Search Results (18)

Pharmacological compounds can disrupt glucose homeostasis, leading to impaired glucose tolerance, hyperglycemia, or newly diagnosed diabetes, as well as worsening glycemic control in patients with pre-existing diabetes. Traditional risk factors alone cannot explain the rapidly growing global incidence of diabetes. Therefore, prevention of insulin resistance could represent an effective strategy. Achieving this goal requires a deeper understanding of the mechanisms underlying the development of insulin resistance, with particular attention to the aryl hydrocarbon receptor (AhR). AhR, a transcription factor functioning as a xenobiotic sensor, plays a key role in various molecular pathways regulating normal homeostasis, organogenesis, and immune function. Activated by a range of exogenous and endogenous ligands, AhR is involved in the regulation of glucose and lipid metabolism as well as insulin sensitivity. However, current findings remain contradictory regarding whether AhR activation exerts beneficial or detrimental effects. This narrative review summarizes recent studies exploring the role of the AhR pathway in insulin secretion and glucose homeostasis across different tissues, and discusses molecular mechanisms involved in this process. Considering that several drugs act as AhR ligands, the review also compares how these ligands affect metabolic pathways of glucose and lipid metabolism and insulin sensitivity, producing either positive or negative effects. Full article

The oxygen-sensing pathway is a crucial regulatory circuit that defines cellular conditions and is extensively exploited in cancer development. Pathogenic mutations in the von Hippel–Lindau (VHL) tumour suppressor impair its role as a master regulator of hypoxia-inducible factors (HIFs), leading to constitutive HIF activation and uncontrolled angiogenesis, increasing the risk of developing clear cell renal cell carcinoma (ccRCC). HIF hyperactivation can sequester HIF-1β, preventing the aryl hydrocarbon receptor (AHR) from correctly activating gene expression in response to endogenous and exogenous ligands such as TCDD (dioxins). In this study, we used protein–protein interaction networks and gene expression profiling to characterize the impact of VHL loss on AHR activity. Our findings reveal specific expression patterns of AHR interactors following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in ccRCC. We identified several AHR interactors significantly associated with poor survival rates in ccRCC patients. Notably, the upregulation of the androgen receptor (AR) and retinoblastoma-associated protein (RB1) by TCDD, coupled with their respective downregulation in ccRCC and association with poor survival rates, suggests novel therapeutic targets. The strategic activation of the AHR via selective AHR modulators (SAhRMs) could stimulate its anticancer activity, specifically targeting RB1 and AR to reduce cell cycle progression and metastasis formation in ccRCC. Our study provides comprehensive insights into the complex interplay between the AHR and HIF pathways in ccRCC pathogenesis, offering novel strategies for targeted therapeutic interventions. Full article

The vast majority of gastric cancer (GC) cases are adenocarcinomas including intestinal and diffuse GC. The incidence of diffuse GC, often associated with poor overall survival, has constantly increased in Western countries. Epidemiological studies have reported increased mortality from GC after occupational exposure to pro-carcinogens that are metabolically activated by cytochrome P450 enzymes through aryl hydrocarbon receptor (AhR). However, little is known about the role of AhR and environmental AhR ligands in diffuse GC as compared to intestinal GC in Western patients. In a cohort of 29, we demonstrated a significant increase in AhR protein and mRNA expression levels in GCs independently of their subtypes and clinical parameters. AhR and RHOA mRNA expression were correlated in diffuse GC. Further, our study aimed to characterize in GC how AhR and the AhR-related genes cytochrome P450 1A1 (CYP1A1) and P450 1B1 (CYP1B1) affect the mRNA expression of a panel of genes involved in cancer development and progression. In diffuse GC, CYP1A1 expression correlated with genes involved in IGF signaling, epithelial–mesenchymal transition (Vimentin), and migration (MMP2). Using the poorly differentiated KATO III epithelial cell line, two well-known AhR pollutant ligands, namely 2-3-7-8 tetrachlorodibenzo-p-dioxin (TCDD) and benzo[a]pyrene (BaP), strongly increased the expression of CYP1A1 and Interleukin1β (IL1B), and to a lesser extend UGT1, NQO1, and AhR Repressor (AhRR). Moreover, the increased expression of CYP1B1 was seen in diffuse GC, and IHC staining indicated that CYP1B1 is mainly expressed in stromal cells. TCDD treatment increased CYP1B1 expression in KATO III cells, although at lower levels as compared to CYP1A1. In intestinal GC, CYP1B1 expression is inversely correlated with several cancer-related genes such as IDO1, a gene involved in the early steps of tryptophan metabolism that contributes to the endogenous AhR ligand kynurenine expression. Altogether, our data provide evidence for a major role of AhR in GC, as an environmental xenobiotic receptor, through different mechanisms and pathways in diffuse and intestinal GC. Our results support the continued efforts to clarify the identity of exogenous AhR ligands in diffuse GC in order to define new therapeutic strategies. Full article

