TY - JOUR. T1 - Indole scaffolds as a promising class of the aryl hydrocarbon receptor ligands. AU - Dvořák, Zdeněk. AU - Poulíková, Karolína. AU - Mani, Sridhar. N1 - Funding Information: We acknowledge financial support from the Czech Science Foundation [19-00236S]; the student grant from Palack? University in Olomouc [PrF-2021-005]. Funding Information: We acknowledge financial support from the Czech Science Foundation [ 19-00236S ]; the student grant from Palacký University in Olomouc [ PrF-2021-005 ]. Publisher Copyright: © 2021 Elsevier Masson SAS. PY - 2021/4/5. Y1 - 2021/4/5. N2 - The aryl hydrocarbon receptor (AhR), deemed initially as a xenobiotic sensor, plays multiple physiological roles and is involved in various pathophysiological processes and many diseases etiology. Therefore, the therapeutic and chemopreventive targeting of AhR is a fundamental issue. To date, thousands of structurally diverse ligands of AhR have been identified. The bottleneck in targeting the AhR is ...
Epithelia function as barriers against environmental insults and express the transcription factor aryl hydrocarbon receptor (AhR). However, AhR function in these tissues is unknown. Here we show that AhR regulates multiciliogenesis in both murine airway epithelia and in Xenopus laevis epidermis. In air-exposed airway epithelia, induction of factors required for multiciliogenesis, including cyclin O (Ccno) and Multicilin (Mcidas), is AhR dependent, and air exposure induces AhR binding to the Ccno promoter. Submersion and hypoxic conditions impede AhR-dependent Ccno induction. This is mediated by the persistence of Notch signalling, as Notch blockade renders multiciliogenesis and Ccno induction by AhR independent from air exposure. In contrast to Ccno induction, air exposure does not induce the canonical AhR target cytochrome P450 1a1 (Cyp1a1). Inversely, exposure to AhR ligands induces Cyp1a1 but not Ccno and impeded ciliogenesis. These data indicate that AhR involvement in detoxification of ...
TY - JOUR. T1 - Expression of aryl hydrocarbon receptor mRNA in porcine retina. AU - Singh, A. K.. AU - Ko, M. S.H.. AU - Shichi, H.. PY - 1996/2/15. Y1 - 1996/2/15. N2 - Purpose. The aryl hydrocarbon receptor (AHR) mediates CYP1A1/1A2 induction by aryl hydrocarbons (e.g. TCDD). AHR proteins are similar to steroid receptors in their mechanism of action but constitute a distinct molecular family (1). In addition to a role in drug metabolism, it was suggested that AHR may regulate the homeostasis and cell differentiation (2). Two Drosophila proteins Sim and Per which are homologous to AHR appear to play roles in neural development and circadian rhythm, respectively. AHR may also have a function in mammalian retina. In this study, therefore, we investigated whether AHR mRNA is expressed in porcine retina. Methods. cDNA was synthesized from porcine retina RNA by RT-PCR using primers designed from mouse AHR cDNA and cloned into pCRTM II vector. DNA was sequenced with SP6 and T7 primers and analyzed ...
Bioflavonoids are plant compounds touted for their potential to treat or prevent several diseases including cancers induced by common environmental chemicals. Much of the biologic activity of one such class of pollutants, polycyclic aromatic hydrocarbons (PAH), is mediated by the aryl hydrocarbon receptor/transcription factor (AhR). For example, the AhR regulates PAH immunotoxicity that manifests as pre-B cell apoptosis in models of B cell development. Because bioflavonoids block PAH-induced cell transformation and are structurally similar to AhR ligands, it was postulated that some of them would suppress PAH-induced, AhR-dependent immunotoxicity, possibly through a direct AhR blockade. This hypothesis was tested using a model of B cell development in which pre-B cells are cultured with and are dependent on bone marrow stromal or hepatic parenchymal cell monolayers. Of seven bioflavonoids screened, galangin (3,5,7-trihydroxyflavone) blocked PAH-induced but not C(2)-ceramide- or H(2)O(2)-induced ...
The aryl hydrocarbon receptor (AhR) is a transcription factor belonging to the Per-ARNT-Sim family of proteins. These proteins sense molecules and stimuli from the cellular/tissue environment, and initiate signaling cascades to elicit appropriate cellular responses. Recent literature suggests an important function of AhR in hematopoietic stem cell (HSC) biology. However, the molecular mechanisms by which AhR signaling regulates HSC functions are unknown. In previous studies, we and others reported that treatment of mice with the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) compromises the competitive reconstitution of bone marrow (BM) cells into irradiated host animals. Additional studies indicated a requirement for AhR in hematopoietic cells and not marrow microenvironment cells. In this study, we tested the hypothesis that TCDD-mediated phenotypic and functional changes of HSCs are a result of changes in gene expression that disrupt stem cell numbers and/or their migration. TCDD ...
The ligand-dependent transcription factor aryl hydrocarbon receptor (AhR) has been implicated in various immune functions. Our previous studies have shown that AhR activation by exposure of ovalbumin (OVA)-immunized mice to the potent ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases immunization-induced IFN- production in the spleen and suppresses the production of Th2 cytokines and OVA-specific antibodies. In the present study, we used transgenic (Tg) mice that express a constitutively active mutant of aryl hydrocarbon receptor (CA-AhR) specifically in T-lineage cells to clarify the role of AhR activation in T cells in these reactions. The results of this study clearly demonstrated that AhR activation only in the T cells augments IFN- production upon OVA immunization. By contrast, production of Th2 cytokines and antibodies were not significantly suppressed by CA-AhR in the T cells. These results suggest that suppression of Th2 cytokines and antibodies production require AhR ...
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the prototypic ligand for the aryl hydrocarbon receptor (AhR), promotes tumor formation in some model systems. However, with regard to breast cancer, epidemiological and animal studies are inconclusive as to whether exposure increases tumor incidence or may instead be protective. We have previously reported that mice exposed to TCDD during pregnancy have impaired differentiation of mammary tissue, including decreased branching and poor development of lobuloalveolar structures. Because normal pregnancy-induced mammary differentiation may protect against subsequent neoplastic transformation, we hypothesized that TCDD-treated mice would be more susceptible to chemical carcinogenesis after parturition. To test this, mice were treated with TCDD or vehicle during pregnancy. Four weeks later, 7,12-dimethylbenz[a]anthracene (DMBA) was administered to induce mammary tumor formation. Contrary to our hypothesis, TCDD-exposed parous mice showed a 4-week delay in ...
Synonyms: AH receptor-interacting protein, AIP, Aryl-hydrocarbon receptor-interacting protein, HBV X-associated protein 2, XAP-2, Immunophilin homolog ARA9, XAP2, ARA9, FKBP16, FKBP37, SMTPHN.. ...
TY - JOUR. T1 - Mechanism of action and development of selective aryl hydrocarbon receptor modulators for treatment of hormone-dependent cancers (Review).. AU - Safe, Stephen. AU - McDougal, Andrew. PY - 2002/6. Y1 - 2002/6. N2 - Ligand-activated receptors are extensively used as targets for developing tissue-selective drugs for treatment of multiple diseases including cancers. The aryl hydrocarbon receptor (AhR) is a basic helix-loop-helix transcription factor that binds both synthetic chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and naturally-occurring phytochemicals, sterols and heme breakdown products. The high affinity ligand TCDD induces several AhR-mediated changes in gene expression, tissue/species-specific toxicities, and both tumorigenic and anticarcinogenic responses including inhibition of estrogen-dependent mammary and uterine tumor formation and growth. Research in this laboratory has demonstrated that TCDD inhibits E2-induced responses in the rodent uterus and ...
