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Tangeretin Attenuates Cerebral Ischemia–Reperfusion-Induced Neuronal Pyroptosis by Inhibiting AIM2 Inflammasome Activation via Regulating NRF2

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Abstract

Pyroptosis is closely involved in the pathopoiesis of cerebral ischemia and reperfusion (I/R) injury which seriously dangers human’s life. Studies report that tangeretin (TANG), which is enriched in the peel of Citrus reticulata, has neuroprotective effects. Here, we explored whether absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis is involved in the cerebral I/R injury and the protective mechanism of TANG against cerebral I/R injury. In this study, we found that TANG treatment effectively alleviated I/R-induced brain injury and inhibited neuronal pyroptosis in an in vivo mice model with middle cerebral artery occlusion/reperfusion (MCAO/R) injury and in an in vitro hippocampal HT22 cell model with oxygen–glucose deprivation and reoxygenation (OGD/R) injury. Furthermore, we found TANG inhibited cerebral I/R-induced neuronal AIM2 inflammasome activation in vivo and in vitro via regulating nuclear factor E2-related factor 2 (NRF2). Moreover, administration of ML385, a chemical inhibitor of NRF2, notably blocked the neuroprotective effects of TANG against cerebral I/R injury. In conclusion, TANG attenuates cerebral I/R-induced neuronal pyroptosis by inhibiting AIM2 inflammasome activation via regulating NRF2. These findings indicate TANG is a potential therapeutic agent for cerebral I/R injury.

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Data Availability

The datasets and materials used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

I/R:

Ischemia and reperfusion

TANG:

Tangeretin

AIM2:

Absent in melanoma 2

NRF2:

Nuclear factor E2-related factor 2

ASC:

Apoptosis-associated speck-like protein containing a caspase recruitment domain

GSDMD:

Gasdermin D

IL‑1β:

Interleukin‑1β

CCA:

Common carotid artery

mNSS:

Modified Neurological Severity Score

CAT:

Catalase

HO1:

Heme oxygenase 1

NQO1:

NAD(P)H dehydrogenase, quinone 1

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Funding

This study was supported by the Science and Technology Planning Project of Guangzhou (202201010966), the Science and Technology Commissioner Project of Guangdong Province (GDKTP2021003800), the fifth batch of national TCM clinical outstanding talents training project (2021271), jointly funded project by the city, schools (institutes), and enterprises of Guangzhou Science and Technology Bureau (SL2022A03J00212), and Guangdong Bureau of Traditional Chinese Medicine Project (20231017).

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Author notes

  1. Guoxing You, Linbo Zheng and Yuanyuan Zhang have contributed equally to this work and share first authorship.

Authors and Affiliations

  1. School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China

    Guoxing You, Yuting Zhang, Yupeng Wang, Wenjie Guo & Jie Zan

  2. Department of Traditional Chinese Medicine, Guangdong Second Provincial General Hospital, Guangzhou, 510310, China

    Linbo Zheng & Hao Liu

  3. The Affiliated Traditional Chinese Medicine Hospital of Guangzhou Medical University, Guangzhou, 510130, China

    Yuanyuan Zhang

  4. Institute of Physiology, National Academy of Sciences of Belarus, Minsk, 220072, Republic of Belarus

    Philipovich Tatiana & Kulchitsky Vladimir

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  1. Guoxing You
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Contributions

Conceptualization, experimental design, data curation, and original draft preparation: GY, LZ, YZ, YW, WG, PT, HL, KV, YZ, and JZ. Investigation and manuscript review: GY, LZ, HL, KV, YZ, and JZ. Supervision and funding acquisition: LZ, KV, YZ, and JZ. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Jie Zan.

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The animal study was reviewed and approved by the Institutional Animal Care and Use Committee of Guangdong Second Provincial General Hospital.

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You, G., Zheng, L., Zhang, Y. et al. Tangeretin Attenuates Cerebral Ischemia–Reperfusion-Induced Neuronal Pyroptosis by Inhibiting AIM2 Inflammasome Activation via Regulating NRF2. Inflammation 47, 145–158 (2024). https://doi.org/10.1007/s10753-023-01900-8

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