Hes1 Knockdown Exacerbates Ischemic Stroke Following tMCAO by Increasing ER Stress-Dependent Apoptosis via the PERK/eIF2α/ATF4/CHOP Signaling Pathway

Li, Yueyong; Zhang, Yingjun; Fu, Haidong; Huang, Hao; Lu, Qifeng; Qin, Houji; Wu, Yingning; Huang, Hua‐Tuo; Mao, Guizhen; Wei, Zhongheng; Pinhu, Liao

doi:10.1007/s12264-019-00411-7

Cited by 40 publications

(25 citation statements)

References 47 publications

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“…Excessive ER stress induces neuronal apoptosis, and in turn aggravates neuronal damage caused by cerebral ischemia [32]. Under this circumstance, GRP78 acts as a sensor and activates PERK and IRE1α, after which downstream signaling molecules such as eIF2α, ATF4, and CHOP are activated [33]. In the present study, we established an OGD cellular model and found that GRP78 was up-regulated at the early stage of hypoxia (3 h) and continued to increase in a time-dependent manner (Fig.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of PDE4 protects neurons against oxygen-glucose deprivation-induced endoplasmic reticulum stress through activation of the Nrf-2/HO-1 pathway

Qin

et al. 2020

Redox Biology

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Inhibition of phosphodiesterase 4 (PDE4) produces neuroprotective effects against cerebral ischemia. However, the involved mechanism remains unclear. Augmentation of endoplasmic reticulum (ER) stress promotes neuronal apoptosis, and excessive oxidative stress is an inducer of ER stress. The present study aimed to determine whether suppression of ER stress is involved in the protective effects of PDE4 inhibition against cerebral ischemia. We found that exposing HT-22 cells to oxygen-glucose deprivation (OGD) significantly activated ER stress, as evidenced by increased expression of the 78-kDa glucose-regulated protein (GRP78), phosphorylated eukaryotic translation-initiation factor 2α (eIF2α), and C/EBP-homologous protein (CHOP). Overexpression of PDE4B increased ER stress, while knocking down PDE4B or treatment with the PDE4 inhibitor, FCPR03, prevented OGD-induced ER stress in HT-22 cells. Furthermore, FCPR03 promoted the translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2) from the cytoplasm to the nucleus. Importantly, the Nrf-2 inhibitor, ML385, blocked the inhibitory role of FCPR03 on OGD-induced ER stress. ML385 also abolished the protective role of FCPR03 in HT-22 cells subjected to OGD. Knocking down heme oxygenase-1 (HO-1), which is a target of Nrf-2, also blocked the protective role of FCPR03, enhanced the level of reactive oxygen species (ROS), and increased ER stress and cell death. We then found that FCPR03 or the antioxidant, N-Acetyl-l-cysteine, reduced oxidative stress in cells exposed to OGD. This effect was accompanied by increased cell viability and decreased ER stress. In primary cultured neurons, we found that FCPR03 reduced OGD-induced production of ROS and phosphorylation of eIF2α. The neuroprotective effect of FCPR03 against OGD in neurons was blocked by ML385. These results demonstrate that inhibition of PDE4 activates Nrf-2/HO-1, attenuates the production of ROS, and thereby attenuates ER stress in neurons exposed to OGD. Additionally, we conclude that FCPR03 may represent a promising therapeutic agent for the treatment of ER stress-related disorders.

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Section: Discussionmentioning

confidence: 99%

Inhibition of PDE4 protects neurons against oxygen-glucose deprivation-induced endoplasmic reticulum stress through activation of the Nrf-2/HO-1 pathway

Qin

et al. 2020

Redox Biology

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“…Prolonged environmental stress triggers signal transduction pathways that lead to apoptosis and thereby heighten pathological processes, leading to cerebral damage (Chi et al, 2019 ). Endoplasmic reticulum stress exerts its vital role in stroke-induced neural apoptosis (Mohammed Thangameeran et al, 2020 ) through activation of downstream CCAATenhancer-binding protein homologous protein (CHOP) and caspase-12 (Chi et al, 2019 ; Chu et al, 2019 ; Li Y. et al, 2020 ). SIRT1 is a nicotine adenine dinucleotide (NAD+)-dependent enzyme that deacetylates numerous transcription factors in response to ischemic stress and is involved in various biological pathways (Chen et al, 2005 ).…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effects of Exercise Postconditioning After Stroke via SIRT1-Mediated Suppression of Endoplasmic Reticulum (ER) Stress

Lee

et al. 2021

Front. Cell. Neurosci.

