A phenolic acid phenethyl urea derivative protects against irradiation-induced osteoblast damage by modulating intracellular redoxstate

Abstract

Because irradiation may cause osteoradionecrosis, antioxidant supplementation is often used to suppress irradiation-mediated injury. This study examined whether a synthetic phenethyl urea compound, (E)-1-(3,4-dihydroxyphenethyl)-3-(3,4-dihydroxystyryl)urea (DPDS-U), prevents irradiation-mediated cellular damage in MC3T3-E1 osteoblastic cells. A relatively high dose of irradiation (>4 Gy) decreased cell viability and proliferation and induced DNA damage and cell cycle arrest at the G(2)/M phase with the attendant increase of cyclin B1. Irradiation with 8 Gy induced intracellular reactive oxygen species (ROS) production and lipid peroxidation, and reduced glutathione content and superoxide dismutase activity in the cells. These events were significantly suppressed by treatment with 200 µM DPDS-U or 5 mM N-acetyl cysteine (NAC). DPDS-U or irradiation alone significantly increased heme oxygenase-1 (HO-1) expression and nuclear factor E2 p45-related factor-2 (Nrf2) nuclear translocation. Interestingly, pretreatment with DPDS-U facilitated irradiation-induced activation of the Nrf2/HO-1 pathway. The potential of DPDS-U to mediate HO-1 induction and protect against irradiation-mediated cellular damage was almost completely attenuated by transient transfection with Nrf2-specific siRNA or treatment with a pharmacological HO-1 inhibitor, zinc protoporphyrin IX. Additional experiments revealed that DPDS-U induced a radioprotective mechanism that differs from that induced by NAC through activation of Nrf2/HO-1 signaling. Collectively, our data suggest that DPDS-U-induced radioprotection is due to its dual function as an antioxidant to remove directly excessive intracellular ROS and as a prooxidant to stimulate intracellular redox-sensitive survival signal.

N-acetyl cysteine inhibits H2O2-mediated reduction in the mineralization of MC3T3-E1 cells by down-regulating Nrf2/HO-1 pathway

“…We previously found that Nrf2-mediated signaling could play dual roles on the viability of cells depending on the condition of stress exposed; under a mild oxidative stress, Nrf2 activation has a protective role by maintaining normal levels of ROS, whereas it leads to cell injury under a persistent oxidative stress (20) . However, the current results highlight that activation of the Nrf2 pathway by H 2 O 2 contributes predominantly to the down-regulation of microenvironmental events required for osteoblast differentiation.…”

Dietary hydroxycinnamates prevent oxidative damages to liver, spleen, and bone marrow cells in irradiation-exposed mice

“…In general, oxidative stress induces translocation of Nrf2 into the nucleus, in which Nrf2 stimulates transcriptional activation of redoxsensitive target genes such as CAT and SOD. It has also been reported that the induction of Nrf2 protects against oxidative-stress-induced DNA damages (23). Therefore, it is hypothesized that irradiationmediated accumulation of intracellular ROS activates the Nrf2 signal, and this activation positively controls cellular homeostasis and redox balance.…”

Dose- and Ion-Dependent Effects in the Oxidative Stress Response to Space-Like Radiation Exposure in the Skeletal System

“…Although others [ 52 , 53 ] have shown the beneficial effects of various antioxidants to confer radioprotection for various osteoblast cell lines, we show here a direct comparison of antioxidant treatment with different radiation species when added to primary, marrow-derived osteoprogenitors. Interestingly, adding SOD at higher doses or for longer periods was not advantageous, emphasizing the importance of carefully titrating radical scavengers such as SOD, possibly to maintain endogenous ROS-dependent signalling.…”