Crosstalk between Oxidative Stress and Ferroptosis/Oxytosis in Ischemic Stroke: Possible Targets and Molecular Mechanisms

Ren, Jiaxin; Li, Chao; Yan, Xiaofeng; Qu, Yang; Yang, Yi; Guo, Zhen‐Ni

doi:10.1155/2021/6643382

Cited by 66 publications

(32 citation statements)

References 147 publications

(247 reference statements)

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“…During ischemic stroke, as the artery that supplies blood to the brain is blocked, the brain cells do not receive blood supply properly and so they are glucose and oxygen-deprived. This results in ATP level depletion and rises the intracellular calcium levels [28], which causes mitochondrial injury, free radical generation, and damages the nucleus and, cell membrane, and eventually leading to cell death [28,29]. As expected, our data showed that high glucose and H/R injury increased the cytotoxicity, oxidative stress and eventually reduced the viability of astrocytes, indicating the success of the injury model.…”

Section: Discussionsupporting

confidence: 71%

EPC-EXs improve astrocyte survival and oxidative stress through different uptaking pathways in diabetic hypoxia condition

et al. 2022

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Background Hyperglycemia contributes to cardiovascular complications in patients with type 2 diabetes. We confirmed that high glucose (HG) induces endothelial dysfunction and cerebral ischemic injury is enlarged in diabetic mice. Stem cell-released exosomes have been shown to protect the brain from ischemic stroke. We have previously shown that endothelial progenitor cells (EPCs)-released exosomes (EPC-EXs) can protect endothelial cells from hypoxia/reoxygenation (H/R) and HG-induced injury. Here, we aim to investigate the effects of EPC-EXs on astrocytes under H/R and HG-induced injury and whether miR-126 enriched EPC-EXs (miR126-EPC-EXs) have enhanced efficacy. Methods EPC-EX uptake and co-localization were measured by fluorescent microscopy using PKH26 and DAPI staining. miR-126 enrichment was achieved by transfecting with miR-126 mimics and quantified with real-time PCR. After co-incubation, cell death or injury was measured by using LDH (Lactate Dehydrogenase) assay. Oxidative stress/ROS (reactive oxygen species) generation was measured by DHE (Dihydroethidium) staining and lipid peroxidation assay. Results The EPC-EXs were effectively taken up by the astrocytes in a concentration as well as time-dependent manners and were co-localized within the nucleus as well as the cytoplasm. Pathway uptake inhibitors revealed that the EPC-EXs are effectively taken up by the clathrin-mediated, caveolin-dependent, and micropinocytosis via PI3K/Akt pathway. H/R and HG-induced a cell injury which could be protected by EPC-EXs evidenced by decreased cell cytotoxicity, oxidative stress, and lipid peroxidation. Moreover, miR-126 overexpression could increase the level of miR-126 in astrocytes and enhance the protective effects of EPC-EXs. Conclusions These results collectively indicate that the EPC-EXs could protect astrocytes against the HG plus H/R-induced damage.

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Section: Discussionsupporting

confidence: 71%

EPC-EXs improve astrocyte survival and oxidative stress through different uptaking pathways in diabetic hypoxia condition

et al. 2022

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“… 212 From another perspective, ferroptosis is also closely associated with oxidative stress, in which signaling pathways such as calcium-related signals, ATF4 and Keap1-Nrf2 signaling pathways play a role. 213 Despite being less frequently discussed, ferroptosis may also be greatly involved in the pathogenesis of ischemic stroke,with a variety of signaling pathways potentially participating in.…”

Section: Pathophysiology and Signaling Pathways Involved In Ischemic ...mentioning

confidence: 99%

Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions

Qin

Yang

Chu

et al. 2022

Sig Transduct Target Ther

148

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Ischemic stroke is caused primarily by an interruption in cerebral blood flow, which induces severe neural injuries, and is one of the leading causes of death and disability worldwide. Thus, it is of great necessity to further detailly elucidate the mechanisms of ischemic stroke and find out new therapies against the disease. In recent years, efforts have been made to understand the pathophysiology of ischemic stroke, including cellular excitotoxicity, oxidative stress, cell death processes, and neuroinflammation. In the meantime, a plethora of signaling pathways, either detrimental or neuroprotective, are also highly involved in the forementioned pathophysiology. These pathways are closely intertwined and form a complex signaling network. Also, these signaling pathways reveal therapeutic potential, as targeting these signaling pathways could possibly serve as therapeutic approaches against ischemic stroke. In this review, we describe the signaling pathways involved in ischemic stroke and categorize them based on the pathophysiological processes they participate in. Therapeutic approaches targeting these signaling pathways, which are associated with the pathophysiology mentioned above, are also discussed. Meanwhile, clinical trials regarding ischemic stroke, which potentially target the pathophysiology and the signaling pathways involved, are summarized in details. Conclusively, this review elucidated potential molecular mechanisms and related signaling pathways underlying ischemic stroke, and summarize the therapeutic approaches targeted various pathophysiology, with particular reference to clinical trials and future prospects for treating ischemic stroke.

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“…Oxidative stress and lipid peroxidation are key events of ferroptosis [ 26 , 27 ]. LncRNA MALAT1 promotes oxidative stress and ROS production in many diseases [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Silencing of lncRNA MALAT1 facilitates erastin-induced ferroptosis in endometriosis through miR-145-5p/MUC1 signaling

Liang

Wang

et al. 2022

Cell Death Discov.

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Endometriosis is a chronic disorder characterized by the implantation of endometrial glands and stroma outside the uterus. However, the pathogenesis of endometriosis is still unclear. To date, there is no fully effective treatment without trauma because of various side effects. Recent data suggest that ferroptosis is a novel recognized form of nonapoptosis-regulated cell death characterized by iron-dependent and lethal lipid peroxidation accumulation, showing great promise in the treatment of many diseases. In the present study, we verified that erastin induced ferroptosis in ectopic endometrial stromal cells (EESCs). Furthermore, we found that the expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was decreased during erastin-induced ferroptosis. Knockdown of MALAT1 significantly aggravated the inhibition of cell viability and increased intracellular iron, Liperfluo, and MDA levels in EESCs upon erastin treatment. Mechanistically, we demonstrated that MALAT1 served as a competing endogenous RNA of miR-145-5p to regulate the expression of MUC1, a suppressor of ferroptosis. MALAT1 knockdown-mediated ferroptotic cell death and MUC1 downregulation could be abrogated by inhibition of miR-145-5p. In addition, miR-145-5p inhibition-mediated ferroptotic cell death could be abolished by MUC1 knockdown. Furthermore, erastin-induced ferroptosis shrunk endometriotic lesions via the MALAT1/miR-145-5p/MUC1 axis in vivo. Taken together, our data indicate that knockdown of MALAT1 facilitates ferroptosis upon erastin treatment via miR-145-5p/MUC1 signaling. The synergistic effect of MALAT1 knockdown and erastin induction in ferroptosis may be a new therapeutic strategy for endometriosis.

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Crosstalk between Oxidative Stress and Ferroptosis/Oxytosis in Ischemic Stroke: Possible Targets and Molecular Mechanisms

Cited by 66 publications

References 147 publications

EPC-EXs improve astrocyte survival and oxidative stress through different uptaking pathways in diabetic hypoxia condition

EPC-EXs improve astrocyte survival and oxidative stress through different uptaking pathways in diabetic hypoxia condition

Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions

Silencing of lncRNA MALAT1 facilitates erastin-induced ferroptosis in endometriosis through miR-145-5p/MUC1 signaling

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