Dihydro-CDDO-Trifluoroethyl Amide (dh404), a Novel Nrf2 Activator, Suppresses Oxidative Stress in Cardiomyocytes

Targeting Nrf2 signaling appears to be an attractive approach for the treatment of maladaptive cardiac remodeling and dysfunction; however, pharmacological modulation of the Nrf2 pathway in the cardiovascular system remains to be established. Herein, we report that a novel synthetic triterpenoid derivative, dihydro-CDDO-trifluoroethyl amide (dh404), activates Nrf2 and suppresses oxidative stress in cardiomyocytes. Dh404 interrupted the Keap1-Cul3-Rbx1 E3 ligase complex-mediated Nrf2 ubiquitination and subsequent degradation saturating the binding capacity of Keap1 to Nrf2, thereby rendering more Nrf2 to be translocated into the nuclei to activate Nrf2-driven gene transcription. A mutant Keap1 protein containing a single cysteine-to-serine substitution at residue 151 within the BTB domain of Keap1 was resistant to dh404-induced stabilization of Nrf2 protein. In addition, dh404 did not dissociate the interaction of Nrf2 with the Keap1-Cul3-Rbx1 E3 ligase complex. Thus, it is likely that dh404 inhibits the ability of Keap1-Cul3-Rbx1 E3 ligase complex to target Nrf2 for ubiquitination and degradation via modifying Cys-151 of Keap1 to change the conformation of the complex. Moreover, dh404 was able to stabilize Nrf2 protein, to enhance Nrf2 nuclear translocation, to activate Nrf2-driven transcription, and to suppress angiotensin II (Ang II)-induced oxidative stress in cardiomyocytes. Knockdown of Nrf2 almost blocked the anti-oxidative effect of dh404. Dh404 activated Nrf2 signaling in the heart. Taken together, dh404 appears to be a novel Nrf2 activator with a therapeutic potential for cardiac diseases via suppressing oxidative stress

Interacting Electrons on a Fluctuating String

We consider the problem of interacting electrons constrained to move on a fluctuating one-dimensional string. An effective low-energy theory for the electrons is derived by integrating out the string degrees of freedom to lowest order in the inverse of the string tension and mass density, which are assumed to be large. We obtain expressions for the tunneling density of states, the spectral function and the optical conductivity of the system. Possible connections with the phenomenology of the cuprate high temperature superconductors are discussed.Comment: 14 pages, 1 figur

Actual therapeutic efficacy of pre-transplant treatment on hepatocellular carcinoma and its impact on survival after salvage living donor liver transplantation.

BACKGROUND: The exact efficacy of pre-liver transplant (LT) therapy for hepatocellular carcinoma (HCC) and the impact on survival after LT remain controversial in regard to salvage LT. MATERIALS AND METHODS: Of 79 patients transplanted in Nagasaki University Hospital between August 1997 and December 2007, 29 patients (36.7%) were indicated for HCC based on the Milan criteria using computed tomography and magnetic resonance imaging. Pre-LT therapy other than liver resection had been performed in 18 cases (62.1%) for 24 lesions. Treated lesions were analyzed histologically using thin slices of the whole explanted liver. RESULTS: Pre-LT therapy included transarterial chemoembolization (TACE) for 10 lesions, percutaneous ethanol injection (PEI) + TACE for 1 lesion, PEI in 6 lesions and ablation therapy in 7 lesions. Under preoperative imaging study, 19 lesions (79.1%) were "thought-to-be" necrotic by pre-LT therapy. However, histologically, viable HCCs were still observed in 9 lesions (9/19 47%). A median interval between the first pre-therapy and LT was 22 months, while last pre-LT therapy and LT was 11 months. No sarcomatous HCC or forced portal venous tumor thrombus was found in all cases with residual lesions. One peritoneal recurrence has occurred after LT, in whom PEI and RFA had been performed before LDLT. The disease free survival after LDLT was comparable to that of cases without pre-LT therapy. CONCLUSION: Half of the preoperatively "thought-to-be" necrotic lesions still contained viable HCC cells after the pre-LT treatment. Overall, the history of pre-LT therapy does not preclude or interfere with subsequent LT, although percutaneous treatment may spread disseminated tumor cell growth under immunosuppression

Degradation of p47 by autophagy contributes to CADM1 overexpression in ATLL cells through the activation of NF-κB

Cell adhesion molecule 1 (CADM1), a member of the immunoglobulin superfamily, is identified as a novel cell surface marker for human T-cell leukemia virus (HTLV-1)-infected T cells. Adult T-cell leukemia/lymphoma (ATLL) is developed in HTLV-1-infected T-cells after a long infection period. To examine the mechanism of CADM1 overexpression in ATLL, we first identified that CADM1 is transcriptionally up-regulated by a transcriptional enhancer element through NF-κB signaling pathway. In HTLV-1-infected T-cells, CADM1 expression is dependent on HTLV-1/Tax through activation of canonical and non-canonical NF-κB; however, in ATLL cells with frequent loss of Tax expression, the activation of canonical NF-κB only enhances the CADM1 expression. Along with active mutations in signaling molecules under T-cell recepor (TCR) signaling, degradation of p47, a negative regulator of NF-κB, was essential for activation of canonical NF-κB through stabilization of NEMO (NF-κB essential modulator). The mechanism of p47 degradation is primarily dependent on activation of lysosomal-autophagy and the autophagy is activated in most of the HTLV-infected and ATLL cells, suggesting that the p47 degradation may be a first key molecular event during HTLV-1 infection to T-cells as a connector of two important signaling pathways, NF-κB and autophagy