A novel mechanism linking ferroptosis and endoplasmic reticulum stress via the circPtpn14/miR-351-5p/5-LOX signaling in melatonin-mediated treatment of traumatic brain injury
A novel mechanism linking ferroptosis and endoplasmic reticulum stress via the circPtpn14/miR-351-5p/5-LOX signaling in melatonin-mediated treatment of traumatic brain injury
复制标题
在褪黑激素介导的创伤性脑损伤治疗中，通过 circPtpn14/miR-351-5p/5-LOX 信号传导将铁死亡和内质网应激联系起来的新机制。
DOI：
10.1016/j.freeradbiomed.2021.12.007
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发表时间：
2021-12-09
影响因子：
7.4
通讯作者：
Liao, Z. B.
中科院分区：
文献类型：
--
作者：
Wu, Chenrui;Du, Mengran;Liao, Z. B.
创伤性脑损伤(TBI)可能导致残疾或破坏性后果，而现有的治疗方法很少。尽管铁性下垂已被证明与颅脑损伤有关，但其潜在的机制却鲜为人知。褪黑素已被证明具有神经保护作用。然而，褪黑素对颅脑损伤的抗铁下垂作用尚不清楚。本研究旨在探讨人脑创伤后是否发生铁下垂，以及褪黑素抑制铁下垂能否在体内和体外对抗脑损伤后血脑屏障(BBB)的损伤。环状RNA(CircRNAs)在大脑中高度表达。首次通过RNA测序检测了褪黑素治疗脑损伤后差异表达的CircRNA。我们发现，脑创伤后人类体内发生了脂质过氧化，而褪黑素显著改善了脑损伤后小鼠的脑功能，减轻了体内和体外的铁下垂和内质网(ER)应激。在接受褪黑素治疗的脑损伤小鼠的损伤脑组织中，共有1826个差异表达的CircRNA被发现(倍变化2，Q<；0.01)，其中921个下调，905个上调。从机制上讲，褪黑素通过作为miR-351-5P海绵，正向调节铁下垂相关的5-脂氧合酶(5-LOX)的表达，降低了CircPtpn14(MMUCIRC_0000130)的水平。此外，大约Ptpn14的过表达部分取消了褪黑素对铁性下垂的抑制作用。总之，我们的发现提供了第一个证据，证明褪黑素可以通过CircPtpn14/miR-351-5p/5-LOX信号来减轻脂质过氧化，从而在脑损伤中发挥抗铁上链和抗内质网应激作用。
Traumatic brain injury (TBI) can lead to disability or devastating consequences with few established treatments. Although ferroptosis has been shown to be involved in TBI, the underlying mechanism was rarely known. Melatonin has been indicated to exhibit neuroprotective activities. However, the anti-ferroptotic effects of melatonin on TBI have not yet to be elucidated. We aimed to investigate whether ferroptosis was induced in humans after TBI and whether ferroptosis inhibition by melatonin could protect against blood-brain barrier (BBB) damage after TBI in vivo and in vitro. Circular RNAs (circRNAs) are highly expressed in the brain. For the first time, differentially expressed circRNA after melatonin treatment for TBI were detected by RNA sequencing. We found that lipid peroxidation was induced in humans after TBI, while melatonin significantly improved brain function of mice after TBI and alleviated ferroptosis and endoplasmic reticulum (ER) stress in vivo and in vitro. A total of 1826 differentially expressed circRNAs were found (fold change 2, Q < 0.01), including 921 downregulated and 905 up-regulated circRNAs in the injured brain tissues of TBI mice receiving melatonin treatment. Mechanistically, melatonin administration reduced the level of circPtpn14 (mmu_circ_0000130), which functioned by acting as a miR-351-5p sponge to positively regulate the expression of the ferroptosis-related 5-lipoxygenase (5-LOX). Moreover, circPtpn14 overexpression partly abolished the inhibitory effects of melatonin on ferroptosis. Collectively, our findings provide the first evidence that melatonin could exert anti-ferroptotic and anti-ER stress effects in brain injury by alleviating lipid peroxidation via the circPtpn14/miR-351-5p/5-LOX signaling.