Patients with ER-negative breast tumors are among the most difficult to treat and exhibit low survival rates due, in part, to metastasis from the breast to various distal sites. Aryl hydrocarbon receptor (AHR) ligands show promise as antimetastatic drugs for estrogen receptor (ER)-negative breast cancer. Triple negative MDA-MB-231 breast cancer cells were treated with eight AHR-active pharmaceuticals including 4-hydroxtamoxifen, flutamide leflunomide, mexiletine, nimodipine, omeprazole, sulindac and tranilast, and the effects of these compounds on cell proliferation (MTT assay) and cell migration (Boyden chamber assay) were examined. The role of the AHR in mediating inhibition of MDA-MB-231 cell invasion was investigated by RNA interference (RNAi) and knockdown of AHR or cotreatment with AHR agonists. Lung metastasis of MDA-MB-231 cells was evaluated in mice administered cells by tail vein injection and prometastatic gene expression was examined by immunohistochemistry. We showed that only the proton
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that upon activation by the toxicant 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) stimulates gene expression and toxicity. AHR is also important for normal mouse physiology and may play a role in cancer progression in the absence of environmental toxicants. The objective of this report was to identify AHR-dependent genes (ADGs) whose expression is regulated by AHR in the absence of toxicants. RNA-Seq analysis revealed that AHR regulated the expression of over 600 genes at an FDR | 10% in MCF-7 breast cancer cells upon knockdown with short interfering RNA. Pathway analysis revealed that a significant number of ADGs were components of TCDD and tumor necrosis factor (TNF) pathways. We also demonstrated that siRNA knockdown of AHR modulated TNF induction of MNSOD and cytotoxicity in MCF-7 cells. Collectively, the major new findings of this report are: (1) endogenous AHR promotes the expression of xenobiotic metabolizing enzymes
Diesel exhaust contains numerous toxic substances that show different modes of action such as triggering aryl hydrocarbon receptor (AhR)-mediated pathways. We investigated AhR-mediated activity of exhaust generated by a heavy-duty diesel engine operated with or without iron- or copper/iron-catalyzed diesel particulate filters (DPFs). AhR agonists were quantified using the DR-CALUX reporter gene assay (exposure of cells for 24 h). We found 54-60 ng 2,3,7,8-tetrachlorodibenzo-p-dioxin CALUX equivalents (TCDD-CEQs) per m3 of exhaust in unfiltered samples and 6-16 ng TCDD-CEQ m3 in DPF-treated samples. DPF applications decreased TCDD-CEQ concentrations by almost 90%. Concentrations of known AhR agonists were determined with GC/HRMS and converted to TCDD-CEQ concentrations using compound-specific relative potency values. The analyzed nine polycyclic aromatic hydrocarbons (PAHs) and the 172,3,7,8-chlorinated dibenzodioxins/furans (23,7,8-PCDD/Fs) contributed only marginally (0.6-1.6%) to the total ...
The aryl hydrocarbon receptor (AHR) is critically involved in several physiologic processes, including cancer progression and multiple immune system activities. We, and others, have hypothesized that AHR modulators represent an important new class of targeted therapeutics. Here, ligand shape-based virtual modeling techniques were used to identify novel AHR ligands on the basis of previously identified chemotypes. Four structurally unique compounds were identified. One lead compound, 2-((2-(5-bromofuran-2-yl)-4-oxo-4H-chromen-3-yl)oxy)acetamide (CB7993113), was further tested for its ability to block three AHR-dependent biologic activities: triple-negative breast cancer cell invasion or migration in vitro and AHR ligand-induced bone marrow toxicity in vivo. CB7993113 directly bound both murine and human AHR and inhibited polycyclic aromatic hydrocarbon (PAH)- and TCDD-induced reporter activity by 75% and 90% respectively. A novel homology model, comprehensive agonist and inhibitor titration ...
Cigarette smoke exposure is associated with chronic and enhanced pulmonary inflammation characterized by increased cytokine production and leukocyte recruitment to the lung. Although the aryl hydrocarbon receptor (AhR) is well-known to mediate toxic effects of environmental contaminants, the AhR has emerged as a suppressor of acute cigarette smoke-induced neutrophilia. As there is currently no information on the AhR prevention of lung inflammation due to varied and prolonged exposure regimes, we exposed control and AhR-/- mice to cigarette smoke for 2 weeks (sub-chronic exposure) utilizing low and high exposure protocols and evaluated pulmonary inflammation. Sub-chronic cigarette smoke exposure increased pulmonary neutrophilia dose-dependently in AhR-/- mice. There was no difference between smoke-exposed AhR+/- and AhR-/- mice in the expression of cytokines associated with neutrophil recruitment. However, expression of pulmonary intercellular adhesion molecule-1 (ICAM-1), an adhesion molecule ...
Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and its expression is influenced by environmental compounds, such as 3-methylcholanthrene (3-MC) and β-naphthoflavone (β-NF). AhR and its downstream genes, such as CYP1A1, are considered to play a pivotal role in xenobiotic responses. AhR signaling has also been proposed to mediate osteogenesis in experimental animals, but its details have remained unclear. Therefore, in this study, we examined the possible roles of AhR in human bone. Immunohistochemical analysis revealed that AhR was detected in both osteoblasts and osteoclasts. We then screened AhR-target genes using a microarray analysis in human osteoblastic hFOB cells. Results of microarray and subsequent PCR analysis did reveal that estrogen metabolizing and synthesizing enzymes, such as CYP1B1 and aromatase, were increased by 3-MC in hFOB and osteosarcoma cell line, MG-63. The subsequent antibody cytokine analysis also demonstrated that interleukin-1β and -6 expression
TY - JOUR. T1 - Ligand-independent activation of the arylhydrocarbon receptor by ETK (Bmx) tyrosine kinase helps MCF10AT1 breast cancer cells to survive in an apoptosis-inducing environment. AU - Fujisawa, Yasuko. AU - Li, Wen. AU - Wu, Dalei. AU - Wong, Patrick. AU - Vogel, Christoph. AU - Dong, Bin. AU - Kung, Hsing Jien. AU - Matsumura, Fumio. PY - 2011/10/1. Y1 - 2011/10/1. N2 - It has been reported that the arylhydrocarbon receptor (AHR) is overexpressed in certain types of breast tumors. However, so far no concrete evidence has been provided yet as to why and how the overexpressed AHR in those cancer cells is functionally activated without exogenous ligands. Here we show that the AHR was functionally activated when estrogen receptor-negative, AHR overexpressing MCF10AT1 human breast cancer cells (designated P20E) were subjected to serum starvation. Transfection of cells with ETK-KQ, a plasmid for kinase-dead epithelial and endothelial tyrosine kinase (ETK), attenuated this AHR activation. ...
GNF351 is a full aryl hydrocarbon receptor (AHR) antagonist. GNF351 competes with a photoaffinity AHR ligand for binding to the AHR with an IC50 of 62 nM. GNF351 is minimal toxicity in mouse or human keratinocytes. - Mechanism of Action & Protocol.
The vT{2} cell line was derived by co-transfection of a 6 thioguanine-resistant derivative of c4 (B13NBii1) [ATCC CRL-2717] cell line using the plasmid pSV2gpt and pBM5/NEO-M1-1. M1-1 is a cDNA clone containing the entire human ARNT cDNA sequence. The cells were expanded in G418 to obtain vT{2} (ATCC CRL-2712). The vT{2} cell line expresses the human aryl hydrocarbon receptor nuclear translocator (ARNT) gene The vectors contain cytomegalovirus (CMV) and SV40 viral DNA sequences and the neomycin resistance gene. ARNT is directly involved in the regulation of xenobiotic metabolism (including chemical carcinogenesis), hypoxia and differentiation during embryogeneses. The parental cell line c4 (B13NBii1) (ATCC CRL-2717) lacks functional ARNT while its derivative vT{2} (ATCC CRL-2712) possesses a complete transfected ARNT cDNA. Together, they can be used to study ARNT processes and the role of ARNT in vivo.
