PMID- 31524237
OWN - NLM
STAT- MEDLINE
DCOM- 20200204
LR  - 20211204
IS  - 1791-3004 (Electronic)
IS  - 1791-2997 (Print)
IS  - 1791-2997 (Linking)
VI  - 20
IP  - 3
DP  - 2019 Sep
TI  - High glucose and bupivacaine‑induced cytotoxicity is mediated by enhanced 
      apoptosis and impaired autophagy via the PERK‑ATF4‑CHOP and IRE1‑TRAF2 signaling 
      pathways.
PG  - 2832-2842
LID - 10.3892/mmr.2019.10524 [doi]
AB  - Bupivacaine has previously been reported to induce neurotoxicity, which is 
      further enhanced by high glucose levels. In the present study, the underlying 
      molecular mechanisms via which bupivacaine induces cytotoxicity under high 
      glucose conditions were investigated in cultured human SH‑SY5Y cells. In order to 
      identify the optimal concentrations of glucose and bupivacaine that induced 
      cytotoxicity, SH‑SY5Y cells were treated with 30‑100 mM glucose and 0.5‑1.0 mM 
      bupivacaine. Based on the dose response experiments, 50 mM glucose and 0.5 mM 
      bupivacaine was used in the present study. The effects that 3‑MA (autophagy 
      inhibitor) and rapamycin (RAPA; autophagy inducer) exerted on cell apoptosis, 
      autophagy and the expression of protein kinase R‑like endoplasmic reticulum 
      kinase (PERK)‑activating transcription factor 4 (ATF4)‑C/EBP‑homologous protein 
      (CHOP) and inositol‑requiring enzyme 1 (IRE1)‑tumor necrosis factor receptor 
      associated factor 2 (TRAF2) signaling proteins were measured in high glucose and 
      bupivacaine‑treated cells. Cell viability was measured using a Cell Counting 
      Kit‑8 assay, cell apoptosis was assessed using flow cytometry, and protein 
      expression was determined using western blot analyses. Compared with the control 
      group, high glucose and bupivacaine significantly increased ATF4, CHOP and 
      caspase‑12 expression, increased apoptosis, and decreased p‑IRE1, TRAF2, 
      LC3‑II/LC3‑I and Beclin1 expression. Promoting autophagy with RAPA partly 
      reversed the high glucose and bupivacaine‑induced changes in p‑PERK, CHOP, TRAF2, 
      Beclin1, caspase‑12 and apoptosis, while inhibiting autophagy with 3‑MA further 
      enhanced the changes in ATF4, CHOP, p‑IRE1, TRAF2 and apoptosis. High glucose and 
      bupivacaine induced cytotoxicity in SH‑SY5Y cells, at least in part, through 
      enhancing cell apoptosis and inhibiting autophagy via the PERK‑ATF4‑CHOP and 
      IRE1‑TRAF2 signaling pathways.
FAU - Liu, Yongzhe
AU  - Liu Y
AD  - Department of Anesthesiology, 7th Medical Center, General Hospital of PLA, 
      Beijing 100700, P.R. China.
FAU - Sun, Li
AU  - Sun L
AD  - Department of Anesthesiology, 7th Medical Center, General Hospital of PLA, 
      Beijing 100700, P.R. China.
FAU - Ma, Yaqun
AU  - Ma Y
AD  - Department of Anesthesiology, 7th Medical Center, General Hospital of PLA, 
      Beijing 100700, P.R. China.
FAU - Wei, Biyu
AU  - Wei B
AD  - Department of Anesthesiology, Shanxi Medical University, Taiyuan, Shanxi 030000, 
      P.R. China.
FAU - Gao, Minglong
AU  - Gao M
AD  - Department of Anesthesiology, 7th Medical Center, General Hospital of PLA, 
      Beijing 100700, P.R. China.
FAU - Shang, Lixin
AU  - Shang L
AD  - Department of Gynecology and Obstetrics, 7th Medical Center, General Hospital of 
      PLA, Beijing 100700, P.R. China.
LA  - eng
PT  - Journal Article
DEP - 20190725
PL  - Greece
TA  - Mol Med Rep
JT  - Molecular medicine reports
JID - 101475259
RN  - 0 (DDIT3 protein, human)
RN  - 0 (TNF Receptor-Associated Factor 2)
RN  - 145891-90-3 (Activating Transcription Factor 4)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - EC 2.7.11.1 (EIF2AK3 protein, human)
RN  - EC 2.7.11.1 (ERN1 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
RN  - EC 3.1.- (Endoribonucleases)
RN  - IY9XDZ35W2 (Glucose)
RN  - Y8335394RO (Bupivacaine)
SB  - IM
MH  - Activating Transcription Factor 4/metabolism
MH  - Apoptosis/*drug effects
MH  - Autophagy/*drug effects
MH  - Bupivacaine/*pharmacology
MH  - Cell Survival/drug effects
MH  - Endoribonucleases/metabolism
MH  - Glucose/*metabolism
MH  - Humans
MH  - Models, Biological
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Signal Transduction/*drug effects
MH  - TNF Receptor-Associated Factor 2/metabolism
MH  - Transcription Factor CHOP/metabolism
MH  - eIF-2 Kinase/metabolism
PMC - PMC6691238
EDAT- 2019/09/17 06:00
MHDA- 2020/02/06 06:00
PMCR- 2019/07/25
CRDT- 2019/09/17 06:00
PHST- 2019/01/10 00:00 [received]
PHST- 2019/06/28 00:00 [accepted]
PHST- 2019/09/17 06:00 [pubmed]
PHST- 2020/02/06 06:00 [medline]
PHST- 2019/09/17 06:00 [entrez]
PHST- 2019/07/25 00:00 [pmc-release]
AID - mmr-20-03-2832 [pii]
AID - 10.3892/mmr.2019.10524 [doi]
PST - ppublish
SO  - Mol Med Rep. 2019 Sep;20(3):2832-2842. doi: 10.3892/mmr.2019.10524. Epub 2019 Jul 
      25.