Dimethyl fumarate improves cognitive deficits in chronic cerebral hypoperfusion rats by alleviating inflammation, oxidative stress, and ferroptosis via NRF2/ARE/NF-κB signal pathway

Yan, Nao; Xu, Zhipeng; Qu, Changhua; Zhang, Junjian

doi:10.1016/j.intimp.2021.107844

Cited by 125 publications

(60 citation statements)

References 127 publications

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“…Microglia, resident immune cells in the central nervous system, exert a critical function in inflammatory responses in the brain [ 33 , 34 ]. Suppressing inflammation and oxidative stress in microglia can mitigate brain damage induced by hypoxia-ischemia [ 35 , 36 ]. Therefore, anti-inflammatory or antioxidant reagents are extremely promising in preventing or ameliorating neuron damage in the wake of ischemia-reperfusion.…”

Section: Discussionmentioning

confidence: 99%

Chlorogenic Acid Prevents Microglia-Induced Neuronal Apoptosis and Oxidative Stress under Hypoxia-Ischemia Environment by Regulating the MIR497HG/miR-29b-3p/SIRT1 Axis

et al. 2022

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Background. Chlorogenic acid (CGA) is a polyphenolic compound with antioxidant and anti-inflammatory properties. CGA has been shown to improve neuroinflammation. This study is aimed at elucidating the exact mechanism by which CGA reduces neuroinflammation. Methods. Oxygen and glucose deprivation (OGD) was utilized to treat BV2 microglia and HT-22 hippocampal neurons to engineer an in vitro model of hypoxic ischemia reperfusion. The levels of inflammatory factors (IL-1β, IL-6, TNF-α, IL-4, and IL-10) and oxidative stress factors (MDA, SOD, and GSH-PX) in microglia were determined by ELISA kits. The neuron proliferation was assessed by CCK-8 assay, and LDH kit was used to determine LDH release in neurons. The fluorescent dye DCF-DA was employed to measure ROS levels in neurons. Correlation of MIR497HG, miR-29b-3p, and SIRT1/NF-κB in neurons and microglia was determined by qRT-PCR. Expressions of inflammatory proteins (COX2, iNOS), oxidative stress pathways (Nrf2, HO-1), and apoptosis-related proteins (Bcl-2, Bax, caspase3, caspase8, and caspase9) in microglia or neurons were determined by western blot. The interactions between MIR497HG and miR-29b-3p, as well as between miR-29b-3p and SIRT1, were determined by dual luciferase assay and RIP assay. Results. CGA attenuated OGD-mediated inflammation and oxidative stress in microglia and inhibited microglia-mediated neuronal apoptosis. CGA increased the levels of MIR497HG and SIRT1 and suppressed the levels of miR-29b-3p in BV2 and HT-22 cells. MIR497HG knockdown, miR-29b-3p upregulation, and SIRT1 inhibition inhibited CGA-mediated anti-inflammatory and neuronal protective functions. There is a targeting correlation between MIR497HG, miR-29b-3p, and Sirt1. MIR497HG sponges miR-29b-3p to regulate SIRT1 expression in an indirect manner. Conclusion. CGA upregulates MIR497HG to curb miR-29b-3p expression, hence initiating the SIRT1/NF-κB signaling pathway and repressing OGD-elicited inflammation, oxidative stress, and neuron apoptosis.

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Section: Discussionmentioning

confidence: 99%

Chlorogenic Acid Prevents Microglia-Induced Neuronal Apoptosis and Oxidative Stress under Hypoxia-Ischemia Environment by Regulating the MIR497HG/miR-29b-3p/SIRT1 Axis

et al. 2022

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“…Besides, ferroptosis is just one of various cell death types in cardiomyocytes induced by DOX. And DMF was reported to inhibit ferroptosis in multiple disease models by activating the Nrf2 pathway ( Qiu et al, 2020 ; Zhang et al, 2020 ; Yan et al, 2021 ; Yang et al, 2021 ). Therefore, we need to further explore the relationship between the Nrf2/Hmox1 axis and ferroptosis in the heart after DOX treatment.…”

Section: Discussionmentioning

confidence: 99%

Dimethyl Fumarate Ameliorates Doxorubicin-Induced Cardiotoxicity By Activating the Nrf2 Pathway

Wang

et al. 2022

Front. Pharmacol.

