Inhibitory effect of alpinetin on IL‐6 expression by promoting cytosine methylation in CpG islands in the IL‐6 promoter region

Hu, Ke; Li, Yuxian; Liang, Minghua; Liu, Lijing; Chen, Yuefu; Huang, Mengxi; Tan, Bifeng; Luo, Yuan; Yin, Huiming

doi:10.1002/mgg3.993

Cited by 6 publications

(5 citation statements)

References 27 publications

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“…Moreover, Hu et al calculated that alpinetin administration (50-1,000 μg/ml for 24 h) apparently activated PPAR and reduced proinflammatory cytokines IL-6 generation in RAW246.7 cells. The mechanism analysis clarified that alpinetin firstly enabled PPAR, whereafter activated DNMT3A and boosted cytimidine methylation of the IL-6 promoter region, and finally reduced IL-6 secretion (Hu et al, 2020).…”

Section: Activation Of Ppar-γmentioning

confidence: 96%

Alpinetin: A Review of Its Pharmacology and Pharmacokinetics

et al. 2022

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Flavonoids isolated from medicinal herbs have been utilized as valuable health-care agents due to their virous biological applications. Alpinetin is a natural flavonoid that emerges in many widely used medicinal plants, and has been frequently applied in Chinese patent drugs. Accumulated evidence has demonstrated that alpinetin possesses a broad range of pharmacological activities such as antitumor, antiinflammation, hepatoprotective, cardiovascular protective, lung protective, antibacterial, antiviral, neuroprotective, and other properties through regulating multiple signaling pathways with low systemic toxicity. However, pharmacokinetic studies have documented that alpinetin may have poor oral bioavailability correlated to its extensive glucuronidation. Currently, the reported pharmacological properties and pharmacokinetics profiles of alpinetin are rare to be scientifically reviewed. In this article, we aimed to highlight the mechanisms of action of alpinetin in various diseases to strongly support its curative potentials for prospective clinical applications. We also summarized the pharmacokinetics properties and proposed some viable strategies to convey an appreciable reference for future advances of alpinetin in drug development.

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Section: Activation Of Ppar-γmentioning

confidence: 96%

Alpinetin: A Review of Its Pharmacology and Pharmacokinetics

et al. 2022

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“…Therefore, the PPAR/DNMT3A pathway is considered the main molecular mechanism involved in reversing inflammatory organ damage by alpinetin. 14 , 15 …”

Section: Introductionmentioning

confidence: 99%

“…Moreover, we found that PPAR activation induced by alpinetin can further promote the synthesis and modification activity of DNA methyltransferase DNMT3A in the nucleus of RAW 246.7 (the macrophage cell line), thus promoting the methylated modification of the IL‐6 promoter and blocked the binding of transcription factors. Therefore, the PPAR/DNMT3A pathway is considered the main molecular mechanism involved in reversing inflammatory organ damage by alpinetin 14,15 …”

Section: Introductionmentioning

confidence: 99%

“…Therefore, the PPAR/DNMT3A pathway is considered the main molecular mechanism involved in reversing inflammatory organ damage by alpinetin. 14,15 Methyl-CpG-binding protein 2 (Mecp2) is a crucial transcriptional regulator for synaptic function that binds to methylated DNA. 16 Our previous study confirmed that Mecp2 could inhibit the binding of the coactivator p300 to the methylated IL-6 promoter in human embryonic kidney cells.…”

Section: Introductionmentioning

confidence: 99%

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Mecp2 promotes the anti‐inflammatory effect of alpinetin via epigenetic modification crosstalk

Hu,

Ma,

Huang

et al. 2024

J Cellular Molecular Medi

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In recent years, inflammatory disorders have emerged as a significant concern for human health. Through ongoing research on anti‐inflammatory agents, alpinetin has shown promising anti‐inflammatory properties, including involvement in epigenetic modification pathways. As a crucial regulator of epigenetic modifications, Mecp2 may play a role in modulating the epigenetic effects of alpinetin, potentially impacting its anti‐inflammatory properties. To test this hypothesis, two key components, p65 (a member of NF‐KB family) and p300 (a type of co‐activator), were screened by the expression profiling microarray, which exhibited a strong correlation with the intensity of LPS stimulation in mouse macrophages. Meanwhile, alpinetin demonstrates the anti‐inflammatory properties through its ability to disrupt the synthesis of p65 and its interaction with promoters of inflammatory genes, yet it did not exhibit similar effects on p300. Additionally, Mecp2 can inhibit the binding of p300 by attaching to the methylated inflammatory gene promoter induced by alpinetin, leading to obstacles in promoter acetylation and subsequently impacting the binding of p65, ultimately enhancing the anti‐inflammatory capabilities of alpinetin. Similarly, in a sepsis mouse model, it was observed that homozygotes overexpressing Mecp2 showed a greater reduction in organ damage and improved survival rates compared to heterozygotes when administered by alpinetin. However, blocking the expression of DNA methyltransferase 3A (DNMT3A) resulted in the loss of Mecp2′s anti‐inflammatory assistance. In conclusion, Mecp2 may augment the anti‐inflammatory effects of alpinetin through epigenetic ‘crosstalk’, highlighting the potential efficacy of a combined therapeutic strategy involving Mecp2 and alpinetin for anti‐inflammatory intervention.

