Matrix metalloproteinase-9 (MMP-9) is a potent endopeptidase implicated in a wide range of inflammatory and neoplastic diseases, including chronic periodontitis, a persistent oral mucosal inflammation attributed prima...Matrix metalloproteinase-9 (MMP-9) is a potent endopeptidase implicated in a wide range of inflammatory and neoplastic diseases, including chronic periodontitis, a persistent oral mucosal inflammation attributed primarily to infection by P. gingivalis. Here, we review the signaling pathways engaged by P. gingivalis in controlling the processing and secretion of MMP-9. The induction in oral mucosal expression of MMP-9 by P. gingivalis relays primarily on its key endotoxin, LPS, engagement of TLR4 and the activation of MAPK, ERK and p38 cascades implicated in the stimulation of Rac1 and cPLA2. The ERK-mediated cPLA2 phosphorylation plays an essential role in its membrane translocation with Rac1, while p38 localization with Rac1 promotes cPLA2 activation and the induction in MMP-9. Moreover, the induction in MMP-9 secretion by the LPS and the modulatory influence of peptide hormone, ghrelin, occur at the level of MMP-9 processing between ER and Golgi, with the involvement of factors that control secretory cargo sorting, Arf1 GTPase and PKD2. The secretion of MMP-9, furthermore, occurs in concert with the changes in stability dynamics of microtubules (MTs), which affect the Golgi localization of Arf1 and the recruitment and activation of PKD2. The induction in MMP-9 secretion by LPS is accompanied by the enhancement in MT stabilization and α-tubulin phosphorylation on Ser, while the MT destabilization associated with the modulatory influence of ghrelin, is manifested by α-tubulin phosphorylation on Tyr. Thus, the factors capable of affecting MT dynamics and MMP-9 secretion present a tempting target for the therapeutic intervention in the treatment of chronic periodontitis.展开更多
Current colorectal cancer (CRC) treatments exhibit unwanted cytotoxicity against healthy proliferating cells. Hence, these therapeutics demand higher specificity upon drug delivery, a task that may be facilitated by t...Current colorectal cancer (CRC) treatments exhibit unwanted cytotoxicity against healthy proliferating cells. Hence, these therapeutics demand higher specificity upon drug delivery, a task that may be facilitated by the discovery of anticancer agents bearing critical mechanisms of action. Baicalein is a flavonoid with promising anticancer activity, among other pharmacological benefits, and has therefore been of high clinical interest. We tested baicalein in vitro for its effect on several CRC hallmarks, including the suppression of metastasis (the spread of cancer cells from their initial site), the ability to induce apoptosis (cell death), and the inhibition of proliferation (the growth of cells). The suppression of the metastasis of CRC cells was recorded via two studies: the cell migration assay and the in silico docking of baicalein with toll-like receptor 4 (TLR4) and matrix metalloproteinase-9 (MMP-9). Results from the cell migration assay showed that baicalein inhibited metastasis by up to 25.76% (p 0.01) in a concentration-dependent manner. We then reinforced these results by docking baicalein with TLR4 (binding affinity: -8.4 kcal/mol) and docking baicalein with MMP-9 (binding affinity: -7.9 kcal/mol), classifying strong binding affinities as those less than -6.0 kcal/mol. The induction of cell death was measured using a caspase activity assay. Again, a docking study was done to reinforce the findings from the primary in vitro experiment, though this time between baicalein and caspase-3 (binding affinity: -7.1 kcal/mol). Despite mixed observations in concentration dependence, caspase activity, relative to control, reached a maximal increase of 88.6% (p 0.01), and results from the MTT assay demonstrated a survival rate, relative to control, of as low as 59.64%. Considerations for future studies include the testing of baicalein in vivo and on more aberrative CRC cell lines.展开更多
文摘Matrix metalloproteinase-9 (MMP-9) is a potent endopeptidase implicated in a wide range of inflammatory and neoplastic diseases, including chronic periodontitis, a persistent oral mucosal inflammation attributed primarily to infection by P. gingivalis. Here, we review the signaling pathways engaged by P. gingivalis in controlling the processing and secretion of MMP-9. The induction in oral mucosal expression of MMP-9 by P. gingivalis relays primarily on its key endotoxin, LPS, engagement of TLR4 and the activation of MAPK, ERK and p38 cascades implicated in the stimulation of Rac1 and cPLA2. The ERK-mediated cPLA2 phosphorylation plays an essential role in its membrane translocation with Rac1, while p38 localization with Rac1 promotes cPLA2 activation and the induction in MMP-9. Moreover, the induction in MMP-9 secretion by the LPS and the modulatory influence of peptide hormone, ghrelin, occur at the level of MMP-9 processing between ER and Golgi, with the involvement of factors that control secretory cargo sorting, Arf1 GTPase and PKD2. The secretion of MMP-9, furthermore, occurs in concert with the changes in stability dynamics of microtubules (MTs), which affect the Golgi localization of Arf1 and the recruitment and activation of PKD2. The induction in MMP-9 secretion by LPS is accompanied by the enhancement in MT stabilization and α-tubulin phosphorylation on Ser, while the MT destabilization associated with the modulatory influence of ghrelin, is manifested by α-tubulin phosphorylation on Tyr. Thus, the factors capable of affecting MT dynamics and MMP-9 secretion present a tempting target for the therapeutic intervention in the treatment of chronic periodontitis.
文摘Current colorectal cancer (CRC) treatments exhibit unwanted cytotoxicity against healthy proliferating cells. Hence, these therapeutics demand higher specificity upon drug delivery, a task that may be facilitated by the discovery of anticancer agents bearing critical mechanisms of action. Baicalein is a flavonoid with promising anticancer activity, among other pharmacological benefits, and has therefore been of high clinical interest. We tested baicalein in vitro for its effect on several CRC hallmarks, including the suppression of metastasis (the spread of cancer cells from their initial site), the ability to induce apoptosis (cell death), and the inhibition of proliferation (the growth of cells). The suppression of the metastasis of CRC cells was recorded via two studies: the cell migration assay and the in silico docking of baicalein with toll-like receptor 4 (TLR4) and matrix metalloproteinase-9 (MMP-9). Results from the cell migration assay showed that baicalein inhibited metastasis by up to 25.76% (p 0.01) in a concentration-dependent manner. We then reinforced these results by docking baicalein with TLR4 (binding affinity: -8.4 kcal/mol) and docking baicalein with MMP-9 (binding affinity: -7.9 kcal/mol), classifying strong binding affinities as those less than -6.0 kcal/mol. The induction of cell death was measured using a caspase activity assay. Again, a docking study was done to reinforce the findings from the primary in vitro experiment, though this time between baicalein and caspase-3 (binding affinity: -7.1 kcal/mol). Despite mixed observations in concentration dependence, caspase activity, relative to control, reached a maximal increase of 88.6% (p 0.01), and results from the MTT assay demonstrated a survival rate, relative to control, of as low as 59.64%. Considerations for future studies include the testing of baicalein in vivo and on more aberrative CRC cell lines.