Rescuing neuronal cell death by RAIDD- and PIDD- derived peptides and its implications for therapeutic intervention in neurodegenerative diseases.

Caspase-2 is known to be involved in oxidative-stress mediated neuronal cell death. In this study, we demonstrated that rotenone-induced neuronal cell death is mediated by caspase-2 activation via PIDDosome formation. Our newly designed TAT-fused peptides, which contains wild-type helix number3 (H3) from RAIDD and PIDD, blocked the PIDDosome formation in vitro. Furthermore, peptides inhibited rotenone-induced caspase-2-dependent apoptosis in neuronal cells. These results suggest that PIDD- or RAIDD-targeted peptides might be effective at protecting against rotenone-induced neurotoxicity. Our peptides are novel neuronal cell apoptosis inhibitors that might serve as a prototype for development of drugs for the treatment of neurodegenerative diseases.

Withaferin A inhibits matrix metalloproteinase-9 activity by suppressing the Akt signaling pathway.

Withaferin A (Wit A), a steroidal lactone isolated from Withania somnifera, exhibits anti-inflammatory, immuno-modulatory and anti-angiogenic properties and antitumor activities. In the present study, we investigated the effects of Wit A on protease-mediated invasiveness of the human metastatic cancer cell lines Caski and SK-Hep1. We found that treatment with Wit A resulted in marked inhibition of the TGF­ß­induced increase in expression and activity of matrix metalloproteinase (MMP)­9 in Caski cell line. These effects of Wit A were dose-dependent and showed a correlation with suppression of MMP­9 mRNA expression levels. Treatment with Wit A resulted in an ~1.6-fold induction of MMP-9 promoter activity, which was also suppressed by treatment with Wit A in Caski cells. We found that treatment with Wit A resulted in inhibition of TGF­ß­induced phosphorylation of Akt, which was involved in the downregulation of expression of MMP-9 at the protein level. Introduction with constitutively active (CA)­Akt resulted in a partial increase in the secretion of TGF-ß-induced MMP-9 blocked by treatment with Wit A in Caski cells. According to these results, Wit A may inhibit the invasive and migratory abilities of Caski cells through a reduction in MMP-9 expression through suppression of the pAkt signaling pathway. These findings indicate that use of Wit A may be an effective strategy for control of metastasis and invasiveness of tumors.