Although our skin is not the primary visual organ in humans, it acts as a light sensor, playing a significant role in maintaining our health and overall well-being. Thanks to the presence of a complex and sophisticated optotransduction system, the skin interacts with the visible part of the electromagnetic spectrum and with ultraviolet (UV) radiation. Following a brief overview describing the main photosensitive molecules that detect specific electromagnetic radiation and their associated cell pathways, we analyze their impact on physiological functions such as melanogenesis, immune response, circadian rhythms, and mood regulation. In this paper, we focus on 6-formylindolo[3,2-b]carbazole (FICZ), a photo oxidation derivative of the essential amino acid tryptophan (Trp). This molecule is the best endogenous agonist of the Aryl hydrocarbon Receptor (AhR), an evolutionarily conserved transcription factor, traditionally recognized as a signal transducer of both exogenous and endogenous chemical signals. Increasing evidence indicates that AhR is also involved in light sensing within the skin, primarily due to its ligand FICZ, which acts as both a chromophore and a photosensitizer. The biochemical reactions triggered by their interaction impact diverse functions and convey crucial data to our body, thus adding a piece to the complex puzzle of pathways that allow us to decode and elaborate environmental stimuli. Full article

The aryl hydrocarbon receptor (AhR) is a decisive regulatory ligand-dependent transcription factor. It binds highly diverse ligands, which can be categorized as either endogenous or exogenous. Ligand binding activates AhR, which can adjust inflammatory responses by modulating immune cells such as dendritic cells (DCs). However, how different AhR ligand classes impact the phenotype and function of human monocyte-derived DCs (hMoDCs) has not been extensively studied in a comparative manner. We, therefore, tested the effect of the representative compounds Benzo(a)pyrene (BP), 6-formylindolo[3,2-b]carbazole (FICZ), and Indoxyl 3-sulfate (I3S) on DC biology. Thereby, we reveal that BP significantly induces a tolerogenic response in lipopolysaccharide-matured DCs, which is not apparent to the same extent when using FICZ or I3S. While all three ligand classes activate AhR-dependent pathways, BP especially induces the expression of negative immune regulators, and subsequently strongly subverts the T cell stimulatory capacity of DCs. Using the CRISPR/Cas9 strategy we also prove that the regulatory effect of BP is strictly AhR-dependent. These findings imply that AhR ligands contribute differently to DC responses and incite further studies to uncover the mechanisms and molecules which are involved in the induction of different phenotypes and functions in DCs upon AhR activation. Full article

The aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, is important for xenobiotic metabolism and binds to various endogenous and exogenous ligands present in the skin. AhR is known to be associated with diseases in various organs; however, its functions in chronic inflammatory skin diseases, such as atopic dermatitis (AD) and psoriasis (PS), have recently been elucidated. Here, we discuss the molecular mechanisms of AhR related to chronic inflammatory skin diseases, such as AD and PS, and the mechanisms of action of AhR on the skin immune system. The importance of AhR molecular biological pathways, clinical features in animal models, and AhR ligands in skin diseases need to be investigated. In conclusion, the therapeutic effects of AhR ligands are demonstrated based on the relationship between AhR and skin diseases. Nevertheless, further studies are required to elucidate the detailed roles of AhR in chronic inflammatory skin diseases. Full article

Aryl hydrocarbon receptor (AHR) is an important regulator of skin barrier function. It also controls immune-mediated skin responses. The AHR modulates various physiological functions by acting as a sensor that mediates environment–cell interactions, particularly during immune and inflammatory responses. Diverse experimental systems have been used to assess the AHR’s role in skin inflammation, including in vitro assays of keratinocyte stimulation and murine models of psoriasis and atopic dermatitis. Similar approaches have addressed the role of AHR ligands, e.g., TCDD, FICZ, and microbiota-derived metabolites, in skin homeostasis and pathology. Tapinarof is a novel AHR-modulating agent that inhibits skin inflammation and enhances skin barrier function. The topical application of tapinarof is being evaluated in clinical trials to treat psoriasis and atopic dermatitis. In the present review, we summarize the effects of natural and synthetic AHR ligands in keratinocytes and inflammatory cells, and their relevance in normal skin homeostasis and cutaneous inflammatory diseases. Full article

