Effects of poly (ADP-ribose) polymerase-1 (PARP-1) inhibition on sulfur mustard-induced cutaneous injuriesin vitroandin vivo

Abstract

Early studies with first-generation poly (ADP-ribose) polymerase (PARP) inhibitors have already indicated some therapeutic potential for sulfur mustard (SM) injuries. The available novel and more potential PARP inhibitors, which are undergoing clinical trials as drugs for cancer treatment, bring it back to the centre of interest. However, the role of PARP-1 in SM-induced injury is not fully understood. In this study, we selected a high potent specific PARP inhibitor ABT-888 as an example to investigate the effect of PARP inhibitor in SM injury. The results showed that in both the mouse ear vesicant model (MEVM) and HaCaT cell model, PARP inhibitor ABT-888 can reduce cell damage induced by severe SM injury. ABT-888 significantly reduced SM induced edema and epidermal necrosis in MEVM. In the HaCaT cell model, ABT-888 can reduce SM-induced NAD+/ATP depletion and apoptosis/necrosis. Then, we studied the mechanism of PARP-1 in SM injury by knockdown of PARP-1 in HaCaT cells. Knockdown of PARP-1 protected cell viability and downregulated the apoptosis checkpoints, including p-JNK, p-p53, Caspase 9, Caspase 8, c-PARP and Caspase 3 following SM-induced injury. Furthermore, the activation of AKT can inhibit autophagy via the regulation of mTOR. Our results showed that SM exposure could significantly inhibit the activation of Akt/mTOR pathway. Knockdown of PARP-1 reversed the SM-induced suppression of the Akt/mTOR pathway. In summary, the results of our study indicated that the protective effects of downregulation of PARP-1 in SM injury may be due to the regulation of apoptosis, necrosis, energy crisis and autophagy. However, it should be noticed that PARP inhibitor ABT-888 further enhanced the phosphorylation of H2AX (S139) after SM exposure, which indicated that we should be very careful in the application of PARP inhibitors in SM injury treatment because of the enhancement of DNA damage.

Down‑expression of poly(ADP‑ribose) polymerase in p53‑regulated pancreatic cancer cells

“…In the present study, it was also identified that down-expression of PARP-1 (via olaparib) significantly decreased the cellular viability of PanC-1 cells, increased p53 protein expression, decreased expression of pro-caspase-3, increased caspase-3 activity and suppressed Bcl-2 protein expression following the inhibition of ATM activity. Liu et al (24) reported that PARP had an effect on sulfur mustard-induced cutaneous injuries in vitro and in vivo via the caspase-3 signaling pathway.…”

Role of Akt Activation in PARP Inhibitor Resistance in Cancer

“…In contrast, in models of sulfur mustard induced dermatitis, the beneficial effects of the PARP inhibitor ABT-88, as well as the beneficial effects of PARP1 deficiency, appears to involve a significant modulation of the Akt pathway. In these experiments, sulfur mustard exposure decreased Akt phosphorylation in the control group, while in the PARP1/deficiency + sulfur mustard groups, a marked increase in Akt phosphorylation was observed [65].…”

Comparison of TGF-β and Nitric Oxide Production by Adipose-Derived Mesenchymal Stem Cells Between Healthy Pregnant and Preeclamptic Women

“…Despite the exhaustive number of studies on the secretion of TGF-β by human MSCs [24], no study was found examining the secretion of TGF-β by these cells in normal and preeclamptic pregnancies. Eng-1 increased, and concluded that this change could be associated with the severity of disease [25]. On the other hand, by measuring the plasma level of TGF-β in the third trimester of pregnancy, Paracoli et al showed that the level of this factor increased significantly in PE as compared with that in normal pregnancy demonstrating that changes in this factor shows its involvement in the pathophysiology of the disease [26].…”