The matrix metalloproteinase-7 regulates the extracellular shedding of syndecan-2 from colon cancer cells.

The cell surface heparan sulfate proteoglycan syndecan-2 regulates the activation of matrix metalloproteinase-7 (MMP-7) as a docking receptor. Here, we demonstrate the role of MMP-7 on syndecan-2 shedding in colon cancer cells. Western blot analysis showed that shed syndecan-2 was found in the culture media from various colon cancer cells. Overexpression of MMP-7 enhanced syndecan-2 shedding, whereas the opposite was true when MMP-7 levels were knocked-down using small inhibitory RNAs. Consistently, HT29 cells treated with MMP-7, but neither MMP-2 nor MMP-9, showed increased shed syndecan-2 in a time- and concentration-dependent manner. Furthermore, MALDI-TOF MS analysis and N-terminal amino acid sequencing revealed that MMP-7 cleaved both recombinant syndecan-2 and an endogenously glycosylated syndecan-2 ectodomain in the N-terminus at Leu(149) residue in vitro. Taken together, the data suggest that MMP-7 directly mediates shedding of syndecan-2 from colon cancer cells.

Alzheimer's disease drug discovery from herbs: neuroprotectivity from beta-amyloid (1-42) insult.

OBJECTIVE: To comparatively evaluate selected herbs for their ability to protect neuronal cells from direct betaA(1-42) insult. DESIGN: Twenty-seven (27) herbs were selected, extracted with aqueous methanol (90%) and chloroform, and the extracts were evaluated for their ability to protect PC12 rat pheochromocytoma and primary neuronal cells from betaA(1-42) insult using both 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide reduction assay and lactate dehydrogenase efflux assay. RESULTS: Curcuma aromatia (ul-keum) and Zingiber officinale (ginger) extracts effectively protected cells from betaA(1-42) insult, followed by Ginkgo biloba (ginkgo), Polygonatum sp. (King Solomon's seal), Cinnamum cassia (Chinese cinnamon), Rheum coreanum (Korean rhubarb), Gastrodia elata (gastrodia), and Scutellaria baicalensis (skullcap). Several extracts showed cytotoxicity at high concentration (approximately 150 microg/mL), whereas other extracts did not at all protect cells from betaA(1-42) insult. CONCLUSION: Selective herbs may be potentially important resources to discover drug candidates against the onset of Alzheimer's disease.

Design, synthesis, and biological testing of thiosalicylamides as a novel class of calcium channel blockers.

The current research aimed to investigate the importance of the heterocyclic ring system in the structure of the cardiovascular drug diltiazem for its calcium channel blocking activity. The manuscript describes the design, synthesis, and biological testing of a total of 10 S-(p-methoxybenzyl), N-substituted thiosalicylamides as a series of non-cyclic compounds derived from diltiazem's structure. The new compounds maintained all diltiazem pharmacophores except the thiazepine ring system. In vitro evaluation of the new series for calcium channel blocking effects revealed moderate activities with IC50 values in the range of 4.8-56.0 microM. The data suggest that the ring system is not essential for activity; however, its absence leads to a considerable drop of activity relative to that of diltiazem (IC50=0.3 microM). Compounds of the current series showed optimum activity when the aliphatic alkyl chain on the salicylamide nitrogen is part of a piperidine or piperazine ring system substituted at the terminal nitrogen with a benzyl group.

Side-chain length is important for shogaols in protecting neuronal cells from beta-amyloid insult.

Ten shogaols were synthesized to evaluate the importance of the side-chain length in protecting cells from betaA(1-42) insult using PC12 rat pheochromocytoma and IMR-32 human neuroblastoma cells. The compounds cell protectivity against betaA insult was demonstrated using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction assay. The efficacy of cell protection from betaA insult by these shogaols was shown to improve as the length of the side chain increase.