were prepared. The antisense (AS), sense (S), and "scrambled" (Sc) ODNs were intraperitoneally administered. Arthropathy was evaluated with arthritis score, paw edema, and histological examination. Expression of COX-1 and -2 protein and mRNA were examined with immunostaining and reverse-transcription polymerase chain reaction, respectively. COX-2 AS ODN significantly suppressed induction of arthritis in a dose-dependent manner without severe adverse effects, whereas S and Sc ODNs did not show significant inhibitory effects. COX-2 mRNA and protein expression were also suppressed only by COX-2 AS ODN without any alteration of COX-1 expression. These data suggest that selective inhibition of COX-2 with AS ODN may have a therapeutic potency in the treatment of rheumatoid arthritis.
Biochemical and Biophysical Research Communications 04/2000; 269(2):415-21. · 2.48 Impact Factor
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ABSTRACT: The peroxisome proliferator-activated receptor (PPAR)-gamma is a member of the steroid nuclear receptors. Recent studies have demonstrated that PPAR-gamma is expressed in several cancer cells. We examined the PPAR-gamma expression in both normal lung and major types of human lung cancer. The expression of PPAR-gamma mRNA was detected in 2 out of 3 normal lung tissues and its protein was detected in 3 out of 5 normal lung tissues. In contrast, a small cell carcinoma cell line and all other types of lung cancer tissues expressed PPAR-gamma mRNA and its protein. Immunoreactive PPAR-gamma is strongly expressed in cancer cells and moderately in mononuclear cells, endothelial cells and fibroblasts of lung cancer tissues. Our results suggest that PPAR-gamma may play an important role in the pathogenesis and/or progression of lung cancer, and may be a novel therapeutical target for therapy of lung cancer.
Anticancer research 21(4A):2471-6. · 1.73 Impact Factor
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ABSTRACT: Cyclooxygenase (COX)-2 has been reported to play an important role in carcinogenesis. Meloxicam (preferential COX-2 inhibitor) inhibits the growth of COX-2 positive and COX-1 negative colorectal cancer cells. We evaluated the effects of meloxicam on the growth of lung cancer cells. By reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis, COX-2 but not COX-1 was expressed in human non-small cell lung cancer (NSCLC) cell lines (A549 and PC14). In human small cell lung cancer (SCLC) cell line (H841), both COX-1 and COX-2 were not detected. MTT assay and prostaglandin (PG) E2 enzyme immunoassay showed that meloxicam inhibited the growth and PGE2 production of both A549 and PC14, but not H841 cells. These findings suggest that COX-2 may play an important role in the pathogenesis and progression of NSCLC, and that meloxicam may be a useful therapeutic agents in the treatment of NSCLC.
Anticancer research 20(5A):2867-72. · 1.73 Impact Factor
