Nuclear factor erythroid 2-related factors 1 and 2 are able to define the worst prognosis group among high-risk diffuse large B cell lymphomas treated with R-CHOEP.

AIMS: Oxidative stress markers and antioxidant enzymes have previously been shown to have prognostic value and associate with adverse outcome in patients with diffuse large B cell lymphoma (DLBCL). Nuclear factor erythroid 2-related factor 1 (Nrf1) and factor 2 (Nrf2) are among the principal inducers of antioxidant enzyme production. Kelch ECH associating protein 1 (Keap1) is a negative regulator of Nrf2, and BTB (BR-C, ttk and bab) domain and CNC homolog 1 (Bach1) represses the function of both factors. Their significance in DLBCL prognosis is unknown. METHODS: Diagnostic biopsy samples of 76 patients with high-risk DLBCL were retrospectively stained with immunohistochemistry for Nrf1, Nrf2, Keap1 and Bach1, and correlated with clinical data and outcome. RESULTS: Nuclear Nrf2 and nuclear Bach1 expression were associated with adverse clinical features (anaemia, advanced stage, high IPI, high risk of neutropaenic infections), whereas cytoplasmic Nrf1 and Nrf2 were associated with favourable clinical presentation (normal haemoglobin level, no B symptoms, limited stage). None of the evaluated factors could predict survival alone. However, when two of the following parameters were combined: high nuclear score of Nrf2, low nuclear score of Nrf1, high cytoplasmic score of Nrf1 and low cytoplasmic score of Keap1 were associated with significantly worse overall survival. CONCLUSIONS: Nrf1 and Nrf2 are relevant in disease presentation and overall survival in high-risk DLBCL. Low nuclear expression of Nrf1, high cytoplasmic expression of Nrf1, high nuclear expression of Nrf2 and low cytoplasmic expression of Keap1 are associated with adverse outcome in this patient group.

Recombinant human augmenter of liver regeneration protects hepatocyte mitochondrial DNA in rats with obstructive jaundice.

BACKGROUND: Hepatocyte mitochondrial DNA (mtDNA) damage is an important cause of mitochondrial and hepatic function impairment in obstructive jaundice (OJ). This study investigated the protective effect of recombinant human augmenter of liver regeneration (rhALR) on hepatocyte mtDNA in rats with OJ. MATERIALS AND METHODS: Wistar rats were randomly divided into three groups as follows: sham-operation, biliary obstruction and recanalization with rhALR treatment (BDO-RBF-rhALR), and BDO-RBF-Vehicle (n = 48 per group). After biliary obstruction, rats were intraperitoneally injected with 40 µg/kg rhALR in BDO-RBF-rhALR group and same volume of normal saline in other two groups once every 12 h, until sacrifice. Mitochondrial transcription factor A (mtTFA) and nuclear respiratory factor-1 (NRF-1) expression in hepatocytes were detected by real-time reverse transcription-polymerase chain reaction and Western blot. Hepatocyte mtDNA damage was evaluated by real-time-polymerase chain reaction. Mitochondrial and hepatic functions were also assessed. RESULTS: After biliary obstruction, hepatic function was clearly impaired, as shown by the increases in serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels, and the decrease in albumin level. Mitochondrial respiratory control ratio, phosphorus oxygen ratio, and ATP levels (all indicators of mitochondrial function) were decreased. The relative amount of total mtDNA, mtTFA, and NRF-1 expression in rat liver tissues were decreased, whereas the relative amount of deleted mtDNA was increased. However, the damage was significantly improved in the BDO-RBF-rhALR group. After recanalization, these changes were gradually restored, but the recovery was faster in the BDO-RBF-rhALR group than in BDO-RBF-Vehicle group. CONCLUSIONS: rhALR may protect and improve mitochondrial and hepatic functions in rats with OJ by promoting the expression of mtTFA and NRF-1 and by protecting and repairing damaged mtDNA.