Mouse anti Human ARNT antibody, clone 3D10 recognizes human Aryl hydrocarbon receptor nuclear translocator, also known as ARNT, Class E ba
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 mech …
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 mech …
The aryl hydrocarbon receptor (AhR), a transcription factor thats best known because of its role in mediating the toxic responses elicited by poly aromatic hydrocarbons aswell as much other environmental factors; can be involved in breasts cancer development. of AhR knockdown. We demonstrate that AhR knockdown alters the appearance of many genes regarded as linked to cancer tumor. These genes consist of those involved with tryptophan fat burning capacity and cell success (and and multi-drug level of resistance (and and 0.05. KEGG Pathway and Gene Ontology (Move) Enrichment Evaluation The WEB-based Gene Established Evaluation Toolkit (WEBGESTALT) was found in purchase to carry out KEGG pathway and gene ontology (Move) enrichment evaluation over the transcriptome array dataset. Quickly, gene transcripts displaying significant adjustments in expression in the transcriptome array had been mapped with their matching KEGG pathways and Move natural procedures and a hypergeometric OTX015 manufacture ...
The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor that mediates most of the toxic and carcinogenic effects of drugs and environmental toxins collectively known as xenobiotics. Ligand activation of the AhR stimulates the transcription of genes that encode several xenobiotic-metabolizing enzymes. The molecular mechanisms and signaling pathways evoked by the activation of the AhR are becoming increasingly understood and underscore the participation of the AhR in crucial processes, including cellular stress response, proliferation, differentiation, inflammation, and carcinogenesis. Studies now implicate the AhR as an integral part of the multifaceted signal transduction pathway initiated by the exposure of keratinocytes to ultraviolet B radiation (UVB), which is the most ubiquitous hazard to human skin and the principal risk factor for skin cancer. Ligand-dependent activation of the AhR in the cytosol provides a molecular bridge that links cytoplasmic events to ...
The first aim of this work was to fully characterise the three most environmentally abundant mono-ortho-substituted polychlorinated biphenyls (PCBs; PCB 105, 118 and 156) including a re-evaluation of their putative antagonistic effects on AhR. Secondly, the effects of mixed halogenated compounds, currently not included in the TEQ estimation, were investigated as AhR agonists based on their environmental exposure and potency. Quantitative real-time PCR (qRT-PCR) was used to measure the AhR mediated induction of CYP1A1 mRNA in rat H4IIE and human MCF-7 cells. The three mono-ortho-substituted PCBs were shown to be antagonists of rat and human AhRs, an effect which is not currently included in the TEQ calculation. 2-bromo-3,7,8-trichlorodibenzo-p-dioxin (2-B-3,7,8-TriCDD) was found to be an AhR agonist that was 2-fold more potent than 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; considered one of the most potent in the environment). The majority of the other tested compounds were found to be within ...
Lymphoma and leukemia are the most common cancers in children and young adults; in utero carcinogen exposure may contribute to the etiology of these cancers. A polycyclic aromatic hydrocarbon (PAH), dibenzo[a,l]pyrene (DBP), was given to pregnant mice (15 mg/kg body weight, gavage) on gestation day 17. Significant mortalities in offspring, beginning at 12 weeks of age, were observed due to an aggressive T-cell lymphoblastic lymphoma. Lymphocytes invaded numerous tissues. All mice surviving 10 months, exposed in utero to DBP, exhibited lung tumors; some mice also had liver tumors. To assess the role of the aryl hydrocarbon receptor (AHR) in DBP transplacental cancer, B6129SF1/J (AHR(b-1/d), responsive) mice were crossed with strain 129S1/SvIm (AHR(d/d), nonresponsive) to determine the effect of maternal and fetal AHR status on carcinogenesis. Offspring born to nonresponsive mothers had greater susceptibility to lymphoma, irrespective of offspring phenotype. However, when the mother was ...
ABSTRACT The human gut microbiome represents a highly diverse community of trillions of microorganisms that populate the human gastrointestinal tract. Dysbiosis of this community correlates with many different diseases, including colon cancer, inflammatory bowel disease, and opportunistic infections by pathogenic bacteria. Production of bacterial metabolites by the gut microbiota can help mitigate these diseases. Herein, we investigate how SCFAs regulate the human aryl hydrocarbon receptor (AHR) pathway through cell culture stimulation assays to quantify expression and protein levels of AHR target genes, while also looking at nuclear translocation of the receptor ...
Pollutant particles containing environmentally persistent free radicals (EPFRs) are formed during many combustion processes (e.g. thermal remediation of hazardous wastes, diesel/gasoline combustion, wood smoke, cigarette smoke, etc.). Our previous studies demonstrated that acute exposure to EPFRs results in dendritic cell maturation and Th17-biased pulmonary immune responses. Further, in a mouse model of asthma, these responses were enhanced suggesting exposure to EPFRs as a risk factor for the development and/or exacerbation of asthma. The aryl hydrocarbon receptor (AHR) has been shown to play a role in the differentiation of Th17 cells. In the current study, we determined whether exposure to EPFRs results in Th17 polarization in an AHR dependent manner. Exposure to EPFRs resulted in Th17 and IL17A dependent pulmonary immune responses including airway neutrophilia. EPFR exposure caused a significant increase in pulmonary Th17 cytokines such as IL6, IL17A, IL22, IL1β, KC, MCP-1, IL31 and IL33. To
The findings suggest new modalities for cancer prevention and treatment A new Boston University School of Public Health (BUSPH) study has identified for the first time how the aryl hydrocarbon receptor (AhR), an environmental chemical receptor, drives immunosuppression in oral squamous cell carcinoma (OSCC)--and that its removal from malignant cells can result in tumor rejection.…
Oral URA (25 mg/kg/d) suppressed disease progression at prevention, induction, and effector phases of preclinical EAE. Histological evaluation showed that significantly fewer inflammatory cells, decreased demyelination, lower numbers of M1-type microglia and activated DCs, as well as reduced infiltrating Th1/Th17 cells were present in the central nervous system (CNS) of the URA-treated group. URA treatment at 25 μM inhibited the activation of BM-DCs in vitro, restrained Th17 cell differentiation in T cell polarization conditions, and in a DC-CD4+ T cell co-culture system. Moreover, we confirmed URA inhibited pathogenicity of Th17 cells in adoptive EAE. Mechanism of URA action was directly targeting Aryl Hydrocarbon Receptor (AhR) and modulating the signaling pathways ...
B cell lymphoma-6 (BCL6) is highly expressed in germinal center B cells, but how its expression is maintained is still not completely clear. Aryl hydrocarbon receptor interacting protein (AIP) is a co-chaperone of heat shock protein 90. Deletion of Aip in B cells decreased BCL6 expression, reducing germinal center B cells and diminishing adaptive immune responses. AIP was required for optimal AKT signaling in response to B cell receptor stimulation, and AIP protected BCL6 from ubiquitin-mediated proteasomal degradation by the E3-ubiquitin ligase FBXO11 by binding to the deubiquitinase UCHL1, thus helping to maintain the expression of BCL6. AIP was highly expressed in primary diffuse large B cell lymphomas compared to healthy tissue and other tumors. Our findings describe AIP as a positive regulator of BCL6 expression with implications for the pathobiology of diffuse large B cell lymphoma.
