Although the classical NF-κB activation pathway is important in many cellular Doxorubicin chemical structure processes, the noncanonical NF-κB pathway is also important for normal and pathological processes. NF-κB is restricted to the cytoplasm by inhibitory proteins that are degraded when they are specifically phosphorylated; this permits NF-κB to enter the nucleus and activate target genes. Different combinations of NF-κB subunits induce transcription with different timing sequences and recognize different sequences of NF-κB binding sites. The noncanonical pathway is based on processing of the NF-κB2 gene product p100.11, 12 The p52 subunit is generated
from p100 processing by I kappa B kinase alpha, one of the kinase complexes.11, 12 Once produced, p52 can enter the nucleus and induce genes that regulate many processes.12 In other systems, including androgen-sensitive LNCaP cells in vitro and lymphoma cells, NF-κB/p52 encourages cellular growth by protecting cells from apoptosis and stimulating cyclin D1 expression.16, 17 Coculturing of bone marrow stromal cells with lymphoma cells resulted in active p52 generation, which then translocated to the nucleus
and was associated with increased XIAP and cIAP expression; this was similar to what was seen in our system.17 Investigators have shown a significant relationship between NF-KB, XIAP, and the JNK find more cascade.18-20 Bubici and colleagues18 showed that NF-KB–mediated apoptosis suppression involves inhibition of the JNK cascade, which is related to up-regulation of a variety of mediators, including XIAP, which block aspects of the JNK cascade. Similarly, Kaur and colleagues20 showed that XIAP inhibits JNK activation by transforming growth factor β1 and counteracts transforming growth factor β1–induced apoptosis. This is consistent with our findings, in which CXCR2
knockout mice increased XIAP levels, decreased JNK levels, and Resveratrol decreased apoptosis and mortality. Other investigators have used leflunomide with APAP toxicity and have shown a protective effect due to the inhibition of APAP-induced JNK activation. This decreased Bcl-2 and Bcl-XL activation and decreased apoptosis.19 This is also consistent with our studies. In contrast, other investigators have shown that APAP-induced activation of JNK promotes necrosis by a direct effect on mitochondria.21, 22 “
“Liver transplantation is an effective, life-prolonging procedure for selected patients with end-stage liver disease due to a wide variety of etiologies, including autoimmune, cholestatic and metabolic liver diseases, viral hepatitis and certain malignancies.