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Doxorubicin (DOX) is limited in clinical application because of its cardiotoxicity. Oxidative stress and apoptosis are crucial in DOX-induced cardiac injury. Dimethyl fumarate (DMF) is an FDA-approved oral drug with powerful effects to reduce oxidative stress and apoptosis through the Nrf2 pathway. This study was aimed to determine whether DMF can protect against DOX-induced cardiac injury. We used both neonatal rat cardiomyocytes (NRCMs) in vitro and DOX-induced cardiac toxicity in vivo to explore the effects of DMF. The results showed that DMF significantly improved cell viability and morphology in NRCMs. In addition, DMF alleviated DOX-induced cardiac injury in rats, as evidenced by decreased CK-MB, LDH levels, improved survival rates, cardiac function, and pathological changes. Moreover, DMF significantly inhibited cardiac oxidative stress by reducing MDA levels and increasing GSH, SOD, and GSH-px levels. And DMF also inhibited DOX-induced cardiac apoptosis by modulating Bax, Bcl-2 and cleaved caspase-3 expression. Moreover, DMF exerted its protective effects against DOX by promoting Nrf2 nuclear translocation, which activated its downstream antioxidant gene Hmox1. Silencing of Nrf2 attenuated the protective effects of DMF in NRCMs as manifested by increased intracellular oxidative stress, elevated apoptosis levels, and decreased cell viability. In addition, DMF showed no protective effects on the viability of DOX-treated tumor cells, which suggested that DMF does not interfere with the antitumor effect of DOX in vitro. In conclusion, our data confirmed that DMF alleviated DOX-induced cardiotoxicity by regulating oxidative stress and apoptosis through the Nrf2 pathway. DMF may serve as a new candidate to alleviate DOX-related cardiotoxicity in the future.

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“…Another factor involved in the neurodegeneration of the hippocampus post-ischemia is the disturbance of zinc and iron homeostasis [ 109 , 110 , 111 ]. Zinc levels remain constant in the adult animal’s hippocampus and are involved in learning and memory [ 112 ].…”

Section: Metals In Post-ischemic Hippocampusmentioning

confidence: 99%

“…Iron deposition and overload are important triggers of ferroptosis. Ferroptosis is a new form of iron-dependent cell death and differs from other types of cell death such as apoptosis, necrosis and autophagy in biochemical, morphological and genetic aspects [ 111 ]. Ferroptosis is characterized by iron accumulation, lipid peroxidation, production of reactive oxygen species, reduced glutathione levels, suppression of glutathione peroxidase 4 and altered expression of many genes [ 111 , 122 ].…”

Section: Metals In Post-ischemic Hippocampusmentioning

confidence: 99%

Post-Ischemic Neurodegeneration of the Hippocampus Resembling Alzheimer’s Disease Proteinopathy

Pluta

Januszewski

Czuczwar

2021

IJMS

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In this review, we summarize, inter alia, the protein and gene changes associated with Alzheimer’s disease and their role in post-ischemic hippocampal neurodegeneration. In the hippocampus, studies have revealed dysregulation of the genes for the amyloid protein precursor metabolism and tau protein that is identical in nature to Alzheimer’s disease. Data indicate that amyloid and tau protein, derived from brain tissue and blood due to increased permeability of the blood–brain barrier after ischemia, play a key role in post-ischemic neurodegeneration of the hippocampus, with concomitant development of full-blown dementia. Thus, the knowledge of new neurodegenerative mechanisms that cause neurodegeneration of the hippocampus after ischemia, resembling Alzheimer’s disease proteinopathy, will provide the most important therapeutic development goals to date.

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Dimethyl fumarate improves cognitive deficits in chronic cerebral hypoperfusion rats by alleviating inflammation, oxidative stress, and ferroptosis via NRF2/ARE/NF-κB signal pathway

Cited by 125 publications

References 127 publications

Chlorogenic Acid Prevents Microglia-Induced Neuronal Apoptosis and Oxidative Stress under Hypoxia-Ischemia Environment by Regulating the MIR497HG/miR-29b-3p/SIRT1 Axis

Chlorogenic Acid Prevents Microglia-Induced Neuronal Apoptosis and Oxidative Stress under Hypoxia-Ischemia Environment by Regulating the MIR497HG/miR-29b-3p/SIRT1 Axis

Dimethyl Fumarate Ameliorates Doxorubicin-Induced Cardiotoxicity By Activating the Nrf2 Pathway

Post-Ischemic Neurodegeneration of the Hippocampus Resembling Alzheimer’s Disease Proteinopathy

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