Page contains details about example of polymer-coated aryl hydrocarbon receptor transcription factor-binding ligand loaded magnetic nanoparticles . It has composition images, properties, Characterization methods, synthesis, applications and reference articles : nano.nature.com
AIP (aryl hydrocarbon receptor interacting protein), Authors: Sayka Barry, Márta Korbonits. Published in: Atlas Genet Cytogenet Oncol Haematol.
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p>The checksum is a form of redundancy check that is calculated from the sequence. It is useful for tracking sequence updates.,/p> ,p>It should be noted that while, in theory, two different sequences could have the same checksum value, the likelihood that this would happen is extremely low.,/p> ,p>However UniProtKB may contain entries with identical sequences in case of multiple genes (paralogs).,/p> ,p>The checksum is computed as the sequence 64-bit Cyclic Redundancy Check value (CRC64) using the generator polynomial: x,sup>64,/sup> + x,sup>4,/sup> + x,sup>3,/sup> + x + 1. The algorithm is described in the ISO 3309 standard. ,/p> ,p class=publication>Press W.H., Flannery B.P., Teukolsky S.A. and Vetterling W.T.,br /> ,strong>Cyclic redundancy and other checksums,/strong>,br /> ,a href=http://www.nrbook.com/b/bookcpdf.php>Numerical recipes in C 2nd ed., pp896-902, Cambridge University Press (1993),/a>),/p> Checksum:i ...
We have analyzed the possible role of the aryl-hydrocarbon receptor (AHR) in the aging process of mice using a homozygous null mouse (Ahr-/-) line as a model. We studied 52 male and female Ahr-/- mice aged from 6-13 months. Forty-six percent died or were ill by 13 months of age. Ahr-/- mice developed age-related lesions in several organs, some of which were apparent after only 9 months of age. Cardiovascular alterations included cardiomyopathy (100%) with hypertrophy and focal fibrosis. Vascular hypertrophy and mild fibrosis were found in the portal areas of the liver (81%), and vascular hypertrophy and mineralization were common in the uterus (70%). Gastric hyperplasia that progressed with age into polyps was evident in the pylorus of 71% of the mice over 9 months of age. Ahr-/- mice had T-cell deficiency in their spleens but not in other lymphoid organs. The immune system deficiency described previously could be the origin for the rectal prolapse found in 48% of the null mice, associated
Cheung, YL, Snelling, J, Mohammed, NND, Gray, TJB and Ioannides, C (1996) Interaction with the aromatic hydrocarbon receptor, CYP1A induction, and mutagenicity of a series of diaminotoluenes: Implications for their carcinogenicity ...
ARNTL - ARNTL (untagged)-Human aryl hydrocarbon receptor nuclear translocator-like (ARNTL), transcript variant 1 available for purchase from OriGene - Your Gene Company.
Summary/Abstract The aryl hydrocarbon receptor (AhR) is known for mediating the toxicity of environmental pollutants such as dioxins and numerous dioxin-like compounds. Due to the widespread occurrence in our environment and the high toxic potential, these contaminants are of concern to promote malignancies including breast cancer. More recently it has been found that the AhR may also act as a critical receptor protein in tumor promotion independent from exogenous ligands, which is based on immune tolerance and increased survival in cancer cells. Consequently, the AhR has emerged as an attractive target for new drugs in cancer therapy. Furthermore, the AhRs action is restricted by a specific repressor protein, the AhR Repressor (AhRR). The AhRR is a ligand-independent, transcriptionally inactive AhR-like protein and is thought to repress AhR signaling. While AhRR effectively blocks AhR, the role of AhRR as a tumor suppressor gene is only poorly understood. We established a transgenic mouse ...
Conclusions and implications.Currently, there are several signaling cascades that define a novel biological theme in which the interplay between nuclear export and protein degradation plays a major role in determining the magnitude and duration of gene regulation. For example, the level of p53 protein is controlled in part by nuclear export and subsequent degradation by cytoplasmic proteases (8, 14,44, 45). If nuclear export of p53 is inhibited, there is a general upregulation of p53-dependent genes (8, 37). Another pathway involves p27Kip1, p27Kip1 is a cyclin-dependent kinase that arrests cells in G1(40) and appears to be reduced in certain types of cancer (43). Importantly, the level of p27Kip1 is controlled in part through nuclear export following association with p38 (JAB1), a protein that contains an NES and allows export of p27Kip1 to the cytoplasm for degradation (27,46). The common theme in both pathways is that the export of the effector protein from the nucleus results in reduced ...
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Analysis of compounds present in complex matrices is always a challenge, which can be partly overcome by applying various sample preparation techniques prior to detection. Ideally, the extraction techniques should be as selective as possible, to minimize the concentration of interfering substances. In addition, results can be improved by efficient chromatographic separation of the sample components. The elimination of interfering substances is especially important when utilizing mass spectrometry (MS) as a detection technique since they influence the ionization yields. It is also important to optimize ionization methods in order to minimize detection limits.. In the work this thesis is based upon, selective solid phase extraction (SPE) materials, a restricted access material (RAM) and graphitized carbon black (GCB) were employed for clean up and/or pre-concentration of analytes in plasma, urine and agricultural drainage water prior to liquid chromatography/mass spectrometry (LC/MS). Two SPE ...
Genetic heterogeneity is widespread in tumors, but poorly documented in cell lines. According to immunoglobulin hypermutation analysis, the diffuse large B-cell lymphoma cell line U-2932 comprises two subpopulations faithfully representing original tumor subclones. We set out to identify molecular causes underlying subclone-specific expression affecting 221 genes including surface markers and the germinal center oncogenes BCL6 and MYC. Genomic copy number variations explained 58/221 genes differentially expressed in the two U-2932 clones. Subclone-specific expression of the aryl-hydrocarbon receptor (AhR) and the resulting activity of the AhR/ARNT complex underlaid differential regulation of 11 genes including MEF2B. Knock-down and inhibitor experiments confirmed that AhR/ARNT regulates MEF2B, a key transcription factor for BCL6. AhR, MEF2B and BCL6 levels correlated not only in the U-2932 subclones but in the majority of 23 cell lines tested, indicting overexpression of AhR as a novel mechanism ...
Genetic heterogeneity is widespread in tumors, but poorly documented in cell lines. According to immunoglobulin hypermutation analysis, the diffuse large B-cell lymphoma cell line U-2932 comprises two subpopulations faithfully representing original tumor subclones. We set out to identify molecular causes underlying subclone-specific expression affecting 221 genes including surface markers and the germinal center oncogenes BCL6 and MYC. Genomic copy number variations explained 58/221 genes differentially expressed in the two U-2932 clones. Subclone-specific expression of the aryl-hydrocarbon receptor and the resulting activity of the AhR/ARNT complex underlay differential regulation of 11 genes including MEF2B. Knock-down and inhibitor experiments confirmed that AhR/ARNT regulates MEF2B, key transcription factor for BCL6. AhR, MEF2B and BCL6 levels correlated not only in the U-2932 subclones but in the majority of 23 cell lines tested, indicting overexpression of AhR as novel mechanism behind ...