In recent years, aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, has been considered to be involved in aging phenotypes across several species. This receptor is a highly conserved biosensor that is activated by numerous exogenous and endogenous molecules, including microbiota metabolites, to mediate several physiological and toxicological functions. Brain aging hallmarks, which include glial cell activation and inflammation, increased oxidative stress, mitochondrial dysfunction, and cellular senescence, increase the vulnerability of humans to various neurodegenerative diseases. Interestingly, many studies have implicated AhR signaling pathways in the aging process and longevity across several species. This review provides an overview of the impact of AhR pathways on various aging hallmarks in the brain and the implications for AhR signaling as a mechanism in regulating aging-related diseases of the brain. We also explore how the nature of AhR ligands determines the outcomes of several signaling pathways in brain aging processes. Full article

The aryl-hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates numerous cellular responses. Originally investigated in toxicology because of its ability to bind environmental contaminants, AhR has attracted enormous attention in the field of immunology in the last 20 years. In addition, the discovery of endogenous and plant-derived ligands points to AhR also having a crucial role in normal cell physiology. Thus, AhR is emerging as a promiscuous receptor that can mediate either toxic or physiologic effects upon sensing multiple exogenous and endogenous molecules. Within this scenario, several factors appear to contribute to the outcome of gene transcriptional regulation by AhR, including the nature of the ligand as such and its further metabolism by AhR-induced enzymes, the local tissue microenvironment, and the presence of coregulators or specific transcription factors in the cell. Here, we review the current knowledge on the array of transcription factors and coregulators that, by interacting with AhR, tune its transcriptional activity in response to endogenous and exogenous ligands. Full article

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that has emerged as an important player in asthma control. AhR is responsive to environmental molecules and endogenous or dietary metabolites and regulates innate and adaptive immune responses. Binding of this receptor by different ligands has led to seemingly opposite responses in different asthma models. In this review, we present two sides of the same coin, with the beneficial and deleterious roles of AhR evaluated using known endogenous or exogenous ligands, deficient mice or antagonists. On one hand, AhR has an anti-inflammatory role since its activation in dendritic cells blocks the generation of pro-inflammatory T cells or shifts macrophages toward an anti-inflammatory M2 phenotype. On the other hand, AhR activation by particle-associated polycyclic aromatic hydrocarbons from the environment is pro-inflammatory, inducing mucus hypersecretion, airway remodelling, dysregulation of antigen presenting cells and exacerbates asthma features. Data concerning the role of AhR in cells from asthmatic patients are also reviewed, since AhR could represent a potential target for therapeutic immunomodulation. Full article

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that plays a crucial role in bone remodeling through altering the interplay between bone-forming osteoblasts and bone-resorbing osteoclasts. While effects of AhR signaling in osteoblasts are well understood, the role and mechanism of AhR signaling in regulating osteoclastogenesis is not widely understood. AhR, when binding with exogenous ligands (environmental pollutants such as polycylic aryl hydrocarbon (PAH), dioxins) or endogenous ligand indoxyl-sulfate (IS), has dual functions that are mediated by the nature of the binding ligand, binding time, and specific pathways of distinct ligands. In this review, AhR is discussed with a focus on (i) the role of AhR in osteoclast differentiation and function and (ii) the mechanisms of AhR signaling in inhibiting or promoting osteoclastogenesis. These findings facilitate an understanding of the role of AhR in the functional regulation of osteoclasts and in osteoclast-induced bone destructive conditions such as rheumatoid arthritis and cancer. Full article

The aryl hydrocarbon receptor (AhR) is a nuclear protein which, upon association with certain endogenous and exogenous ligands, translocates into the nucleus, binds DNA and regulates gene expression. Tryptophan (Trp) metabolites are one of the most important endogenous AhR ligands. The intestinal microbiota is a critical player in human intestinal homeostasis. Many of its effects are mediated by an assembly of metabolites, including Trp metabolites. In the intestine, Trp is metabolized by three main routes, leading to kynurenine, serotonin, and indole derivative synthesis under the direct or indirect involvement of the microbiota. Disturbance in Trp metabolism and/or AhR activation is strongly associated with multiple gastrointestinal, neurological and metabolic disorders, suggesting Trp metabolites/AhR signaling modulation as an interesting therapeutic perspective. In this review, we describe the most recent advances concerning Trp metabolism and AhR signaling in human health and disease, with a focus on nutrition as a potential therapy to modulate Trp metabolites acting on AhR. A better understanding of the complex balance between these pathways in human health and disease will yield therapeutic opportunities. Full article

