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Propofol-induced MiR-20b expression initiates endogenous cellular signal changes mitigating hypoxia/re-oxygenation-induced endothelial autophagy in vitro.

ABSTRACT: Certain miRNAs can attenuate hypoxia/re-oxygenation-induced autophagic cell death reported in our previous studies, but how these miRNAs regulate the autophagy-related cellular signaling pathway in preventing cell death is largely unknown. In the current study, the autophagy-related miRNAs of hsa-miR-20b were investigated in an in vitro model of hypoxia/re-oxygenation-induced endothelial autophagic cell death. Of these, miR-20b was found to be the most important miRNA which targeted on the key autophagy kinase ULK1 and inhibited hypoxia/re-oxygenation injury-induced autophagy by decreasing both autophagosomes and LC3I to II transition rate and P62 degradation. These processes were reversed by the transfection of an miR-20b inhibitor. Re-expression of ULK1 restores miR-20b-inhibited autophagy. Propofol, a commonly used anesthetic, promoted miR-20b and METTL3 expression and attenuated endothelial autophagic cell death. The inhibited endogenous expression of miR-20b or silenced METTL3 diminished the protective effect of propofol and accentuated autophagy. Additionally, METTL3 knockdown significantly inhibited miR-20b expression but up-regulated pri-miR-20b expression. Together, our data shows that propofol protects against endothelial autophagic cell death induced by hypoxia/re-oxygenation injury, associated with activation of METTL3/miR-20b/ULK1 cellular signaling.

SUBMITTER: Lu Y

PROVIDER: S-EPMC7442825 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Propofol-induced MiR-20b expression initiates endogenous cellular signal changes mitigating hypoxia/re-oxygenation-induced endothelial autophagy in vitro.

Lu Yue Y Wang Sijie S Cai Shuyun S Gu Xiaoxia X Wang Jingjing J Yang Yue Y Hu Zhe Z Zhang Xihe X Ye Yongcai Y Shen Siman S Joshi Kiran K Ma Daqing D Ma Daqing D Zhang Liangqing L

Cell death & disease 20200813 8

Certain miRNAs can attenuate hypoxia/re-oxygenation-induced autophagic cell death reported in our previous studies, but how these miRNAs regulate the autophagy-related cellular signaling pathway in preventing cell death is largely unknown. In the current study, the autophagy-related miRNAs of hsa-miR-20b were investigated in an in vitro model of hypoxia/re-oxygenation-induced endothelial autophagic cell death. Of these, miR-20b was found to be the most important miRNA which targeted on the key a ...[more]

PMID: 32826852

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Project description:Perfluorocarbon nanoparticles have been reported to deliver oxygen to tumors and reduce hypoxia-induced radioresistance, however few studies have been carried out to study its role in reducing hypoxia-induced chemoresistance. The oxygenation effect also varies dramatically between different perfluorocarbon formulations and protocols, and there have been no efficient tools to monitor dynamic changes of tumor oxygenation non-invasively. Our goal was to promote tumor oxygenation using perfluorooctyl bromide (PFOB) nanoemulsion and to assess its role in sensitizing tumors to cisplatin treatment. A novel optical imaging protocol was also created to monitor the dynamic changes of tumor oxygenation in real-time. Methods: PFOB nanoemulsion with high oxygen-carrying capacity was prepared and administered to tumor-bearing mice intravenously. Tumor oxygenation was monitored using optical imaging with a hypoxia probe injected intratumorally, thus the oxygenation dynamics and best oxygenation protocol were determined. Various treatment groups were studied, and the tumor growth was monitored to evaluate the role of oxygenation in sensitizing tumors to cisplatin treatment. Results: PFOB nanoemulsion with and without pre-oxygenation along with carbogen breathing resulted in much better tumor oxygenation compared to carbogen breathing alone, while PFOB with air breathing did not show significant increase in tumor oxygenation. Pre-oxygenated PFOB with carbogen breathing produced the most effective oxygenation as early as 5 min post administration. In vitro and in vivo data showed preoxygenated PFOB nanoemulsion with carbogen breathing could increase cisplatin-mediated apoptosis of cancer cells and inhibited tumor growth at a low dose of cisplatin (1 mg/kg) treatment. Furthermore, the treatment did not induce nephrotoxicity. Conclusions: Preoxygenated PFOB nanoemulsion with carbogen breathing can effectively increase tumor oxygenation, which has a great potential to prevent/overcome hypoxia-induced chemotherapy resistance. In addition, optical imaging with intratumoral injection of the hypoxia probe was an efficient tool to monitor tumor oxygenation dynamics during PFOB administration, providing better understanding on oxygenation effects under different protocols.

Project description:BACKGROUND:Postoperative neurocognitive dysfunction induced by anesthetics, particularly in elderly patients with impaired oxygenation, is a common complication of surgery and is eliciting increased interest in clinical practice. To investigate the effects of anesthetics on neurocognition, we compared the effects of propofol versus sevoflurane on cerebral oxygenation and cognitive outcome in patients with impaired cerebral oxygenation undergoing general anesthesia. METHODS:Sixty-three patients with impaired cerebral oxygenation (jugular venous bulb oxygen saturation [SjvO2] <50%) or cerebral blood flow/cerebral metabolic rate of oxygen ([CBF/CMRO2] ?15%) undergoing elective abdominal surgery were randomly allocated into propofol group (group P) or sevoflurane group (group S). The clinical parameters and jugular venous bulb blood gas analysis were monitored throughout the surgical procedure. Cognitive function was assessed with the mini-mental state examination and Montreal Cognitive Assessment at day 1 and day 7 following surgery. S100? protein in plasma was measured using enzyme-linked immunosorbent assay. RESULTS:The SjvO2 increased during anesthesia induction and surgery when compared to baseline but had no significant difference between group P and group S. When compared to baseline, the CBF/CMRO2 was increased only at the end of surgery and extubation in group P; however, the CBF/CMRO2 in group S was increased during anesthesia induction at 1 hour, 2 hours, end of surgery, and extubation. Furthermore, the CBF/CMRO2 in group S was significantly higher than that in group P during anesthesia induction at 1 hour, 2 hours, and end of surgery. S100? protein did not significantly change at extubation and 1 day after surgery in both groups when compared to baseline. There was no significant difference in mini-mental state examination and Montreal Cognitive Assessment scores between group P and group S at all time points. CONCLUSION:Sevoflurane showed similar effects in postoperative neurocognitive function as propofol but could improve cerebral oxygenation in patients with impaired cerebral oxygenation.

Dataset Information

Propofol-induced MiR-20b expression initiates endogenous cellular signal changes mitigating hypoxia/re-oxygenation-induced endothelial autophagy in vitro.

Publications

Propofol-induced MiR-20b expression initiates endogenous cellular signal changes mitigating hypoxia/re-oxygenation-induced endothelial autophagy in vitro.

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