Complete information for AHR gene (Protein Coding), Aryl Hydrocarbon Receptor, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
Fig. 6. Functional investigation of the AHRR 3-MC-dependent PGx-eQTL. (A) The 3-MC-dependent PGx-eQTL for AHRR included 10 SNPs across peaks 13161, 13163, and 13164 in intron 4 of the AHRR gene. (B) The variant SNP genotypes for the 10 linked SNPs that were across three AHR-binding peaks in intron 4 of the AHRR gene were associated with an increase after 3-MC treatment, and the wild-type was associated with a decrease after 3-MC treatment. (C) The luciferase plasmid that contained the variant SNP genotypes for the SNPs surrounding peak 13161 (as indicated by the dashed lines) demonstrated no difference in LCLs or HepG2 cells and a smaller increase than the wild-type SNP genotype in HMC3 cells, which was suggestive. (D) The luciferase plasmid that contained the variant genotypes for the five SNPs near peak 13163 in intron 4 of the AHRR gene (as indicated by the dashed lines) demonstrated a larger increase in luciferase activity after 3-MC treatment than the wild-type in LCLs, HepG2, and HMC3-the ...
Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a candidate interactome (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon ...
E. A. Andreasen, Mathew, L. K., Löhr, C. V., Hasson, R., and Tanguay, R. L., Aryl hydrocarbon receptor activation impairs extracellular matrix remodeling during zebra fish fin regeneration., Toxicological sciences : an official journal of the Society of Toxicology, vol. 95, no. 1, pp. 215-26, 2007. ...
E. A. Andreasen, Mathew, L. K., Löhr, C. V., Hasson, R., and Tanguay, R. L., Aryl hydrocarbon receptor activation impairs extracellular matrix remodeling during zebra fish fin regeneration., Toxicological sciences : an official journal of the Society of Toxicology, vol. 95, no. 1, pp. 215-26, 2007. ...
BACKGROUND: Replacing beta-cells by islet-transplantation can cure type 1 diabetes, but up to 70% of beta-cells die within 10 days of transplantation. ARNT (Aryl hydrocarbon Receptor Nuclear Translocator) regulates beta-cell function, and potentially survival. Lack of ARNT impairs the ability of beta-cells to respond to physiological stress and potentiates the onset of diabetes, but the exact role of ARNT in graft outcome is unknown. AIM: To investigate the effect of beta-cell deletion of ARNT on graft outcomes. METHODS: Islets were isolated from donor mice which had beta-cell specific ARNT-deletion (beta-ARNT) or littermate floxed controls. The islets were transplanted into diabetic SCID recipients in ratios of (a) 3 donors: 1 recipient, (b) 1 donor: 1 recipient or (c) (1/2) of the islets from 1 donor: 1 recipient. After 28 days, the kidney containing the graft was removed (nephrectomy) to exclude regeneration of the endogenous pancreas. RESULTS: In the supra-physiological-mass model (3:1), both groups
Pregnancies complicated by severe fetal growth restriction with abnormal umbilical artery Doppler velocimetry (FGRadv) are at substantial risk for adverse perinatal and long-term outcomes. Impaired angiogenesis of the placental vasculature in these pregnancies results in a sparse, poorly branched vascular tree, which structurally contributes to the abnormally elevated fetoplacental vascular resistance that is clinically manifested by absent or reversed umbilical artery Doppler indices. Previous studies have shown that aryl hydrocarbon receptor nuclear translocator (ARNT) is a key mediator of proper placental angiogenesis, and within placental endothelial cells (ECs) from human FGRadv pregnancies, low expression of ARNT leads to decreased vascular endothelial growth factor A (VEGFA) expression and deficient tube formation. Thus, the aim of the present study was to determine the effect of VEGFA administration or ARNT overexpression on angiogenic potential of FGRadv ECs. ECs were isolated and ...
In patients with CKD, not only renal but also, nonrenal clearance of drugs is altered. Uremic toxins could modify the expression and/or activity of drug transporters in the liver. We tested whether the uremic toxin indoxyl sulfate (IS), an endogenous ligand of the transcription factor aryl hydrocarbon receptor, could change the expression of the following liver transporters involved in drug clearance: SLC10A1, SLC22A1, SLC22A7, SLC47A1, SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCB11, ABCC2, ABCC3, ABCC4, ABCC6, and ABCG2 We showed that IS increases the expression and activity of the efflux transporter P-glycoprotein (P-gp) encoded by ABCB1 in human hepatoma cells (HepG2) without modifying the expression of the other transporters. This effect depended on the aryl hydrocarbon receptor pathway. Presence of human albumin at physiologic concentration in the culture medium did not abolish the effect of IS. In two mouse models of CKD, the decline in renal function associated with the accumulation of IS in ...
Author(s): Hu, Qin; He, Guochun; Zhao, Jing; Soshilov, Anatoly; Denison, Michael S; Zhang, Aiqian; Yin, Huijun; Fraccalvieri, Domenico; Bonati, Laura; Xie, Qunhui; Zhao, Bin | Abstract: 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
Tachibana K, Kobayashi Y, Tanaka T, Tagami M, Sugiyama A, Katayama T, Ueda C, Yamasaki D, Ishimoto K, Sumitomo M, Uchiyama Y, Kohro T, Sakai J, Hamakubo T, Kodama T, Doi T; Gene expression profiling of potential peroxisome proliferator-activated receptor (PPAR) target genes in human hepatoblastoma cell lines inducibly expressing different PPAR isoforms.; Nucl Recept, 2005 PubMed Europe PMC Scholia ...
Tachibana K, Kobayashi Y, Tanaka T, Tagami M, Sugiyama A, Katayama T, Ueda C, Yamasaki D, Ishimoto K, Sumitomo M, Uchiyama Y, Kohro T, Sakai J, Hamakubo T, Kodama T, Doi T; Gene expression profiling of potential peroxisome proliferator-activated receptor (PPAR) target genes in human hepatoblastoma cell lines inducibly expressing different PPAR isoforms.; Nucl Recept, 2005 PubMed Europe PMC Scholia ...
TY - JOUR. T1 - Role of AhR/ARNT system in skin homeostasis. AU - Furue, Masutaka. AU - Takahara, Masakazu. AU - Nakahara, Takeshi. AU - Uchi, Hiroshi. PY - 2014/1/1. Y1 - 2014/1/1. N2 - Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that binds to structurally diverse synthetic and naturally occurring chemicals including dioxins, flavonoids, tryptophan photoproducts, and Malassezia metabolites. Upon binding to its ligands, cytoplasmic AhR translocates to the nucleus, heterodimerizes with aryl hydrocarbon receptor nuclear translocator (ARNT), and mediates numerous biological and toxicological effects by inducing the transcription of various AhR-responsive genes. AhR ligation controls oxidation/antioxidation, epidermal barrier function, photo-induced response, melanogenesis, and innate immunity. This review summarizes recent advances in the understanding of the regulatory mechanisms of skin homeostasis mediated by the AhR/ARNT system.. AB - Aryl hydrocarbon receptor ...
Berberine and the methylenedioxy ring-opening derivatives palmatine and jatrorrhizine are active ingredients in immunomodulatory plants, such as goldenseal. This study aimed to illustrate the effects of protoberberines on aryl hydrocarbon receptor (AhR) activation and cytochrome P450 (CYP) 1 in the estrogen receptor (ER)α(+) MCF-7 breast cancer cells. Among protoberberines at non-cytotoxic concentrations (≤10 μM), berberine had the most potent and statistically significant effects on AhR activation and CYP1A1/1A2/1B1 mRNA induction. The 24-h exposure to 10 μM berberine did not change CYP1A1 mRNA stability, protein level and function. Berberine significantly increased micro RNA (miR)-21-3p by 36% and the transfection of an inhibitor of miR-21-3p restored the induction of CYP1A1 protein with a 50% increase. These findings demonstrate that the ring opening of the methylenedioxyl moiety in berberine decreased AhR activation in MCF-7 cells. While CYP1A1 mRNA was elevated, berberine-induced miR-21-3p
The Drosophila spineless (ss) gene encodes a basic-helix-loop-helix-PAS transcription factor that is required for proper specification of distal antennal identity, establishment of the tarsal regions of the legs, and normal bristle growth. ss is the closest known homolog of the mammalian aryl hydrocarbon receptor (Ahr), also known as the dioxin receptor. Dioxin and other aryl hydrocarbons bind to the PAS domain of Ahr, causing Ahr to translocate to the nucleus, where it dimerizes with another bHLH-PAS protein, the aryl hydrocarbon receptor nuclear translocator (Arnt). Ahr:Arnt heterodimers then activate transcription of target genes that encode enzymes involved in metabolizing aryl hydrocarbons. In this report, we present evidence that Ss functions as a heterodimer with the Drosophila ortholog of Arnt, Tango (Tgo). We show that the ss and tgo genes have a close functional relationship: loss-of-function alleles of tgo were recovered as dominant enhancers of a ss mutation, and tgo-mutant somatic ...
