Plant Occurring Flavonoids as Modulators of the Aryl Hydrocarbon Receptor

Abstract

The aryl hydrocarbon receptor (AhR) is a transcription factor deeply implicated in health and diseases. Historically identified as a sensor of xenobiotics and mainly toxic substances, AhR has recently become an emerging pharmacological target in cancer, immunology, inflammatory conditions, and aging. Multiple AhR ligands are recognized, with plant occurring flavonoids being the largest group of natural ligands of AhR in the human diet. The biological implications of the modulatory effects of flavonoids on AhR could be highlighted from a toxicological and environmental concern and for the possible pharmacological applicability. Overall, the possible AhR-mediated harmful and/or beneficial effects of flavonoids need to be further investigated, since in many cases they are contradictory. Similar to other AhR modulators, flavonoids commonly exhibit tissue, organ, and species-specific activities on AhR. Such cellular-context dependency could be probably beneficial in their pharmacotherapeutic use. Flavones, flavonols, flavanones, and isoflavones are the main subclasses of flavonoids reported as AhR modulators. Some of the structural features of these groups of flavonoids that could be influencing their AhR effects are herein summarized. However, limited generalizations, as well as few outright structure-activity relationships can be suggested on the AhR agonism and/or antagonism caused by flavonoids.

Lactobacillus plantarum FNCC 0137 fermented red Moringa oleifera exhibits protective effects in mice challenged with Salmonella typhi via TLR3/TLR4 inhibition and down-regulation of proinflammatory cytokines

“…The balance between Tregs and effector T cells reflects the immune homeostasis [ 61 ]. A previous study reported that quercetin and other flavonoids could modulate the aryl hydrocarbon receptor (Ahr), which further influenced Tregs' activation via Foxp3, the main transcription factor for Tregs [ [62] , [63] , [64] ]. On the other hand, the activation of heme oxygenase-1 (HO1) via the Nrf2/HO-1 signaling pathway is reported to increase Foxp3 expression.…”

Mediterranean Diet as a Shield against Male Infertility and Cancer Risk Induced by Environmental Pollutants: A Focus on Flavonoids

“…Indeed, it is known that testicular functions (i.e., spermatogenesis and sperm motility), and hence male fertility, are affected by activation of AHR induced by environmental toxicants [223]. Therefore, AhR has been studied as an interesting target of pollutant-induced cancers and, specifically, natural products, among which flavonoids, have seized the attention of the scientific community in these regards [224]. In particular, the isoflavone genistein from soy was showed to hamper TCDD-dependent downregulation and methylation of BRCA-1, whose alteration is known to play a pivotal role in the onset of breast cancer, along with decreasing levels of DNMT-1 and cyclin D1 in MCF-7 cells, proving the role of genistein in counteracting ER (estrogen receptor) α-positive breast cancer cells via antagonizing AhR [225].…”

Flavonoid mediated selective cross-talk between plants and beneficial soil microbiome

“…Plant flavonoids are polyphenolic chemicals obtained mostly from vegetables, nuts, seeds, and fruits that are important components of green tea and cocoa-based beverages. Flavonoids have been proven to show anticancer effects through a variety of mechanisms, including anti-oxidation, inactivation of carcinogen, apoptosis induction, angiogenesis inhibition, and alterations of multidrug resistance (Goya-Jorge et al 2021 ; Kapoor et al 2021 ). Consumption of flavonoids has been demonstrated to have cardiovascular and antithrombotic therapeutic benefits due to antiplatelet action.…”