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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Androstadienes, Animals, Antineoplastic Agents, Apoptosis, BH3 Interacting Domain Death Agonist Protein, Carrier Proteins, Caspase Inhibitors, Caspases, Enzyme Inhibitors, Hepatocytes, I-kappa B Proteins, In Vitro Techniques, Liver Failure, Male, Mice, Mice, Inbred BALB C, Minor Histocompatibility Antigens, Myeloid Cell Leukemia Sequence 1 Protein, NF-KappaB Inhibitor alpha, NF-kappa B, Neoplasm Proteins, Phosphatidylinositol 3-Kinases, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, Specific Pathogen-Free Organisms, Tumor Necrosis Factor-alpha, Wortmannin, bcl-2-Associated X Protein, bcl-Associated Death Protein, bcl-X Protein.
user
Is inhibition of nuclear factor kappaB and phosphatidylinositol 3-kinase/Akt essential for massive hepatocyte apoptosis induced by tumor necrosis factor alpha in mice? Context: Tumor necrosis factor (TNF)-alpha itself does not induce liver injury in normal mice or hepatocytes. Rather, this event, especially in vitro, is explained by the fact that the TNF-alpha/TNF receptor system not only triggers downstream signals leading to apoptosis but also induces an antiapoptotic pathway through the activation of nuclear factor (NF)-kappaB. The aim of this study was to determine whether inhibition of antiapoptotic pathways influences the susceptibility of mice to TNF-alpha. Here, we focused on the roles of NF-kappaB and phosphatidylinositol 3-kinase (PI3K)-regulated serine/threonine kinase Akt. TNF-alpha was administered to BALB/c mice after treatment with an adenovirus expressing a mutant form IkappaBalpha (Ad5IkappaB), the PI3K inhibitor wortmannin, or both. Liver injury was assessed biochemically and histologically. The expression of Bcl-2 family members and caspase activity were examined. In the mice livers, treatment with Ad5IkappaB or the wortmannin suppressed the activation of NF-kappaB or Akt, respectively. Suppression of either NF-kappaB or Akt showed a slight increase in transaminase levels and focal liver cell death after TNF-alpha administration. However, in mice treated with both Ad5IkappaB and wortmannin, TNF-alpha administration resulted in massive hepatocyte apoptosis and hemorrhagic liver destruction in mice. The combination of Ad5IkappaB, wortmannin, and TNF-alpha markedly increased the activation of caspase-3 and -9, and activated caspase-8 to a lesser degree, suggesting that TNF-alpha-induced hepatocyte apoptosis is dependent on type II cell death signaling pathway, probably through the mitochondria. Inhibition of the NF-kappaB and PI3K/Akt pathways had no effect on expression of Bcl-2 families.
assistant
The inducible activation of NF-kappaB and constitutive activation of Akt regulate hepatocyte survival against TNF-alpha, which occurs independent of Bcl-2 families. Final Decision: yes