6-Formylindolo[3,2-b]carbazole (FICZ) is a potent aryl hydrocarbon receptor (AHR) agonist that is efficiently metabolized by AHR-regulated cytochrome P4501 enzymes. FICZ is a proposed physiological AHR ligand that induces its own degradation as part of a regulatory negative feedback loop. In vitro studies in cells show that CYP1 inhibition in the presence of FICZ results in enhanced AHR activation, suggesting that FICZ accumulates in the cell when its metabolism is blocked. We used zebrafish (Danio rerio) embryos to investigate the in vivo effects of FICZ when CYP1A is knocked down or inhibited. Embryos were injected with morpholino antisense oligonucleotides targeting CYP1A (CYP1A-MO), Ahr2, or a combination of both. FICZ exposure of non-injected embryos or embryos injected with control morpholino had little effect. In CYP1A-MO-injected embryos, however, FICZ dramatically increased mortality, incidence and severity of pericardial edema and circulation failure, reduced hatching frequency, ...
Anti-androgen flutamide suppresses hepatocellular carcinoma cell proliferation via the aryl hydrocarbon receptor mediated induction of transforming growth factor-β1.
Simple helixCloopChelix/PerCArntCSim (bHLH/PAS) transcription factors function broadly in development, stress and homeostasis response. particular features of neuronal bHLH/PAS elements and/or to prevent neuronal bHLH/PAS Rabbit Polyclonal to EFNB3 elements from interfering with AhR/Arnt signalling. Launch The mammalian simple helixCloopChelix/PerCArntCSim (bHLH/PAS) family members of transcription elements comprises of 19 structurally related protein that are important for a variety of natural procedures, including air homeostasis, xenobiotic Lumacaftor response, neurogenesis, urge for food control and circadian tempo (1,2). Prototypical signal-regulated associates of this family members consist of the aryl hydrocarbon receptor (AhR) and hypoxia-inducible factor-alphas (HIF-s), which exert their actions by heterodimerizing with the common bHLH/PAS partner proteins aryl hydrocarbon receptor nuclear translocator (Arnt), to type energetic DNA-binding processes. In addition, Arnt provides been ...
Objectives Dioxin-like chemicals are known to exert their effect by binding to aryl hydrocarbon receptor (AhR), forming complexes with aryl hydrocarbon nuclear translocator (ARNT), and binding to specific dioxin responsive elements in promoter region to regulate the transcription of specific genes. In human, induction of cytochrome P450 (CYP) family of enzymes is well documented. In previous study, CYP1A2 induction had been reported to be an excellent biomarker of dioxin exposure and human health effects in people highly exposed to dioxin-like chemicals, the Yucheng cohort. The goal of this study is to examine the relationship between inducibility of CYP1A2 and genetic polymorphisms of AhR, ARNT, and AhRR in human.. ...
TY - JOUR. T1 - Signaling pathway for 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced TNF-α production in differentiated THP-1 human macrophages. AU - Cheon, Hyeon Joo. AU - Woo, Young Seok. AU - Ji, Young Lee. AU - Hee, Sook Kim. AU - Hyun, Jin Kim. AU - Cho, Sungwon. AU - Nam, Hee Won. AU - Sohn, Jeongwon. PY - 2007/8/31. Y1 - 2007/8/31. N2 - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a prototypic halogenated aromatic hydrocarbon (HAH), is known as one of the most potent toxicants. At least a part of its toxic effects appears to be derived from its ability to induce TNF-α production. However, the signaling pathway of TCDD that leads to TNF-α expression has not been elucidated. In this study, we investigated the signaling mechanism of TCDD-induced TNF-α expression in PMA-differentiated THP-1 macrophages. TCDD induced both mRNA and protein expression of TNF-α in a dose- and time-dependent manner. α-Naphthoflavone (NF), an aryl hydrocarbon receptor (AhR) inhibitor, prevented the TCDD-induced ...
Project Description: Damage to nerve fibers along with degeneration and death of neurons (neurodegeneration) are associated with chronic disability in MS. Dr. Jacqueline Quandt and her research team aim to characterize the role of neuronal PAS4 (Npas4) and aryl hydrocarbon receptor nuclear translocator (ARNT2), two molecules with an established role in damage of nerve fibers and neurodegeneration. These molecules have neuroprotective properties, the potential to influence the earliest steps of neurodegeneration at disease onset, as well as the potential to contribute to recovery while limiting progression in MS. From a previous grant, also supported by the MS Society, the research team shows that both Npas4 and ARNT2 are regulated over the disease course of an animal model of MS: prior to disease onset each are increased, presumably in response to early stressors, yet levels decline with disease onset and are lowest at peak disease. The research team will (1) localize and compare Npas4 and ARNT2 ...
Hypoxia, a condition of low tissue O2 concentration, plays an important role in normal physiological processes and tumor formation. Under hypoxic conditions mammalian cells up regulate the expression of hypoxic genes, including induction of angiogenesis and a switch to anaerobic metabolism, in order to survive. HIF-1 (Hypoxia Inducible Factor-1) is one of the key regulators of the transcriptional response to oxygen deprivation (1). HIF-1 is composed of two subunits, HIF-1alphaand HIF-1beta also known as aryl hydrocarbon receptor nuclear translocator (ARNT)) that are members of the basic helix-loop-helix (bHLH) Per-Arnt-Sim (PAS) (bHLH-PAS) family of transcription factors. HIF-1 is essential for angiogenesis, embryonic development, and is associated with tumor progression, erythropoiesis, vascular development/remodeling, vasodilation, and glucose/energy metabolism. The over expression of HIF-1alphahas been demonstrated in many common human cancers including prostate and breast, in which ...
Low oxygen levels (hypoxia) trigger a variety of adaptive responses with the Hypoxia-inducible factor 1 (HIF-1) complex acting as a master regulator. HIF-1 consists of a heterodimeric oxygen-regulated ? subunit (HIF-1?) and constitutively expressed ? subunit (HIF-1?) also known as aryl hydrocarbon receptor nuclear translocator (ARNT), regulating genes involved in diverse processes including angiogenesis, erythropoiesis and glycolysis. The identification of HIF-1 interacting proteins is key to the understanding of the hypoxia signaling pathway. Besides the regulation of HIF-1? stability, hypoxia also triggers the nuclear translocation of many transcription factors including HIF-1? and ARNT. Notably, most of the current methods used to study such protein-protein interactions (PPIs) are based on systems where protein levels are artificially increased through protein overexpression. Protein overexpression often leads to non-physiological results arising from temporal and spatial artifacts. Here we ...
