Alpinetin exerts anti-colitis efficacy by activating AhR, regulating miR-302/DNMT-1/CREB signals, and therefore promoting Treg differentiation

Abstract

Alpinetin, a flavonoid compound extracted from the seeds of Alpinia katsumadai Hayata, has been demonstrated to exert massive biological properties. This study aimed to evaluate the effect of alpinetin on dextran sulfate sodium (DSS)-induced colitis, and elucidate the potential mechanisms. Alpinetin significantly alleviated colitis in mice, accompanied with restored Th17/Treg balance in colons. In vitro, alpinetin directly promoted Treg differentiation but exerted little effect on Th17 differentiation, and the action was in an aryl hydrocarbon receptor (AhR)-dependent manner. It acted as a potential AhR activator, evidenced by increased expression of CYP1A1, dissociation of AhR/HSP90 complexes, AhR nuclear translocation, XRE-driven luciferase reporter gene and DNA-binding activity of AhR/ARNT/XRE in T cells. Furthermore, alpinetin significantly promoted expression of miR-302 but not others, and restrained expression of DNMT-1 and methylation level of Foxp3 promoter region in CD4+ T cells and colons of colitis mice. However, the association of CREB and Foxp3 promoter region but not expression, nuclear translocation and DNA-binding activity of CREB was up-regulated by alpinetin in CD4+ T cells. The relationship of alpinetin-adjusted AhR activation, expressions of miR-302 and DNMT-1, association of CREB and Foxp3 promoter region, and Treg differentiation was confirmed by using CH223191, siAhR, miR-302 inhibitor and pcDNA3.1(+)-mDNMT-1. Finally, CH223191 abolished the amelioration of alpinetin on colitis, induction of Treg cells and regulation of miR-302/DNMT-1/CREB signals in colons of colitis mice. In conclusion, alpinetin ameliorated colitis in mice via activating AhR, regulating miR-302/DNMT-1/CREB signals, therefore promoting Treg differentiation.

Metabolic Profiling of Alpinetin in Rat Plasma, Urine, Bile and Feces after Intragastric Administration

“…It is considered as the primary active ingredient of Zingiberaceae ( Alpinia katsumadai Hayata) [2]. Modern pharmacological research shows a series of pharmacological activities that are involved in alpinetin, including anti-inflammatory [3,4,5,6], anti-cancer [7,8,9,10], anti-oxidant effects [11]. Alpinetin was found to improve the sensitivity of drug-resistant lung cancer cells to cis-diammined dichloridoplatium [10], which may be used as a potential drug for combination therapy.…”

Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome

“…139 Interestingly, alpinetin (an AHR agonist)-mediated AHR activation modulates miR-302/DNMT-1/CREB signaling, thereby increasing Treg differentiation and conferring protection against colitis. 140 Additionally, IEC-specific AHR deletion contributes to dysfunctional Wntβ-catenin signaling, which largely impairs the differentiation of ISCs into IECs due to unrestricted ISC proliferation, rendering mice susceptible to inflammation-induced colonic tumorigenesis. 141 This phenotype could subsequently be rescued via treatment with AHR agonists.…”

Phytochemical Regulation of RNA in Treating Inflammatory Bowel Disease and Colon Cancer: Inspirations from Cell and Animal Studies

“…In colitis mice, pineal hormone can up-regulate the expression of miR-302, down-regulate the expression of DNA methyl-1, promote the association of CREB and Foxp3 promoter region, and effectively alleviate colitis symptoms (Lv et al, 2018). miR-191a can down-regulate mRNA and protein levels of its target gene zonula occludes 1.…”