15-deoxyspergualin prevents mucosal injury by inhibiting production of TNF-α and down-regulating expression of MD-1 in a murine model of TNBS-induced colitis
Sungkyunkwan University, Sŏul, Seoul, South KoreaInternational Immunopharmacology (Impact Factor: 2.47). 09/2007; 7(8):1003-12. DOI: 10.1016/j.intimp.2007.02.015
The immunosuppressive drug 15-deoxyspergualin (DSG) is currently being used in clinical trials to prolong graft survival and reverse graft rejection. Here we evaluated whether DSG has a potential for ameliorating diseases characterized by mucosal inflammation. Using a murine model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, we were able to demonstrate that DSG reduced the severity of colitis. Therefore, colitic mice pretreated with DSG showed a striking improvement of the wasting disease compared with colitic mice, as assessed by weight loss as well as clinical, macroscopic and microscopic analysis. Also, we observed the significant change occurred in the CD19(+) B cell subset, which was decreased 15% in DSG pretreated colitic mice compared with colitic mice. However, DSG pretreatment does not influence the apoptotic population of T and B cells. Compared with colitic mice, down-regulation of TNF-alpha production was observed in DSG pretreated colitic mice. In addition, DSG pretreated colitic mice significantly reduced expression of MD-1 compared with colitic mice on B cells and dendritic cells (DCs). Therefore, pretreatment with DSG resulted in a significant histologic improvement, protecting against mucosal ulcerations and reduced inflammatory response by modulating expression of MD-1, which plays a very important role in immune response on B cells and DCs. Also, this improvement was paralleled by a reduction in TNF-alpha levels. Collectively, current results demonstrate that DSG may be an effective agent for the treatment of diseases characterized by mucosal inflammation.
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ABSTRACT: Water extract of Geijigajakyak-Tang (GJT) consisting of five crude drugs [dried root of P. lactiflora Peony (Paeoniaceae), dried trunk bark of C. cassia Blume (Lauraceae), seed of Z. jujube var. inermis Mill (Rhamnaceae), fresh root of Z. officinale Rocoe (Zingiberaceae) and dried trunk bark of G. uralensis Fish (Leguminosae)] is a folk medicine used for the treatment of chronic colitis. This study was designed to further elucidate the effect of GJT on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. GJT orally given to mice before and after TNBS intoxication, and their clinical and morphological changes, myeloperoxidase (MPO) activity and malondialdehyde (MDA) levels in colon tissues, were evaluated on Day 8 post-TNBS. Furthermore, the effect of six major constituents of individual herbs on ileum smooth muscle contraction and neutrophil chemotaxis was studied. GJT had a significant anti-inflammatory effect based on clinical and morphologic changes, MPO activity and MDA levels in colon tissues as compared with sham control. GJT and 5 major active constituents of individual herbs, paeoniflorin, cinnamaldehyde, jujuboside A, jujubogenin, and diammonium glycyrhhizinate significantly inhibited neutrophil chemotaxis. GJT significantly inhibited muscle contraction (IC(50); 2.10 +/- 0.11 mg/ml), and 1,8-cineol has the most spasmolytic activity (IC(50); 0.10 +/- 0.03 mg/ml). GJT has significant anti-inflammatory effects on TNBS-induced colitis via inhibitions of smooth muscle contraction and neutrophil chemotaxis.
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ABSTRACT: The molecular chaperone, heat shock protein 70 (Hsp70), acts at multiple steps in a protein's life cycle, including during the processes of folding, trafficking, remodeling and degradation. To accomplish these various tasks, the activity of Hsp70 is shaped by a host of co-chaperones, which bind to the core chaperone and influence its functions. Genetic studies have strongly linked Hsp70 and its co-chaperones to numerous diseases, including cancer, neurodegeneration and microbial pathogenesis, yet the potential of this chaperone as a therapeutic target remains largely underexplored. Here, we review the current state of Hsp70 as a drug target, with a special emphasis on the important challenges and opportunities imposed by its co-chaperones, protein-protein interactions and allostery.
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