Inhibitors of metalloprotease, gamma-sectretase, protein kinase C and Rho kinase inhibit wild-type adenoviral replication
PLOS ONE
Authors: Liu, Alice; Ildefonso, Cristhian J.; Bond, Wesley S.; Hurwitz, Mary Y.; Hurwitz, Richard L.
Abstract
Adenoviruses cause upper respiratory infections, conjunctivitis, keratitis, and gastrointestinal illness. These can be fatal in immunocompromised individuals. Adenoviruses have also been engineered into viral vectors to deliver therapeutic genes or induce immunity as vaccine carriers. The success of ocular gene therapy is driven partly by the immunologic and biochemical influences of the intraocular environment. We have shown that versican and hyaluronan modulate adenoviral vector transgene expression through CD44 signaling. Herein we explored the role of these pathways on virus replication and viral protein expression of wild type adenovirus. We report that the addition of vitreous humor (which contains both versican and hyaluronan) increases viral hexon protein levels. Vitreous humor also increased wild type adenovirus DNA replicationin vitro. Metalloproteinase and gamma-secretase inhibitors, which inhibit CD44 proteolytic activation, blocked adenoviral replicationin vitro. Similarly, protein kinase C and RhoA kinase inhibitors, both proteins associated with CD44 mediated pathways, also inhibited wild type adenoviral replicationin vitro. Application of metalloproteinase and gamma-secretase inhibitors to human conjunctival explants sharply decreased adenoviral vector gene expression. Our results demonstrate that pharmacologic delivery of these inhibitors is easily achievable. The inhibition of these enzymes should be explored as potential therapies of wild type adenoviral infections.
L1CAM, CA9, KLK6, HPN, and ALDH1A1 as Potential Serum Markers in Primary and Metastatic Colorectal Cancer Screening
DIAGNOSTICS
Authors: Tieng, Francis Yew Fu; Abu, Nadiah; Sukor, Surani; Mohd Azman, Zairul Azwan; Mahamad Nadzir, Norshahidah; Lee, Learn-Han; Ab Mutalib, Nurul Syakima
Abstract
Background: Colorectal cancer (CRC) screening at the earlier stages could effectively decrease CRC-related mortality and incidence; however, accurate screening strategies are still lacking. Considerable interest has been generated in the detection of less invasive tests requiring a small sample volume with the potential to detect several cancer biomarkers simultaneously. Due to this, the ELISA-based method was undertaken in this study. Methods: Concentrations of neural cell adhesion molecule L1 (L1CAM), carbonic anhydrase IX (CA9), mesothelin (MSLN), midkine (MDK), hepsin (HPN), kallikrein 6 (KLK6), transglutaminase 2 (TGM2) aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), epithelial cell adhesion molecule (EpCAM), and cluster of differentiation 44 (CD44) from blood serum of 36 primary CRC and 24 metastatic CRC (mCRC) were calculated via MAGPIX(R)System (Luminex Corporation, USA). Results: Significantly increased concentration (p< 0.05) of three serum biomarkers (L1CAM, CA9, and HPN) were shown in mCRC when compared with primary CRC. HPN and KLK6 showed significant differences (p< 0.05) in concentration among different stages of CRC. In contrast, levels of HPN and ALDH1A1 were significantly elevated (p< 0.05) in chemotherapy-treated CRC patients as compared with nontreated ones. Conclusion: Serum biomarkers could act as a potential early CRC diagnostics test, but further additional testings are needed.