Effects of poly (ADP-ribose) polymerase-1 (PARP-1) inhibition on sulfur mustard-induced cutaneous injuries in vitro and in vivo
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...
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| Format: | Article |
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PeerJ Inc.
2016-04-01
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| Online Access: | https://peerj.com/articles/1890.pdf |
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| author | Feng Liu Ning Jiang Zhi-yong Xiao Jun-ping Cheng Yi-zhou Mei Pan Zheng Li Wang Xiao-rui Zhang Xin-bo Zhou Wen-xia Zhou Yong-xiang Zhang |
| author_facet | Feng Liu Ning Jiang Zhi-yong Xiao Jun-ping Cheng Yi-zhou Mei Pan Zheng Li Wang Xiao-rui Zhang Xin-bo Zhou Wen-xia Zhou Yong-xiang Zhang |
| author_sort | Feng Liu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T06:21:51Z |
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| id | doaj.art-5f99986d0beb46d8b372397a02c75890 |
| institution | Directory Open Access Journal |
| issn | 2167-8359 |
| language | English |
| last_indexed | 2024-03-09T06:21:51Z |
| publishDate | 2016-04-01 |
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| spelling | doaj.art-5f99986d0beb46d8b372397a02c758902023-12-03T11:34:49ZengPeerJ Inc.PeerJ2167-83592016-04-014e189010.7717/peerj.1890Effects of poly (ADP-ribose) polymerase-1 (PARP-1) inhibition on sulfur mustard-induced cutaneous injuries in vitro and in vivoFeng Liu0Ning Jiang1Zhi-yong Xiao2Jun-ping Cheng3Yi-zhou Mei4Pan Zheng5Li Wang6Xiao-rui Zhang7Xin-bo Zhou8Wen-xia Zhou9Yong-xiang Zhang10Beijing Institute of Pharmacology and Toxicology, Beijing, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing, ChinaBeijing Institute of Pharmacology and Toxicology, Beijing, ChinaEarly 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.https://peerj.com/articles/1890.pdfSulfur mustardPARP-1DNA damageNAD+ApoptosisNecrosis |
| spellingShingle | Feng Liu Ning Jiang Zhi-yong Xiao Jun-ping Cheng Yi-zhou Mei Pan Zheng Li Wang Xiao-rui Zhang Xin-bo Zhou Wen-xia Zhou Yong-xiang Zhang Effects of poly (ADP-ribose) polymerase-1 (PARP-1) inhibition on sulfur mustard-induced cutaneous injuries in vitro and in vivo PeerJ Sulfur mustard PARP-1 DNA damage NAD+ Apoptosis Necrosis |
| title | Effects of poly (ADP-ribose) polymerase-1 (PARP-1) inhibition on sulfur mustard-induced cutaneous injuries in vitro and in vivo |
| title_full | Effects of poly (ADP-ribose) polymerase-1 (PARP-1) inhibition on sulfur mustard-induced cutaneous injuries in vitro and in vivo |
| title_fullStr | Effects of poly (ADP-ribose) polymerase-1 (PARP-1) inhibition on sulfur mustard-induced cutaneous injuries in vitro and in vivo |
| title_full_unstemmed | Effects of poly (ADP-ribose) polymerase-1 (PARP-1) inhibition on sulfur mustard-induced cutaneous injuries in vitro and in vivo |
| title_short | Effects of poly (ADP-ribose) polymerase-1 (PARP-1) inhibition on sulfur mustard-induced cutaneous injuries in vitro and in vivo |
| title_sort | effects of poly adp ribose polymerase 1 parp 1 inhibition on sulfur mustard induced cutaneous injuries in vitro and in vivo |
| topic | Sulfur mustard PARP-1 DNA damage NAD+ Apoptosis Necrosis |
| url | https://peerj.com/articles/1890.pdf |
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