Isoliquiritin ameliorates depression by suppressing NLRP3-mediated pyroptosis via miRNA-27a/SYK/NF-κB axis.
Open accessAbstract
BACKGROUND: The NLRP3-mediated pyroptosis, which could be regulated by miRNA-27a, is a key player in the development of depression. Isoliquiritin is a phenolic flavonoid compound that has been demonstrated to suppress NLRP3-mediated pyroptosis. However, it is still unknown whether isoliquiritin could confer antidepressant activity via decreasing NLRP3-mediated pyroptosis by stimulating miRNA-27a. Thus, in the current study, we explored the antidepressant activity of isoliquiritin and its underlying mechanism. METHODS: Expression of miRNA-27a in depressed patients or mice was measured using qRT-PCR. Luciferase reporter assay was performed to illustrate the link between miRNA-27a and SYK. Lipopolysaccharide (LPS) and chronic social defeat stress (CSDS) depression models were established to investigate the antidepressant actions of isoliquiritin. Changes in miRNA-27a/SYK/NF-κB axis and NLRP3-mediated pyroptosis were also examined. The role of miRNA-27a in isoliquiritin-related antidepressant effect was further investigated by using miRNA-27a inhibitors and mimics of miRNA-27a. RESULTS: Our results showed the miRNA-27a expression was downregulated in the serum of depressed patients, and decreased serum and hippocampus expression of miRNA-27a were observed in rodent models of depression. SYK gene expression was significantly reduced by miRNA-27a mimic incubation. Isoliquiritin profoundly attenuated LPS or CSDS-induced depressive symptoms, as well as CSDS-induced anxiety behavior. In the hippocampus, LPS and CSDS decreased miRNA-27a mRNA expression; increased the protein levels of SYK, p-NF-κB, and NLRP3: cleaved Caspase-1, IL-1β, and GSDMD-N: and elevated the concentration of IL-1β, IL-6, and TNF-α, which were all restored by isoliquiritin administration. Meanwhile, isoliquiritin upregulated the hippocampal NeuN protein level, improved the survival and morphology of neurons, and decreased pyroptosis-related neuronal cell death. Moreover, isoliquiritin protected primary microglia against LPS and adenosine triphosphate (ATP) elicited NLRP3 inflammasome activation in vitro, evidenced by declined protein levels of p-NF-κB, NLRP3; cleaved Caspase-1, IL-1β, and GSDMD-N; upregulated miRNA-27a mRNA expression; and decreased the mRNA and protein levels of SYK. Nevertheless, miRNA-27a inhibitors significantly reversed isoliquiritin-generated therapeutic efficacy in CSDS mice and in vitro. Furthermore, the cytoprotective effect of isoliquiritin was similar to that of miRNA-27a mimics in LPS and ATP-treated primary microglia. Taken together, these findings suggest that isoliquiritin possesses potent antidepressant property, which requires miRNA-27a/SYK/NF-κB axis controlled decrease of pyroptosis via NLRP3 cascade.
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In MMD, miRNAs are associated with depression caused by various illnesses and with response to specific treatments such as isoliquiritin, oligonucleotides, or purinergic receptor.
“In MMD, it has been reported that miRNAs are not only involved in the pathogenesis of the disease [17], but are also associated with depression caused by various illnesses [18, 19], as well as the response to specific treatments such as isoliquiritin [20], oligonucleotides [21], or purinergic receptor [22], confirming their potential as disease monitoring biomarkers.”
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- Authors
- Li, Y., Song, W., Tong, Y., Zhang, X., Zhao, J., Gao, X., Yong, J., & Wang, H.
- Affiliations
- Ningxia Medical University (CN)
- Corresponding author
- Wang, Hanqing
- Venue
- Journal of Neuroinflammation
- Published
- 2021-01-05
- Volume
- 18
- Issue
- 1
- Pages
- 1-1
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC7786465
- OpenAlex
- W3119186431
- Cited by
- 295
- References
- 43
- Citations by year
- 2026: 36 · 2025: 71 · 2024: 65 · 2023: 59 · 2022: 53 · 2021: 11
- FWCI
- 27.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81603227, 81460645)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plant Extracts Effects
- Keywords
- isoliquiritin, depression, antidepressant effects, NLRP3 inflammasome, pyroptosis, Syk, NF-κB signaling, hippocampus, microglia, neuroinflammation, chronic social defeat stress, lipopolysaccharide, neuronal survival, neuroprotection
- MeSH terms
- Pyroptosis, NLR Family, Pyrin Domain-Containing 3 Protein, Syk Kinase, Social Defeat, Adolescent, Adult, Animals, Animals, Newborn, Cells, Cultured, Chalcone, Depression, Female, Glucosides, Humans, Male, Mice, Inbred C57BL, Middle Aged, NF-kappa B, MicroRNAs, Mice, Young Adult
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