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While it is well-known that pre-stroke exercise conditioning reduces the incidence of stroke and the development of comorbidities, it is unclear whether post-stroke exercise conditioning is also neuroprotective. The present study investigated whether exercise postconditioning (PostE) induced neuroprotection and elucidated the involvement of SIRT1 regulation on the ROS/ER stress pathway. Adult rats were subjected to middle cerebral artery occlusion (MCAO) followed by either: (1) resting; (2) mild exercise postconditioning (MPostE); or (3) intense exercise postconditioning (IPostE). PostE was initiated 24 h after reperfusion and performed on a treadmill. At 1 and 3 days thereafter, we determined infarct volumes, neurological defects, brain edema, apoptotic cell death through measuring pro- (BAX and Caspase-3) and anti-apoptotic (Bcl-2) proteins, and ER stress through the measurement of glucose-regulated protein 78 (GRP78), inositol-requiring 1α (IRE1α), protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), C/EBP homologous protein (CHOP), Caspase-12, and SIRT1. Proteins were measured by Western blot. ROS production was detected by flow cytometry.Compared to resting rats, both MPostE and IPostE significantly decreased brain infarct volumes and edema, neurological deficits, ROS production, and apoptotic cell death. MPostE further increased Bcl-2 expression and Bcl-2/BAX ratio as well as BAX and Caspase-3 expressions and ROS production (*p < 0.05). Both PostE groups saw decreases in ER stress proteins, while MPostE demonstrated a further reduction in GRP78 (***p < 0.001) and Caspase-12 (*p < 0.05) expressions at 1 day and IRE1α (**p < 0.01) and CHOP (*p < 0.05) expressions at 3 days. Additionally, both PostE groups saw significant increases in SIRT1 expression.In this study, both mild and intense PostE levels induced neuroprotection after stroke through SIRT1 and ROS/ER stress pathway. Additionally, the results may provide a base for our future study regarding the regulation of SIRT1 on the ROS/ER stress pathway in the biochemical processes underlying post-stroke neuroprotection. The results suggest that mild exercise postconditioning might play a similar neuroprotective role as intensive exercise and could be an effective exercise strategy as well.

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“…The time window of mechanical thrombectomy is only 6 h and is not sufficient. The timely restoration of blood flow results in oxidative stress, inflammatory responses, and endoplasmic reticulum stress [8][9][10]. Therefore, it is crucial to find a way to avoid or attenuate cerebral ischemia-reperfusion injury to improve treatment of ischemia stroke.…”

Section: Introductionmentioning

confidence: 99%

Asiaticoside Alleviates Cerebral Ischemia-Reperfusion Injury via NOD2/Mitogen-Activated Protein Kinase (MAPK)/Nuclear Factor kappa B (NF-κB) Signaling Pathway

et al. 2020

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Background: Cerebral ischemia-reperfusion injury (CIRI) remains a serious health problem. Centella asiatica formulations are used to treat central nervous system disorders. In the present study, asiaticoside, an extract of the plant Centella asiatica, was investigated in CIRI in vivo and vitro. Material/Methods: We made a CIRI model in vivo in SD rats treated by middle cerebral artery occlusion, and a cell model of ischemiareperfusion injury was made in PC12 cells treated by deprivation of oxygen and glucose/restoration. CIRI in vivo was assessed by scores of neurological functions, encephaledema, and cerebral infarction area. Inflammation level and oxidative stress level were detected by the appropriate kits. TUNEL assay was performed for assessment of cell apoptosis and Western blot analysis was performed to assess protein expression levels. CCK8 assay was performed for evaluation of cell survival and flow cytometer was used to detect cell apoptosis in vitro. Results: Nervous function injury, brain edema, cell apoptosis, infarct size, apoptosis-related protein expressions, and protein expressions of the NOD2/MAPK/NF-kB signaling pathway in the CIRI model were all reversed by asiaticoside in rats. The cell apoptosis, inflammation level, and oxidative stress level in the model of cerebral ischemia-reperfusion injury were reduced by asiaticoside. The effects of asiaticoside on CIRI were reversed by NOD 2 agonists. Conclusions: Asiaticoside showed a protective effect against cerebral ischemia-reperfusion injury via the NOD2/MAPK/NF-kB signaling pathway. These findings are vital for future research on use of asiaticoside in CIRI, providing a new avenue for alleviating CIRI.

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Hes1 Knockdown Exacerbates Ischemic Stroke Following tMCAO by Increasing ER Stress-Dependent Apoptosis via the PERK/eIF2α/ATF4/CHOP Signaling Pathway

Cited by 40 publications

References 47 publications

Inhibition of PDE4 protects neurons against oxygen-glucose deprivation-induced endoplasmic reticulum stress through activation of the Nrf-2/HO-1 pathway

Inhibition of PDE4 protects neurons against oxygen-glucose deprivation-induced endoplasmic reticulum stress through activation of the Nrf-2/HO-1 pathway

Neuroprotective Effects of Exercise Postconditioning After Stroke via SIRT1-Mediated Suppression of Endoplasmic Reticulum (ER) Stress

Asiaticoside Alleviates Cerebral Ischemia-Reperfusion Injury via NOD2/Mitogen-Activated Protein Kinase (MAPK)/Nuclear Factor kappa B (NF-κB) Signaling Pathway

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