DNA methylation is associated with cancer, metabolic, neurological, and autoimmune disorders. Hypomethylation of aryl hydrocarbon receptor repressor (AHRR) especially at cg05575921 is associated with smoking and lung cancer. Studies on the association between AHRR methylation at cg05575921 and sources of polycyclic aromatic hydrocarbon (PAH) other than smoking are limited. The aim of our study was to assess the pattern of blood DNA methylation at cg05575921 in non-smoking Taiwanese adults living in areas with different PM2.5 levels. Data on blood DNA methylation, smoking, and residence were retrieved from the Taiwan Biobank dataset (2008-2015). Current and former smokers, as well as individuals with incomplete information were excluded from the current study. The final analysis included 708 participants (279 men and 429 women) aged 30-70 years. PM2.5 levels have been shown to increase as one moves from the northern through central towards southern Taiwan. Based on this trend, the study areas were
DNA methylation is associated with cancer, metabolic, neurological, and autoimmune disorders. Hypomethylation of aryl hydrocarbon receptor repressor (AHRR) especially at cg05575921 is associated with smoking and lung cancer. Studies on the association between AHRR methylation at cg05575921 and sources of polycyclic aromatic hydrocarbon (PAH) other than smoking are limited. The aim of our study was to assess the pattern of blood DNA methylation at cg05575921 in non-smoking Taiwanese adults living in areas with different PM2.5 levels. Data on blood DNA methylation, smoking, and residence were retrieved from the Taiwan Biobank dataset (2008-2015). Current and former smokers, as well as individuals with incomplete information were excluded from the current study. The final analysis included 708 participants (279 men and 429 women) aged 30-70 years. PM2.5 levels have been shown to increase as one moves from the northern through central towards southern Taiwan. Based on this trend, the study areas were
Dioxins are extremely widespread, toxic and persistent pollutants, as well as a major concern for human health. The Aryl hydrocarbon receptor (Ahr) is the key component in the metabolic response to dioxins. Ahr is a cytoplasmic bHLH-PAS transcription factor that, upon binding with dioxin, translocates to the nucleus. There it forms a complex with the Ah receptor nuclear transloator (Arnt), another bHLH-PAS protein, and binds to the eight-nucleotide XRE motif to control gene expression. Previous work with Ahr knock-out mice revealed the existence of dioxin-independent activity for Ahr in development, but the relationship between the two activities of Ahr remains unclear. Our work uses Drosophila to clarify this question, which is central for therapies seeking inactivation of Ahr. The Drosophila Ahr homologue, spineless(ss), does not bind dioxins, however, it physically interacts with Tango (Tgo), Arnts fly homologue, and controls gene expression through the XRE motif during development. Here I ...
TY - JOUR. T1 - AH receptor, ARNT, glucocorticoid receptor, EGF receptor, EGF, TGFα, TGFβ1, TGFβ2, and TGFβ3 expression in human embryonic palate, and effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). AU - Abbott, B. D.. AU - Probst, M. R.. AU - Perdew, Gary H.. AU - Buckalew, A. R.. PY - 1998/8/1. Y1 - 1998/8/1. N2 - Protein and mRNA for epidermal growth factor (EGF), transforming growth factor-alpha (TGFα), EGF receptor, transforming growth factor-beta 1 (TGFβ1), TGFβ2, TGFβ3, glucocorticoid receptor (GR), the aryl hydrocarbon receptor (AhR), and the Ah receptor nuclear translocator (ARNT) were localized in gestational days (GD) 49-59 human embryonic secondary palates. The response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was determined for expression of these genes following palatal organ culture. Craniofacial tissues were shipped in medium from the Human Embryology Laboratory, University of Washington, Seattle, WA. Half of each specimen was cultured in control medium and ...
The CYP1A1 and CYP1B1 genes are members of aromatic hydrocarbon receptor battery genes. The expression of these genes, therefore, is thought to be induced concomitantly through the activation of aromatic hydrocarbon receptor. In agreement with this concept, both CYP1A1 and CYP1B1 mRNAs were induced by the treatment of human blood monocytes with dioxins or PAHs in vitro (11 , 12) . The subjects whose leukocytes were analyzed in this study were workers occupationally exposed to dioxins at waste incinerators (9) . Thus, we expected that both CYP1A1 and CYP1B1 mRNAs might be induced by environmental exposure to dioxins. However, we found that the expression of only CYP1B1 mRNA was induced, whereas the expression of CYP1A1 mRNA was not induced. The reason accounting for the fact that only CYP1B1 mRNA was induced is not known at present.. After the first report on the significant association between AHH inducibility in human lymphocytes and the bronchogenic cancer risk (3) , many papers have appeared ...
We have developed an approach to classify toxicants based upon their influence on profiles of mRNA transcripts. Changes in liver gene expression were examined after exposure of mice to 24 model treatments that fall into five well-studied toxicological categories: peroxisome proliferators, aryl hydrocarbon receptor agonists, noncoplanar polychlorinated biphenyls, inflammatory agents, and hypoxia-inducing agents. Analysis of 1200 transcripts using both a correlation-based approach and a probabilistic approach resulted in a classification accuracy of between 50 and 70%. However, with the use of a forward parameter selection scheme, a diagnostic set of 12 transcripts was identified that provided an estimated 100% predictive accuracy based on leave-one-out cross-validation. Expansion of this approach to additional chemicals of regulatory concern could serve as an important screening step in a new era of toxicological testing.. ...
Hydrocarbon halide, or hydrocarbon for short, refers to the product produced during the process of hydrogen atoms replaced by by halogen (fluorine, chlorine, bromine, iodine) in the hydrocarbon molecules. According to the different hydrocarbon groups, it could be divided into categories like aliphatic halogenated hydrocarbons (including saturated and unsaturated halogenated hydrocarbons), aromatic halogenated hydrocarbons. According to the amount of halogen atoms contained in the molecule, it could be divided into categories like halogenated hydrocarbons, dihalogenated hydrocarbons and polyhalogenated hydrocarbons. Most of the halogenated hydrocarbons are liquid. The proportion of Iodinated hydrocarbons, brominated hydrocarbons and polyhalogenated hydrocarbons are all higher than 1. They are insoluble in water and could be dissolved in any proportion with hydrocarbons, they also could dissolve many other organics. The proportion of Hydrocarbon halide would decreases with the increase of the ...
Science & Technology, Life Sciences & Biomedicine, Pharmacology & Pharmacy, Toxicology, PHARMACOLOGY & PHARMACY, TOXICOLOGY, Phenethyl isothiocyanate, Isothiocyanates, Cytochrome P450, Chemoprevention, Glucosinolates, ARYL-HYDROCARBON RECEPTOR, ADDUCT FORMATION, ENZYME-SYSTEMS, O-DEALKYLATION, CANCER RISK, RAT, SULFORAPHANE, INHIBITION, ERUCIN, ACTIVATION ...
Abstract: : Purpose:Mutations in several genes with expression limited to the photoreceptors and pinealocytes, such as the cone-rod homeobox gene (CRX), peripherin/RDS, and the gene encoding the aryl-hydrocarbon receptor interacting protein (AIPL1), are known to cause inherited retinopathy. Patients with mutations in these genes frequently cite secondary symptoms such as severe sleep abnormalities, or insomnia, but these complaints are often dismissed as due to limited physical activity in blind individuals. Due to the embryological, structural, and functional relationship of the photoreceptors and pinealocytes, it is possible that mutations causing photoreceptor degeneration in these patients might impact pineal function, resulting in abnormal circadian entrainment and these secondary symptoms. However, it is unknown how many retinopathy genes are also pineal-expressed or how many patients could be affected; therefore, we sought to determine which of the known retinopathy genes are pineal ...
