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Chemotherapy resistance is the dominant challenge in the treatment of acute myeloid leukemia (AML). Nuclear factor E2-related factor 2 (Nrf2) exerts a vital function in drug resistance of many tumors. Nevertheless, the potential molecular mechanism of Nrf2 regulating the base excision repair pathway that mediates AML chemotherapy resistance remains unclear. Here, in clinical samples, we found that the high expression of Nrf2 and base excision repair pathway gene encoding 8-hydroxyguanine DNA glycosidase (OGG1) was associated with AML disease progression. In vitro, Nrf2 and OGG1 were highly expressed in drug-resistant leukemia cells. Upregulation of Nrf2 in leukemia cells by lentivirus transfection could decrease the sensitivity of leukemia cells to cytarabine, whereas downregulation of Nrf2 in drug-resistant cells could enhance leukemia cell chemosensitivity. Meanwhile, we found that Nrf2 could positively regulate OGG1 expression in leukemia cells. Our chromatin immunoprecipitation assay revealed that Nrf2 could bind to the promoter of OGG1. Furthermore, the use of OGG1 inhibitor TH5487 could partially reverse the inhibitory effect of upregulated Nrf2 on leukemia cell apoptosis. In vivo, downregulation of Nrf2 could increase the sensitivity of leukemia cell to cytarabine and decrease OGG1 expression. Mechanistically, Nrf2-OGG1 axis-mediated AML resistance might be achieved by activating the AKT signaling pathway to regulate downstream apoptotic proteins. Thus, this study reveals a novel mechanism of Nrf2-promoting drug resistance in leukemia, which may provide a potential therapeutic target for the treatment of drug-resistant/refractory leukemia.

In the present experiment, effects of sodium hydrosulfide (NaHS), a H2S donor, on the oxidative damage, antioxidant capacity and the growth of cucumber hypocotyls and radicles were studied under 100 mmol L−1 NaCl stress. NaCl treatment significantly induced accumulation of H2O2 and thiobarbituric acid-reactive substances (TBARS) in cucumber hypocotyls and radicles, and application of NaHS dramatically reduced the accumulation of H2O2 and lipid peroxidation. However, the alleviating effects greatly depended on the concentrations of NaHS, and 400 μmol L−1 NaHS treatment showed the most significant effects. Corresponding to the change of lipid peroxidation, higher activities of antioxidant enzymes as well as the antioxidant capacity indicated as DPPH scavenging activity, chelating activity of ferrous ions and hydroxyl radical (·OH) scavenging activity were induced by NaHS treatment under NaCl stress, especially by 400 μmol L−1 NaHS treatment. With the alleviating lipid peroxidation, the amylase activities in cotyledons were increased, and the length of cucumber hypocotyls and radicles were significantly promoted by NaHS treatment under NaCl stress. Unlike the effects of NaHS, pretreatment with other sodium salts including Na2S, Na2SO4, NaHSO4, Na2SO3, NaHSO3 and NaAc did not show significant effects on the growth of cucumber hypocotyls and radicles. These salts do not release H2S. Based on above results, it can be concluded that the effects of NaHS in the experiment depended on the H2S rather than other compounds derived from NaHS, and the alleviating effects might related with its function in modulating antioxidant capacity and amylase activities.

A new fluorogenic and chromogenic probe rhodamine B spirolactam (1) was developed that in aqueous solutions exhibited a highly selective and sensitive "turn-on" type spectral response toward NO detection following a NO-induced spiro-ring opening reaction in 1.

A novel spirocyclic compound (4R)-4-(4-hydroxy-benzyl) spiro [4,5] dec-1-en-8-ol (sequosempervirin A) was isolated from the branches and leaves of Sequoia sempervirens. Its structure and relative stereochemistry were mainly determined by MS, 2D NMR and X-ray means, which is the first naturally occurring norlignan containing one spirocycle with C6 (cyclohexane)-C2-C3-C6 skeleton. (C) 2004 Elsevier Ltd. All rights reserved.