nitrophenols and Acute-Disease

Our previous study [Bhave, V. S., Donthamsetty, S., Latendresse, J. R., Muskhelishvili, L., and Mehendale, H. M. 2008-this issue. Secretory phospholipase A(2) mediates progression of acute liver injury in the absence of sufficient COX-2. Toxicol Appl Pharmacol] showed that in the absence of sufficient induction and co-presence of cyclooxygenase-2 (COX-2), secretory phospholipase A(2) (sPLA(2)) appearing in the intercellular spaces for cleanup of post-necrotic debris seems to contribute to the progression of toxicant-initiated liver injury, possibly by hydrolysis of membrane phospholipids of hepatocytes in the perinecrotic areas. To further test our hypothesis on the protective role of COX-2, male Fisher-344 rats were administered a selective COX-2 inhibitor, NS-398, and then challenged with a moderately toxic dose of CCl(4). This led to a 5-fold increase in the susceptibility of the COX-2 inhibited rats to CCl(4) hepatotoxicity and mortality. The CCl(4) bioactivating enzyme CYP2E1 protein, CYP2E1 enzyme activity, and the (14)CCl(4)-derived radiolabel covalently bound to the liver proteins were unaffected by the COX-2 inhibitor suggesting that the increased hepatotoxic sensitivity of the COX-2 inhibited rats was not due to higher bioactivation of CCl(4). Further investigation showed that this increased mortality was due to higher plasma and hepatic sPLA(2) activities, inhibited PGE(2) production, and progression of liver injury as compared to the non-intervened rats(.) In conclusion, inhibition of COX-2 mitigates the tissue protective mechanisms associated with COX-2 induction, which promotes sPLA(2)-mediated progression of liver injury in an acute liver toxicity model. Because increased sPLA(2) activity in the intercellular space is associated with increased progression of injury, and induced COX-2 is associated with hepatoprotection, ratios of hepatic COX-2 and sPLA(2) activities may turn out to be a useful tool in predicting the extent of hepatotoxicities.

Topics: Acute Disease; Alanine Transaminase; Animals; Blotting, Western; Carbon Radioisotopes; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Corn Oil; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cytochrome P-450 CYP2E1; Dinoprostone; Disease Progression; Drug Synergism; Liver; Male; Microsomes, Liver; Nitrobenzenes; Nitrophenols; Phospholipases A2, Secretory; Rats; Rats, Inbred F344; Sulfonamides; Survival Rate

FLT3 defines a promising target for the treatment of acute myeloid leukemia (AML). In contrast to their efficacy in cell lines, FLT3-specific inhibitors as single agents have only modest clinical activity in patients with AML. As demonstrated here, overexpression of anti-apoptotic proteins of the BCL2 family leads to resistance against FLT3 inhibitors in a hematopoietic cell line model with activating FLT3 mutations. The susceptibility to FLT3 inhibition could be restored by treatment with the novel BH3 mimetic ABT-737. Primary AML samples tested in our study showed a high expression of BCL2 protein, but not of BCL-xL or MCL1. BCL2 protein levels were not reduced after dephosphorylation of FLT3 and its downstream target STAT5 in patient samples with FLT3 internal tandem duplications. Interestingly, treatment with ABT-737 caused apoptotic cell death in all primary AML samples at submicromolar level and synergized efficiently with FLT3 inhibition in AML samples with activating FLT3 mutations. In contrast to AML cell lines, BCR-ABL transformed human cells showed resistance to ABT-737, which might be due to the induction of MCL1 by BCR-ABL. Inhibition of BCL2 family members might define a novel highly efficient and specific strategy in the combined or monotreatment of AML.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Apoptosis; bcl-X Protein; Biphenyl Compounds; Blotting, Western; Cell Proliferation; Cells, Cultured; Drug Resistance, Neoplasm; Flow Cytometry; fms-Like Tyrosine Kinase 3; Humans; Karyotyping; Leukemia, Myeloid; Middle Aged; Molecular Mimicry; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; Nitrophenols; Peptide Fragments; Piperazines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; STAT5 Transcription Factor; Sulfonamides; Trans-Activators

Topics: Acute Disease; Animals; Haemonchiasis; Nitrophenols; Parasite Egg Count; Rain; Seasons; Sheep; Sheep Diseases; Trichostrongyloidiasis

Topics: Acute Disease; Humans; Kinetics; Nitrophenols; Parathion; Time Factors

Topics: Acute Disease; Adolescent; Adult; Aged; Child, Preschool; Female; Humans; Male; Middle Aged; Nitrophenols; Parathion

Topics: Acute Disease; Age Factors; Autopsy; Biphenyl Compounds; Child, Preschool; Female; Humans; Male; Nitrophenols; Oxidative Phosphorylation; Poisoning