Ever since the 1970s, when profound immunosuppression caused by exogenous dioxin-like compounds was first observed, the involvement of the aryl hydrocarbon receptor (AHR) in immunomodulation has been the focus of considerable research interest. Today it is established that activation of this receptor by its high-affinity endogenous ligand, 6-formylindolo[3,2-b]carbazole (FICZ), plays important physiological roles in maintaining epithelial barriers. In the gut lumen, the small amounts of FICZ that are produced from L-tryptophan by microbes are normally degraded rapidly by the inducible cytochrome P4501A1 (CYP1A1) enzyme. This review describes how when the metabolic clearance of FICZ is attenuated by inhibition of CYP1A1, this compound passes through the intestinal epithelium to immune cells in the lamina propria. FICZ, the level of which is thus modulated by this autoregulatory loop involving FICZ itself, the AHR and CYP1A1, plays a central role in maintaining gut homeostasis by potently up-regulating the expression of interleukin 22 (IL-22) by group 3 innate lymphoid cells (ILC3s). IL-22 stimulates various epithelial cells to produce antimicrobial peptides and mucus, thereby both strengthening the epithelial barrier against pathogenic microbes and promoting colonization by beneficial bacteria. Dietary phytochemicals stimulate this process by inhibiting CYP1A1 and causing changes in the composition of the intestinal microbiota. The activity of CYP1A1 can be increased by other microbial products, including the short-chain fatty acids, thereby accelerating clearance of FICZ. In particular, butyrate enhances both the level of the AHR and CYP1A1 activity by stimulating histone acetylation, a process involved in the daily cycle of the FICZ/AHR/CYP1A1 feedback loop. It is now of key interest to examine the potential involvement of FICZ, a major physiological activator of the AHR, in inflammatory disorders and autoimmunity. Full article

Aryl hydrocarbon receptor (AhR), an evolutionary conserved transcription factor, is a pleiotropic signal transductor. Thanks to its promiscuous ligand binding domain, during the evolution of eukaryotic cells its developmental functions were integrated with biosensor functions. Its activation by a multitude of endogenous and exogenous molecules stimulates its participation in several pathways, some of which are linked to inflammation and breast cancer (BC). Over time, the study of this malignancy has led to the identification of several therapeutic targets in cancer cells. An intense area of study is dedicated to BC phenotypes lacking adequate targets. In this context, due to its high constitutive activation in BC, AhR is currently gaining more and more attention. In this review, I have considered its interactions with: 1. the immune system, whose dysregulation is a renowned cancer hallmark; 2. interleukin 6 (IL6) which is a pivotal inflammatory marker and is closely correlated to breast cancer risk; 3. NF-kB, another evolutionary conserved transcription factor, which plays a key role in immunoregulatory functions, inflammatory response and breast carcinogenesis; 4. kynurenine, a tryptophan-derived ligand that activates and bridges AhR to chronic inflammation and breast carcinogenesis. Overall, the data here presented form an interesting framework where AhR is an interesting connector between inflammation and BC. Full article

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that senses environmental exogenous and endogenous ligands or xenobiotic chemicals. In particular, exposure of the liver to environmental metabolism-disrupting chemicals contributes to the development and propagation of steatosis and hepatotoxicity. However, the mechanisms for AhR-induced hepatotoxicity and tumor propagation in the liver remain to be revealed, due to the wide variety of AhR ligands. Recently, quantitative structure–activity relationship (QSAR) analysis using deep neural network (DNN) has shown superior performance for the prediction of chemical compounds. Therefore, this study proposes a novel QSAR analysis using deep learning (DL), called the DeepSnap–DL method, to construct prediction models of chemical activation of AhR. Compared with conventional machine learning (ML) techniques, such as the random forest, XGBoost, LightGBM, and CatBoost, the proposed method achieves high-performance prediction of AhR activation. Thus, the DeepSnap–DL method may be considered a useful tool for achieving high-throughput in silico evaluation of AhR-induced hepatotoxicity. Full article