The Aryl Hydrocarbon Receptor (AhR) Mediates the Counter-Regulatory Effects of Pelargonidins in Models of Inflammation and Metabolic Dysfunctions

Abstract

Pelargonidins are anthocyanidins thought to be beneficial for the human health, although controversies exist over the doses needed and the unclear mechanism of action, along with poor systemic bioavailability. One putative target of pelargonidins is the aryl hydrocarbon receptor (AhR). A synthetic pelargonidin (Mt-P) was synthesized by the methylation of the pelargonidin (the natural compound indicated as P). Mt-P transactivated the AhR with an EC50 of 1.97 µM and was ~2-fold more potent than the natural compound. In vitro Mt-P attenuated pro-inflammatory activities of Raw264.7 macrophage cells in an AhR-dependent manner. In vivo, administration of the Mt-P in Balb/c mice resulted in a dose-dependent attenuation of signs and symptoms of colitis induced by TNBS. A dose of 5 mg/kg Mt-P, but not the natural compound P, reversed intestinal inflammation and increased expression of Tnf-α, Ifn-ƴ, and Il-6, while promoted the expansion of regulatory T cells and M2 macrophages. In C57BL/6J mice fed a high fat diet (HFD), Mt-P attenuated body weight gain, intestinal and liver inflammation, and ameliorated insulin sensitivity, while worsened liver steatosis by up-regulating the liver expression of Cd36 and Apo100b. These effects were abrogated by AhR gene ablation. Mt-P is a synthetic pelargonidin endowed with robust AhR agonist activity that exerts beneficial effects in murine models of inflammation and metabolic dysfunction.

Cornelian Cherry Iridoid-Polyphenolic Extract Improves Mucosal Epithelial Barrier Integrity in Rat Experimental Colitis and Exerts Antimicrobial and Antiadhesive Activities In Vitro

“…The impact of polyphenols containing plant extracts [ 42 , 43 , 63 , 64 ] or pure phenolic compounds [ 65 , 66 ] on TNF- α and IL-17 colonic levels was studied by some other research studies. Furthermore, it is noteworthy that in TNBS-subjected rats, one of the polyphenol groups, anthocyanins, especially pelargonidin, not only reversed intestinal inflammation and increased expression of TNF- α and IL-6 but also promoted the anti-inflammatory M2 macrophage expansion, which is inhibited by chemerin [ 67 ]. We did not find any previous studies investigating the impact of polyphenolic compounds, including cornelian cherry extract on chemerin tissue levels during TNBS colitis.…”

Discovery of a AhR flavonoid agonist that counter-regulates ACE2 expression in rodent models of inflammation and attenuates ACE2-SARS-CoV2 interaction in vitro

“…While, similarly to other anthocyanins, pelargonidin is thought to be beneficial for human health [23–25], controversies exist over the doses needed to reach these effects, along with poor systemic bioavailability and unclear mechanism(s) of action. In a previous study we have shown that the natural pelargonidin function as AhR ligand in vitro and attenuates intestinal inflammation in AhR-dependent manner [26]. In the present study we have investigated the potential of the natural pelargonidin in regulating ACE2 expression in colon in models of intestinal inflammation caused by exposure of wild type and AhR −/− mice to a high caloric intake and intestinal irritants.…”

“…In a previous study we have shown that the natural pelargonidin function as AhR ligand in vitro and attenuates intestinal inflammation in AhR-dependent manner [26]. In the present study we have investigated the potential of the natural pelargonidin in regulating ACE2 expression in colon in models of intestinal inflammation caused by exposure of wild type and AhR -/mice to a high caloric intake and intestinal irritants.…”

Regulation of Intestinal Inflammation by Dietary Fats

“…Furthermore, AhR is targeted by pelargonidins, a type of anthocyanidins thought to be beneficial for overall human health. A synthetic pelargonidin (Mt-P) transactivates AhR, and has been shown, in HFD-fed C57BL/6J mice, to attenuate body weight gain, intestinal and liver inflammation, and ameliorate insulin sensitivity, while worsening liver steatosis, of which were abrogated by gene ablation of AhR ( 232 ). Another study in DSS-colitis rats explored the effects of the anthocyanin, pelargonidin 3-glucoside (P3G), on IBD and metabolic syndrome.…”