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JNK inhibitor alleviates apoptosis of fetal neural stem cells induced by emulsified isoflurane.
Oncotarget. 2017 Nov 07; 8(55):94009-94019.O

Abstract

Isoflurane can provide both neuroprotection and neurotoxicity in various culture models and in rodent developing brains. Emulsified Isoflurane (EI) is an emulsion formulation of isoflurane, while its underlying molecular mechanism of developemental nerve toxicity largely remains unclear. We hypothesized that EI induced fetal neural stem cells (FNSCs) apoptosis, endoplasmic reticulum (ER) stress and c-Jun N-terminal kinase (JNK) activation. FNSCs were isolated from the cortex of SD rats during 14 days of gestation. The cell viability, cell apoptotic rates and the expression of apoptosis-related protein Caspase3, inositol requiring enzyme 1 (IRE1), poly (adenosine diphosphate-ribose) polymerase (PARP), Bax, Bcl-2, JNK, p-JNK and XBP1 were determined. Specific inhibition was performed by siRNA-targeting of JNK in FNSCs. EI could increase the p-JNK, JNK and caspase3 protein expression, the JNK pathway was activated by EI, and EI-induced apoptosis was blocked by inhibiting JNK pathway with SP600125 or JNK-small interfering RNA (siRNA), EI enhanced the level of IRE1, PARP, Bax/Bcl-2 and XBP1, which led FNSCs to apoptosis and ER stress. Meanwhile, dilatation of the ER lumens in FNSCs treated by EI for 24 h was significant. Green fluorescent protein (GFP) positive cell ratios were significantly decreased by FNSCs transfecting with JNK gene silencing. JNK was efficiently silenced in siRNA-JNK1 group. The results provided in-vitro evidence which supports that the underlying mechanisms of EI-induced apoptosis are the induction of ER stress and sequent JNK activation. Together, these data suggest that JNK inhibiting might be applied for improving therapeutic outcomes in anesthestics-induced neurotoxicity.

HIGHLIGHTS

1. Prolonged treatment with high-dose EI decreased the survival level of FNSCs by inducing apoptosis and inhibiting proliferation via the JNK signaling pathway. 2. EI induced ER stress and sequent JNK activation. 3. JNK inhibiting might be applied for improving therapeutic outcomes in anesthestics-induced neurotoxicity.

Authors+Show Affiliations

Department of Anesthesiology, First Affiliated Hospital of AnHui Medical University, Hefei 230022, PR China.Department of Anesthesiology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, PR China.Department of Anesthesiology, First Affiliated Hospital of AnHui Medical University, Hefei 230022, PR China.Department of Anesthesiology, First Affiliated Hospital of AnHui Medical University, Hefei 230022, PR China.Department of Anesthesiology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, PR China.Department of Anesthesiology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, PR China.Department of Anesthesiology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, PR China.School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China.Department of Anesthesiology, First Affiliated Hospital of AnHui Medical University, Hefei 230022, PR China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29212205

Citation

Zhou, Lei, et al. "JNK Inhibitor Alleviates Apoptosis of Fetal Neural Stem Cells Induced By Emulsified Isoflurane." Oncotarget, vol. 8, no. 55, 2017, pp. 94009-94019.
Zhou L, Yang Z, Lu X, et al. JNK inhibitor alleviates apoptosis of fetal neural stem cells induced by emulsified isoflurane. Oncotarget. 2017;8(55):94009-94019.
Zhou, L., Yang, Z., Lu, X., Li, X., An, X., Chai, J., Yang, Q., Yan, S., & Li, Y. (2017). JNK inhibitor alleviates apoptosis of fetal neural stem cells induced by emulsified isoflurane. Oncotarget, 8(55), 94009-94019. https://doi.org/10.18632/oncotarget.21505
Zhou L, et al. JNK Inhibitor Alleviates Apoptosis of Fetal Neural Stem Cells Induced By Emulsified Isoflurane. Oncotarget. 2017 Nov 7;8(55):94009-94019. PubMed PMID: 29212205.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - JNK inhibitor alleviates apoptosis of fetal neural stem cells induced by emulsified isoflurane. AU - Zhou,Lei, AU - Yang,Zeyong, AU - Lu,Xianfu, AU - Li,Xingxing, AU - An,Xiaohu, AU - Chai,Jing, AU - Yang,Qiling, AU - Yan,Shikai, AU - Li,Yuanhai, Y1 - 2017/10/04/ PY - 2016/11/22/received PY - 2017/09/13/accepted PY - 2017/12/8/entrez PY - 2017/12/8/pubmed PY - 2017/12/8/medline KW - JNK KW - apoptosis KW - emulsified isoflurane KW - fetal neural stem cells KW - neurotoxicity SP - 94009 EP - 94019 JF - Oncotarget JO - Oncotarget VL - 8 IS - 55 N2 - : Isoflurane can provide both neuroprotection and neurotoxicity in various culture models and in rodent developing brains. Emulsified Isoflurane (EI) is an emulsion formulation of isoflurane, while its underlying molecular mechanism of developemental nerve toxicity largely remains unclear. We hypothesized that EI induced fetal neural stem cells (FNSCs) apoptosis, endoplasmic reticulum (ER) stress and c-Jun N-terminal kinase (JNK) activation. FNSCs were isolated from the cortex of SD rats during 14 days of gestation. The cell viability, cell apoptotic rates and the expression of apoptosis-related protein Caspase3, inositol requiring enzyme 1 (IRE1), poly (adenosine diphosphate-ribose) polymerase (PARP), Bax, Bcl-2, JNK, p-JNK and XBP1 were determined. Specific inhibition was performed by siRNA-targeting of JNK in FNSCs. EI could increase the p-JNK, JNK and caspase3 protein expression, the JNK pathway was activated by EI, and EI-induced apoptosis was blocked by inhibiting JNK pathway with SP600125 or JNK-small interfering RNA (siRNA), EI enhanced the level of IRE1, PARP, Bax/Bcl-2 and XBP1, which led FNSCs to apoptosis and ER stress. Meanwhile, dilatation of the ER lumens in FNSCs treated by EI for 24 h was significant. Green fluorescent protein (GFP) positive cell ratios were significantly decreased by FNSCs transfecting with JNK gene silencing. JNK was efficiently silenced in siRNA-JNK1 group. The results provided in-vitro evidence which supports that the underlying mechanisms of EI-induced apoptosis are the induction of ER stress and sequent JNK activation. Together, these data suggest that JNK inhibiting might be applied for improving therapeutic outcomes in anesthestics-induced neurotoxicity. HIGHLIGHTS: 1. Prolonged treatment with high-dose EI decreased the survival level of FNSCs by inducing apoptosis and inhibiting proliferation via the JNK signaling pathway. 2. EI induced ER stress and sequent JNK activation. 3. JNK inhibiting might be applied for improving therapeutic outcomes in anesthestics-induced neurotoxicity. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/29212205/JNK_inhibitor_alleviates_apoptosis_of_fetal_neural_stem_cells_induced_by_emulsified_isoflurane_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=21505 DB - PRIME DP - Unbound Medicine ER -
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