A constitutive active MAPK/ERK pathway due to BRAFV600E positively regulates AHR pathway in PTC

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor mediating the toxicity and tumor-promoting properties of dioxin. AHR has been reported to be overexpressed and constitutively active in a variety of solid tumors, but few data are currently available concerning its role in thyroid cancer. In this study we quantitatively explored a series of 51 paired-normal and papillary thyroid carcinoma (PTC) tissues for AHR-related genes. We identified an increased AHR expression/activity in PTC, independently from its nuclear dimerization partner and repressor but strictly related to a constitutive active MAPK/ERK pathway. The AHR up-regulation followed by an increased expression of AHR target genes was confirmed by a meta-analysis of published microarray data, suggesting a ligand-independent active AHR pathway in PTC. In-vitro studies using a PTC-derived cell line (BCPAP) and HEK293 cells showed that BRAF(V600E) may directly modulate AHR localization, induce AHR expression and activity in an exogenous ligand-independent manner. The AHR pathway might represent a potential novel therapeutic target for PTC in the clinical practice

Xenobiotic-induced activation of human aryl hydrocarbon receptor target genes in Drosophila is mediated by the epigenetic chromatin modifiers

Aryl hydrocarbon receptor (AHR) is the key transcription factor that controls animal development and various adaptive processes. The AHR\u27s target genes are involved in biodegradation of endogenous and exogenous toxins, regulation of immune response, organogenesis, and neurogenesis. Ligand binding is important for the activation of the AHR signaling pathway. Invertebrate AHR homologs are activated by endogenous ligands whereas vertebrate AHR can be activated by both endogenous and exogenous ligands (xenobiotics). Several studies using mammalian cultured cells have demonstrated that transcription of the AHR target genes can be activated by exogenous AHR ligands, but little is known about the effects of AHR in a living organism. Here, we examined the effects of human AHR and its ligands using transgenic Drosophila lines with an inducible human AhR gene. We found that exogenous AHR ligands can increase as well as decrease the transcription levels of the AHR target genes, including genes that control proliferation, motility, polarization, and programmed cell death. This suggests that AHR activation may affect the expression of gene networks that could be critical for cancer progression and metastasis. Importantly, we found that AHR target genes are also controlled by the enzymes that modify chromatin structure, in particular components of the epigenetic Polycomb Repressive complexes 1 and 2. Since exogenous AHR ligands (alternatively - xenobiotics) and small molecule inhibitors of epigenetic modifiers are often used as pharmaceutical anticancer drugs, our findings may have significant implications in designing new combinations of therapeutic treatments for oncological diseases. © Akishina et al

Aryl hydrocarbon receptor activation during in vitro and in vivo digestion of raw and cooked broccoli (brassica oleracea var. Italica)

Broccoli is rich in glucosinolates, which can be converted upon chewing and processing into Aryl hydrocarbon Receptor (AhR) ligands. Activation of AhR plays an important role in overall gut homeostasis but the role of broccoli processing on the generation of AhR ligands is still largely unknown. In this study, the effects of temperature, cooking method (steaming versus boiling), gastric pH and further digestion of broccoli on AhR activation were investigated in vitro and in ileostomy subjects. For the in vitro study, raw, steamed (t = 3 min and t = 6 min) and boiled (t = 3 min and t = 6 min) broccoli were digested in vitro with different gastric pH. In the in vivo ileostomy study, 8 subjects received a broccoli soup or a broccoli soup plus an exogenous myrosinase source. AhR activation was measured in both in vitro and in vivo samples by using HepG2-Lucia™ AhR reporter cells. Cooking broccoli reduced the AhR activation measured after gastric digestion in vitro, but no effect of gastric pH was found. Indole AhR ligands were not detected or detected at very low levels both after intestinal in vitro digestion and in the ileostomy patient samples, which resulted in no AhR activation. This suggests that the evaluation of the relevance of glucosinolates for AhR modulation in the gut cannot prescind from the way broccoli is processed, and that broccoli consumption does not necessarily produce substantial amounts of AhR ligands in the large intestine

Ginsenosides are novel naturally-occurring aryl hydrocarbon receptor ligands.

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates many of the biological and toxicological actions of structurally diverse chemicals. In this study, we examined the ability of a series of ginsenosides extracted from ginseng, a traditional Chinese medicine, to bind to and activate/inhibit the AHR and AHR signal transduction. Utilizing a combination of ligand and DNA binding assays, molecular docking and reporter gene analysis, we demonstrated the ability of selected ginsenosides to directly bind to and activate the guinea pig cytosolic AHR, and to stimulate/inhibit AHR-dependent luciferase gene expression in a recombinant guinea pig cell line. Comparative studies revealed significant species differences in the ability of ginsenosides to stimulate AHR-dependent gene expression in guinea pig, rat, mouse and human cell lines. Not only did selected ginsenosides preferentially activate the AHR from one species and not others, mouse cell line was also significantly less responsive to these chemicals than rat and guinea pig cell lines, but the endogenous gene CYP1A1 could still be inducted in mouse cell line. Overall, the ability of these compounds to stimulate AHR signal transduction demonstrated that these ginsenosides are a new class of naturally occurring AHR agonists

