REPORTS been implicated in autoinflammatory and autoimmune conditions, neurodegenerative diseases, and cancer metastasis . As an example of the effects of agents inhibiting multiple steps in inflammation, the inhibitory effects of Myricetin on IL-1B induced production of inflammatory mediators (MMP-1 and IL-6) and activation of the MAP Kinase (MAPK) signaling pathway have been investigated in SW982 human synovial sarcoma cells, a line capable of secreting high levels of inflammatory cytokines and MMPs . The goal of the study was to test the potential therapeutic and protective effect of Myricetin on rheumatoid arthritis, a chronic inflammatory disease. The results were consistent with our data in showing that Myricetin had anti-proteolytic activity and an inhibitory effect on IL-1B induced inflammatory mediators. Furthermore, Myricetin down-regulated the MAPK signaling pathway involved in the activation of transcription factors that induce the synthesis of MMP-1 and cytokines. Further investigations of the potential therapeutic effects of blocking cytokine-mediated inflammation have highlighted the significant connection between inflammation and diabetes. Type II diabetes is a chronic disease in which production of IL-1B is triggered by the high levels of circulating glucose. IL-1B-mediated inflammation progressively destroys B cells in the pancreas and causes the initiation of the “pre-diabetic” stage. Clinical evidence has shown that when IL-1B was blocked, diabetic patients required 66% less insulin to obtain the same level of glycemic control; agents that can contribute to downregulation of inflammatory cascades can therefore offer the potential to salvage B islet cells by reducing cytokine-mediated inflammation . A more direct role of COL308 in reducing tissue injury associated with diabetes was demonstrated in a study in the Department of Oral Biology and Pathology at Stony Brook University conducted by Drs. Lorne Golub, Hsi-Ming Lee, and Maria Ryan. These investigators showed that rats rendered diabetic through administration of streptozotocin or through the effects of homozygosity for the ob gene experienced aggressive bone and
tooth loss resembling severe periodontitis. This iatrogenic periodontal disease was controlled effectively with the nonantimicrobial chemically-modified tetracycline COL-308 administered orally to the animals [11, 5, 12, 4]. Similar results have recently been obtained by Drs. Golub and Lee using analogs of thermorubin synthesized by Dr. Francis Johnson in the Department of Chemistry at Stony Brook University in unpublished studies. COL-308 has also been shown to inhibit VEGF secretion and endothelial cell angiogenesis induced by breast tumor cell lines by inhibiting the inflammatory pathway that results in Nf-kB activation [6, 13]. It remains for our laboratory to establish whether the effects of compounds like COL-308 and Thermorubin can be attributed to reductions in levels of final products of the Nf-kB pathway that could be achieved specifically through inhibition of HDACs. HDACs are known to remove an acetyl group from the protein STAT-1, resulting in its diminished capacity to block Nf-kB activation. It has been argued that HDAC inhibitors are effective protectors of acetylated STAT1, ensuring that it can efficiently prevent NF-kB activation and thereby reduce the expression of multiple inflammatory cytokines and mediators . Histone Deacetylase Inhibitors have
also been tested for their capacity to reduce inflammation of pancreatic islet tissues. Vorinostat (SAHA), a potent hydroxamic acid designed to target the essential zinc in HDACs, has been shown to reduce cytokine-mediated nitric oxide formation, thereby helping to protect isolated islet cells from diminished insulin secretion . SAHA and other hydroxamate HDAC inhibitors such as Trichostatin A, have also been shown to significantly enhance neuroprotection and decrease B-amyloid production in animal models of neurodegenerative diseases such as Alzheimer’s disease . Furthermore, results of clinical trials showed that many hematopoietic malignancies have been responsive to HDAC inhibitors . Favorable responses were associated with low toxicity due to the ability of HDAC inhibitors to mediate anti-inflammatory and immunosuppressive actions while increasing the expression of pro-apoptotic genes silenced in malignant cells. In recent years, there has been a great focus on natural dietary products that can be useful as chemopreventive or chemotherapeutic agents for many diseases including cancer. Both Myricetin and Tellimagrandin are “antioxidant” polyphenolic compounds and possess substantial anti-carcinogenic and anti-
Figure 3: Normalized inhibition of MMP-9 peptidolytic activity by 25, 50, 100, and 200 μM Thermorubin, COL-308, Myricetin, and Tellimagrandin. All the inhibitors showed 50% inhibition in the 25 μM range. Tellimagrandin had the highest inhibition potency followed by Thermorubin and COL-308. Inhibtion by Myricetin showed only limited dose dependence.
The Stony Brook Young Investigators Review, Fall 2011