Low molecular mass polypeptide 2 is an inducible immunoproteasome subunit. The expression of low molecular mass polypeptide 2 has not been examined in the intestine of patients with inflammatory bowel disease. This study was designed to determine whether the intestinal expression of low molecular mass polypeptide 2 was enhanced in a group of patients with inflammatory bowel disease compared with a group of control patients without inflammatory bowel disease. Moreover, we examined the association between low molecular mass polypeptide 2 expression and histologic pathology in these patients.
Twenty-one patients participated in the study. These included six control subjects without inflammatory bowel disease, eight patients with ulcerative colitis, and seven patients with Crohn's disease. Intestinal low molecular mass polypeptide 2 expression was evaluated by immunohistochemistry, as well as by Western blot. Histology scores (0-40 severity scale) were determined on the same sections of intestine as those used for low molecular mass polypeptide 2 histochemistry.
By immunohistochemistry, low molecular mass polypeptide 2 expression was significantly enhanced (P < 0.05 vs. control subjects) throughout visibly diseased areas of colon, rectum, and ileum from patients with inflammatory bowel disease. Low molecular mass polypeptide 2 expression also was increased in macroscopically normal intestine from patients with inflammatory bowel disease compared with normal tissue from control subjects. There was a significant correlation (P < 0.0001) between low molecular mass polypeptide 2 expression and histologic pathology in our patients. Western blot results confirmed that low molecular mass polypeptide 2 expression was enhanced in patients with ulcerative colitis (3.1-fold) and in patients with Crohn's disease (3.5-fold).
Intestinal low molecular mass polypeptide 2 expression is significantly increased in inflammatory bowel disease. The association between intestinal low molecular mass polypeptide 2 expression and histologic pathology suggests that this proteasome subunit plays a role in the pathogenesis of inflammatory bowel disease.
"We found that a variety of solid cancer cell lines as well as patient prostate tumour tissues express high levels of LMP2. Given that LMP2 upregulation is implicated in several pathological disorders and that UK-101 inhibits the growth of prostate cancer cells (Fitzpatrick et al, 2007; Wehenkel et al, 2008), LMP2 may represent a novel drug target. Our knockdown studies indicate that depletion of the LMP2 subunit in PC-3 cells has a growth inhibitory effect, further supporting LMP2 as a novel target. "
[Show abstract][Hide abstract] ABSTRACT: Although the proteasome is a validated anticancer target, the clinical application of its inhibitors has been limited because of inherent systemic toxicity. To broaden clinical utility of proteasome inhibitors as anticancer agents, it is critical to develop strategies to selectively target proteasomes in cancer cells. The immunoproteasome is an alternative form of the constitutive proteasome that is expressed at high levels in cancer tissues, but not in most normal cells in the body.
To validate the immunoproteasome as a chemotherapeutic target, an immunoproteasome catalytic subunit LMP2-targeting inhibitor and siRNA were used. The sensitivity of PC-3 prostate cancer cells to these reagents was investigated using viability assays. Further, a xenograft model of prostate cancer was studied to test the in vivo effects of LMP2 inhibition.
A small molecule inhibitor of the immunoproteasome subunit LMP2, UK-101, induced apoptosis of PC-3 cells and resulted in significant inhibition (~50-60%) of tumour growth in vivo. Interestingly, UK-101 did not block degradation of IκBα in PC-3 cells treated with TNF-α, suggesting that its mode of action may be different from that of general proteasome inhibitors, such as bortezomib, which block IκBα degradation.
These results strongly suggest that the immunoproteasome has important roles in cancer cell growth and thus provide a rationale for targeting the immunoproteasome in the treatment of prostate cancer.
British Journal of Cancer 06/2012; 107(1):53-62. DOI:10.1038/bjc.2012.243 · 4.84 Impact Factor
"The anticolitis effects that were observed with these chemical compounds are encouraging. However, resveratrol and piceatannol have antioxidant properties, while Vidofludimus can inhibit T-cell proliferation [5, 29, 60]. Therefore, further preclinical colitis studies need to be performed with more specific dual inhibitors of NF-κB and STAT3, in order to gauge the clinical potential of this pharmacological approach for IBD. "
[Show abstract][Hide abstract] ABSTRACT: This review identifies possible pharmacological targets for inflammatory bowel disease (IBD) within the IL-23/IL-17 axis. Specifically, there are several targets within the IL-23/IL-17 pathways for potential pharmacological intervention with antibodies or small molecule inhibitors. These targets include TL1A (tumor necrosis factor-like molecule), DR3 (death receptor 3), IL-23, IL-17 and the receptors for IL-23 and IL-17. As related to IBD, there are also other novel pharmacological targets. These targets include inhibiting specific immunoproteasome subunits, blocking a key enzyme in sphingolipid metabolism (sphingosine kinase), and modulating NF-κB/STAT3 interactions. Several good approaches exist for pharmacological inhibition of key components in the IL-23 and IL-17 pathways. These approaches include specific monoclonal antibodies to TL1A, IL-17 receptor, Fc fusion proteins, specific antibodies to IL-17F, and small molecule inhibitors of IL-17 like Vidofludimus. Also, other potential approaches for targeted drug development in IBD include specific chemical inhibitors of SK, specific small molecule inhibitors directed against catalytic subunits of the immunoproteasome, and dual inhibitors of the STAT3 and NF-κB signal transduction systems. In the future, well-designed preclinical studies are still needed to determine which of these pharmacological approaches will provide drugs with the best efficacy and safety profiles for entrance into clinical trials.
[Show abstract][Hide abstract] ABSTRACT: Optimum conditions for maximizing the throughput of an orthogonal frequency division multiplexed (OFDM) system are derived, and an algorithm for achieving them is presented. Theoretical bounds on performance are derived and used to compare OFDM with conventional equalized single carrier QAM for both the conventional error probability criterion and a criterion based on the mean-squared error. OFDM is shown to achieve greater throughput than equalized single carrier QAM, especially at low to intermediate signal-to-noise ratios and on channels with poor spectral properties. As an example, the near end crosstalk-dominated high-speed digital subscriber loop is considered
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