Dioxin Toxicity In Vivo Results from an Increase in the Dioxin-Independent Transcriptional Activity of the Aryl Hydrocarbon Receptor

The Aryl hydrocarbon receptor (Ahr) is the nuclear receptor mediating the toxicity of dioxins -widespread and persistent pollutants whose toxic effects include tumor promotion, teratogenesis, wasting syndrome and chloracne. Elimination of Ahr in mice eliminates dioxin toxicity but also produces adverse effects, some seemingly unrelated to dioxin. Thus the relationship between the toxic and dioxin-independent functions of Ahr is not clear, which hampers understanding and treatment of dioxin toxicity. Here we develop a Drosophila model to show that dioxin actually increases the in vivo dioxin-independent activity of Ahr. This hyperactivation resembles the effects caused by an increase in the amount of its dimerisation partner Ahr nuclear translocator (Arnt) and entails an increased transcriptional potency of Ahr, in addition to the previously described effect on nuclear translocation. Thus the two apparently different functions of Ahr, dioxin-mediated and dioxin-independent, are in fact two different levels (hyperactivated and basal, respectively) of a single function

Cytochrome P4501-inhibiting chemicals amplify aryl hydrocarbon receptor activation and IL-22 production in T helper 17 cells

The aryl hydrocarbon receptor (AHR)controls interleukin 22 production by T helper 17 cells (Th17). IL-22contributes to intestinalhomeostasis but has also been implicated inchronic inflammatory disorders and colorectal cancer, highlighting the need for appropriate regulation of IL-22 production. Upon activation, the AHR induces expression of cytochrome P4501 (CYP1) enzymes that in turn play an important feedback role that curtails the duration of AHR signaling by metabolizingAHRligands. Recently we described how agents that inhibit CYP1 function potentiate AHR signalingby disruptingmetabolic clearance of the endogenous ligand 6-formylindolo[3,2-b]carbazole (FICZ). In the present study, we investigated the immune-modulating effects of environmental pollutants such as polycyclic aromatic hydrocarbons on Th17 differentiation and IL-22 production. Using Th17 cells deficient in CYP1 enzymes (Cyp1a1/1a2/1b1-/-)we show that these chemicals potentiate AHR activation through inhibition of CYP1 enzymes which leads to increases in intracellular AHR agonists. Our findings demonstrate that IL-22 production by Th17 cellsis profoundly enhanced by impaired CYP1-function and strongly suggest that chemicals able to modify CYP1 function or expression may disrupt AHR-mediated immune regulation by altering the levels of endogenous AHR agonist(s)

Modelling sublimation and atomic layer epitaxy in the presence of competing surface reconstructions

We present a solid-on-solid model of a binary AB compound, where atoms of type A in the topmost layer interact via anisotropic interactions different from those inside the bulk. Depending on temperature and particle flux, this model displays surface reconstructions similar to those of (001) surfaces of II-VI semiconductors. We show, that our model qualitatively reproduces mamy of the characteristic features of these materials which have been observed during sublimation and atomic layer epitaxy. We predict some previously unknown effects which might be observed experimentally.Comment: 4 pages, 2 figures. New title, additional figures, minor changes in the text. See http://theorie.physik.uni-wuerzburg.de/~ahr/AB/ for surface images and MPEG movie

HLA class II antibodies at the time of kidney transplantation and cardiovascular outcome : a retrospective cohort study

Background. The negative role of HLA class II donor-specific antibody on graft outcome is well recognized. However, the potentially negative cardiovascular effects of preformed HLA class II antibodies and donor HLA in kidney transplant recipients (KTRs) remain unestablished. Methods. We conducted a single-center, retrospective cohort study including 1115 KTRs (2003–2016) with up to 4449 person-years of follow-up after transplantation and a median follow-up time of 5.1 years (interquartile range, 2.7–7.6). We evaluated the unadjusted and multivariable-adjusted association between pretransplant HLA class I and II antibodies, as well as HLA-DR1 donor/recipient genotype and the primary (major adverse cardiac and cerebrovascular event [MACCE] or all-cause mortality) and secondary (MACCE or cardiovascular mortality) outcome. Results. In a multivariate Cox proportional hazard model, HLA class II antibodies before transplantation were associated with increased adjusted hazard ratio (aHR) for MACCE or all-cause mortality (aHR, 1.71 [1.13–2.60]; P = 0.012) even after adjustment for time-varying covariate graft loss (aHR, 1.68 [1.08–2.62]; P = 0.022) and biopsy-proven acute rejection (aHR, 1.71 [1.13–2.60]; P = 0.012). HLA class II antibodies were also associated with increased aHR for the secondary outcome, MACCE, or cardiovascular mortality (aHR, 1.92 [1.12–3.30]; P = 0.018). We investigated the effect of donor and recipient HLA-DR1 on these outcome parameters and demonstrated that KTRs with HLA-DR1 positive donors had an increased aHR for MACCE with all-cause (aHR, 1.45 [1.09–1.94]; P = 0.012) and cardiovascular mortality (aHR, 1.49 [1.00–2.22]; P = 0.05). Conclusions. Prior sensitization against HLA class II antigens is associated with unfavorable long-term cardiovascular outcome in KTRs independent of graft loss or rejection. Recipients of an HLA-DR1 donor also have an impaired cardiovascular outcome