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Inhibition of plasminogen activator inhibitor-1 attenuates against intestinal fibrosis in mice
( Jin Imai ),( Takashi Yahata ),( Hitoshi Ichikawa ),( Abd Aziz Ibrahim ),( Masaki Yazawa ),( Hideaki Sumiyoshi ),( Yutaka Inagaki ),( Masashi Matsushima ),( Takayoshi Suzuki ),( Tetsuya Mine ),( Kiyo 대한장연구학회 2020 Intestinal Research Vol.18 No.2
Background/Aims: Intestinal fibrosis is a major complication of Crohn’s disease (CD). The profibrotic protein transforming growth factor-β (TGF-β) has been considered to be critical for the induction of the fibrotic program. TGF-β has the ability to induce not only the expression of extracellular matrix (ECM) including collagen, but also the production of plasminogen activator inhibitor-1 (PAI-1) that prevents enzymatic degradation of the ECM during the onset of fibrotic diseases. However, the significance of PAI-1 in the developing intestinal fibrosis has not been fully understood. In the present study, we examined the actual expression of PAI-1 in fibrotic legion of intestinal inflammation and its correlation with the abnormal ECM deposition. Methods: Chronic intestinal inflammation was induced in BALB/c mice using 8 repeated intrarectal injections of 2,4,6-trinitrobenzene sulfonic acid (TNBS). TM5275, a PAI-1 inhibitor, was orally administered as a carboxymethyl cellulose suspension each day for 2 weeks after the sixth TNBS injection. Results: Using a publicly available dataset (accession number, GSE75214) and TNBS-treated mice, we observed increases in PAI-1 transcripts at active fibrotic lesions in both patients with CD and mice with chronic intestinal inflammation. Oral administration of TM5275 immediately after the onset of intestinal fibrosis upregulated MMP-9 (matrix metalloproteinase 9) and decreased collagen accumulation, resulting in attenuation of the fibrogenesis in TNBS-treated mice. Conclusions: PAI-1-mediated fibrinolytic system facilitates collagen degradation suppression. Hence, PAI-1 inhibitor could be applied as an anti-fibrotic drug in CD treatment. (Intest Res 2020;18:219-228)
( Shuntaro Maruyama ),( Tomohito Gohda ),( Yusuke Suzuki ),( Hitoshi Suzuki ),( Yuji Sonoda ),( Saki Ichikawa ),( Zi Li ),( Maki Murakoshi ),( Satoshi Horikoshi ),( Yasuhiko Tomino ) 대한신장학회 2016 Kidney Research and Clinical Practice Vol.35 No.4
Background: IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. Tonsillectomy plus steroid pulse therapy has been able to induce clinical remission in early-stage IgAN. However, its possible effect on systemic and local cytokines and tubular markers has not been fully investigated. Methods: We obtained serum and urine samples from 38 patients just before renal biopsy and third steroid pulse therapy. Markers of tubular damage such as N-acetyl-β- D-glucosaminidase, and kidney injury molecule-1 and inflammation such as interleukin (IL)-6, monocyte chemotactic protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1 were measured by immunoassay. Results: Before renal biopsy, only urinary inflammatory markers, except MCP-1, were associated with glomerular (proteinuria) and/or tubular damage markers. Proteinuria, hematuria, and estimated glomerular filtration rate dramatically improved after therapy. In addition, levels of serum IL-6 and ICAM-1 and all urinary markers declined significantly; however, serum MCP-1 and VCAM-1 levels did not. None of the urinary markers correlated with the serum inflammatory markers. Conclusion: Tonsillectomy plus steroid pulse therapy for patients with IgAN might be useful for improving not only glomerular damage marker but also tubular damage markers through the improvement of local renal inflammation. Copyright ⓒ 2016. The Korean Society of Nephrology. Published by Elsevier. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
A novel HSF1-mediated death pathway that is suppressed by heat shock proteins
Hayashida, Naoki,Inouye, Sachiye,Fujimoto, Mitsuaki,Tanaka, Yasunori,Izu, Hanae,Takaki, Eiichi,Ichikawa, Hitoshi,Rho, Jaerang,Nakai, Akira Wiley (John WileySons) 2006 The EMBO journal Vol.25 No.20
<P>Heat shock response is an adoptive response to proteotoxic stress, and a major heat shock transcription factor 1 (HSF1) has been believed to protect cells from cell death by inducing heat shock proteins (Hsps) that assist protein folding and prevent protein denaturation. However, it is revealed recently that HSF1 also promotes cell death of male germ cells. Here, we found a proapoptotic Tdag51 (T-cell death associated gene 51) gene as a direct target gene of HSF1. Heat shock and other stresses induced different levels of Hsps and Tdag51, which depend on cell types. Hsps bound directly to the N-terminal pleckstrin-homology like (PHL) domain of Tdag51, and suppressed death activity of the C-terminal proline/glutamine/histidine-rich domain. Tdag51, but not major Hsps, were induced in male germ cells exposed to high temperatures. Analysis of Tdag51-null testes showed that Tdag51 played substantial roles in promoting heat shock-induced cell death in vivo. These data suggest that cell fate on proteotoxic condition is determined at least by balance between Hsp and Tdag51 levels, which are differently regulated by HSF1.</P>