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“…DNMT3A, as a major CpG methyltransferase, consists of an N-terminal binding domain and a C-terminal with transmethylation activity [ 21 ], regulating the target genes expression by quickly converting cytosine into 5-methylcytosine [ 22 ]. Galangin was found to promote the methylation of promoter CpG sites of IL-6, a key inflammatory gene, via the PPAR/DNMT3A pathway, thereby inhibiting IL-6 expression [ 23 ]. In summary, methylation induction should be part of the mechanism, wherein galangin intervenes to synthesize inflammatory mediators.…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of Galangin Methylation Modification Based on Cell Imaging on Inflammatory Lung Injury and Its Molecular Mechanism

Jin

et al. 2022

Contrast Media & Molecular Imaging

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Background. Recently, inflammation has become a major threat to human health. Studies have confirmed that some Chinese traditional medicine ingredients may effectively interfere with the expression of inflammatory mediators through epigenetic modification, showing a great potential of the application. Objective. To investigate the role of the PPAR/DNMT3A pathway in the reversal of galangin-mediated inflammatory lung injury, promote the development of new anti-inflammatory drugs, reduce the side effects of chemical synthetic drugs on the body, and prove the effectiveness and safety of galangin in inhibiting inflammatory response and injury. Methods. 120 rats were randomly divided into 6 groups: (Group 1) LPS group; (Group 2) LPS + galangin group; (Group 3) LPS + galangin + GW9662 group; (Group 4) LPS + galangin + DNMT3A siRNA group; (Group 5) LPS + galangin + siRNA negative group; (Group 6) control group. The model of inflammatory lung injury was established by intrathecal instillation of LPS in the first five groups and NS in the control group. SD survival rate was recorded every 24 hours after modeling, lasting for 168 hours. The lung tissues were taken 168 hours after the establishment of the model. The pathological morphology of lung tissue was observed after the staining under the light microscope, and the lung dry/wet weight ratio was calculated after drying. After NS was perfused into lung tissue, the lavage fluid was collected and the levels of IL-6 and TNF-a were measured by ELISA. The contents of PPAR, DNMT3A, phosphorylated p65, and ERK in monocytes were detected by the WB method, and the binding contents of p65 and AP-1 in the promoter regions of IL-6 and TNF-a genes were detected by the Chip-qPCR method. Results. Intraperitoneal injection of galangin could inhibit the synthesis of alveolar inflammatory factors (TFs) in the SD model of lung injury induced by LPS, reduce the degree of pathological injury of lung tissue, and improve the survival rate of the SD model. GW9662 can completely reverse the protective effect, while DNMT3A interference can only partially block its protective effect. In addition, galangin could significantly inhibit the LPS-induced expression of p65 and AP-1 in alveolar monocytes and their binding content in the promoter region of inflammatory genes by activating PPAR/DNMT3A pathway. GW9662 could completely reverse the inhibitory effect of galangin. DNMT3A interference could restore the binding content of transcription factors at the promoter of the inflammatory gene but had no significant effect on its synthesis. Conclusion. Galangin can interfere with the binding of transcription factors to inflammatory gene promoters through the methylation modification induced by PPAR/DNMT3A pathway, so as to inhibit the synthesis of inflammatory molecules and reverse inflammatory lung injury.

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Inhibitory effect of alpinetin on IL‐6 expression by promoting cytosine methylation in CpG islands in the IL‐6 promoter region

Cited by 6 publications

References 27 publications

Alpinetin: A Review of Its Pharmacology and Pharmacokinetics

Alpinetin: A Review of Its Pharmacology and Pharmacokinetics

Mecp2 promotes the anti‐inflammatory effect of alpinetin via epigenetic modification crosstalk

Protective Effect of Galangin Methylation Modification Based on Cell Imaging on Inflammatory Lung Injury and Its Molecular Mechanism

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