3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is one of the most toxic environmental pollutants that cause various biological effects on mammals. The purpose of our study was to identify the genes involved in hepatotoxicity and hepatocarcinogenesis caused by TCDD. C57BL/6 (AhR+/+, wild type) and B6.129-AhR/J (AhR-/-, knock out) mice were injected i.p. with a single treatment of TCDD at the dose of 100 microg/kg body weight. Relative liver weight was significantly increased at 72 hr after TCDD treatment without an apparent histopathological change in AhR+/+ mice (p,0.05). TCDD treatment also significantly increased activity of serum alanine aminotransferase in AhR-/- mice (p,0.05). The liver was analyzed for gene expression profiles 72 hr later. As compared with AhR-/- mice, the expression of 51 genes (,3-fold) was changed in AhR+/+ mice; 28 genes were induced, while 23 genes were repressed. Most of the genes were associated with chemotaxis, inflammation, carcinogenesis, acute-phase response, immune ...
0100] Benzo[a]pyrene-7,8-dihydrodiol promotes checkpoint activation and G2/M arrest in human bronchoalveolar carcinoma H358 cells. Mol Pharmacol, 71: 744-750, 2007. [0101] 9. Ma, Q. Induction of CYP1A1. The AhR/DRE paradigm: transcription, receptor regulation, and expanding biological roles. Curr Drug Metab, 2: 149-164, 2001. [0102] 10. Nebert, D. W., Dalton, T. P., Okey, A. B., and Gonzalez, F. J. Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J Biol Chem, 279: 23847-23850, 2004. [0103] 11. Wang, X., Tomso, D. J., Chorley, B. N., Cho, H. Y., Cheung, V. G., Kleeberger, S. R., and Bell, D. A. Identification of polymorphic antioxidant response elements in the human genome. Hum Mol Genet, 16: 1188-1200, 2007. [0104] 12. Aoki, Y., Hashimoto, A. H., Amanuma, K., Matsumoto, M., Hiyoshi, K., Takano, H., Masumura, K., Itoh, K., Nohmi, T., and Yamamoto, M. Enhanced spontaneous and benzo(a)pyrene-induced mutations in the lung of ...
Persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs) are widespread in aquatic systems. These toxicants bioaccumulate in the tissues of aquatic organisms, especially fish as they occupy a position near the top of the aquatic food web. Teleost fish respond to stressors, including toxicants, by activating a co-ordinated network of adaptive responses, collectively termed the integrated stress response, which allows animals to regain homeostasis. Depending on the nature of the stressor, this stress response may be a generalised endocrine response that occurs at the organismal level and/or a cellular response involving protein synthesis. The cellular response to PCB insult involves aryl hydrocarbon receptor (AhR) activation and the induction of biotransformation enzymes, including cytochrome P4501A (Cyp1A). However, little is known about the mode of action of PCBs in affecting the adaptive stress response in animals. The objective of this thesis was to investigate the role ...
Exposure to traffic-derived particulate matter (PM), such as diesel exhaust particles (DEP), is a leading environmental cause of cardiovascular disease (CVD), and may contribute to endothelial dysfunction and development of atherosclerosis. It is still debated how DEP and other inhaled PM can contribute to CVD. However, organic chemicals (OC) adhered to the particle surface, are considered central to many of the biological effects. In the present study, we have explored the ability of OC from DEP to reach the endothelium and trigger pro-inflammatory reactions, a central step on the path to atherosclerosis. Exposure-relevant concentrations of DEP (0.12 μg/cm2) applied on the epithelial side of an alveolar 3D tri-culture, rapidly induced pro-inflammatory and aryl hydrocarbon receptor (AhR)-regulated genes in the basolateral endothelial cells. These effects seem to be due to soluble lipophilic constituents rather than particle translocation. Extractable organic material of DEP (DEP-EOM) was next
W. H. Bisson, Koch, D. C., Donnell, E. F. , Khalil, S. M., Kerkvliet, N. I., Tanguay, R. L., Abagyan, R., and Kolluri, S., Modeling of the Aryl Hydrocarbon Receptor (AhR) Ligand Binding Domain and Its Utility in Virtual Ligand Screening to Predict New AhR Ligands, Journal of Medicinal Chemistry, vol. 52, no. 18, pp. 5635 - 5641, 2009. ...
W. H. Bisson, Koch, D. C., Donnell, E. F. , Khalil, S. M., Kerkvliet, N. I., Tanguay, R. L., Abagyan, R., and Kolluri, S., Modeling of the Aryl Hydrocarbon Receptor (AhR) Ligand Binding Domain and Its Utility in Virtual Ligand Screening to Predict New AhR Ligands, Journal of Medicinal Chemistry, vol. 52, no. 18, pp. 5635 - 5641, 2009. ...
W. H. Bisson, Koch, D. C., Donnell, E. F. , Khalil, S. M., Kerkvliet, N. I., Tanguay, R. L., Abagyan, R., and Kolluri, S., Modeling of the Aryl Hydrocarbon Receptor (AhR) Ligand Binding Domain and Its Utility in Virtual Ligand Screening to Predict New AhR Ligands, Journal of Medicinal Chemistry, vol. 52, no. 18, pp. 5635 - 5641, 2009. ...
W. H. Bisson, Koch, D. C., Donnell, E. F. , Khalil, S. M., Kerkvliet, N. I., Tanguay, R. L., Abagyan, R., and Kolluri, S., Modeling of the Aryl Hydrocarbon Receptor (AhR) Ligand Binding Domain and Its Utility in Virtual Ligand Screening to Predict New AhR Ligands, Journal of Medicinal Chemistry, vol. 52, no. 18, pp. 5635 - 5641, 2009. ...
CS causes many changes in the microenvironment of head and neck carcinomas. Here, we show that CS induces phenotypic changes, including metabolic reprogramming, in fibroblasts, and that these altered fibroblasts are sufficient to reprogram the overall metabolism of HNSCC and induce its aggressiveness in vitro and in vivo. Moreover, we demonstrate that stromal monocarboxylate transporter MCT4 drives cancer aggressiveness in the context of CS and describe the aryl hydrocarbon receptor (AhR) pathway as a novel pathway regulating the expression of MCT4.. The tumor stroma supports cancer cells and, for example, CAFs promote proliferation, migration, invasion, and resistance to anticancer drugs in a wide array of cancers, including HNSCC (37). CAFs phenotypically differ from normal fibroblasts because they have increased remodeling of the extracellular matrix and increased levels of soluble factors and cytokines, which drive a host of effects on carcinoma cells (38). CAFs also have a reprogrammed ...
IELs are involved in maintaining the integrity of the intestinal surface by preventing bacteria from entering and by stimulating epithelial cell growth. Dr Veldhoen explained, The consequences of losing these immune cells are two-fold. There is a failure to control the tightly regulated make-up of the intestinal bacteria, normally composed of beneficial species that aid digestive processes but which now contains more opportunistic, potentially harmful bacteria. It also results in a more fragile intestinal lining, elevating the risk of intestinal inflammation.. The team discovered that a particular receptor molecule present at high levels on IELs - the aryl hydrocarbon receptor (AhR) - is central to understanding the connection between diet, numbers of IELs and a healthy gut. Earlier studies showed that the receptors activity can be triggered by dietary ingredients found at high levels in vegetables from the mustard or cabbage families; indole-3-carbinol (I3C) for instance can activate AhR, ...
Results In pSS-associated lymphoma the top canonical pathway was Aryl Hydrocarbon Receptor (AHR) signaling, which includes MGST3. Several other canonical pathways also included the genes of the 3-gene biosignature of pSS-associated lymphoma. The downstream effects and gene-gene interactions were explored through molecular networks analysis. Furthermore, important upstream regulators of the 3 biosignature genes include NFE2L2, PPARA and TOCF1 were identified.. The pathway analyses of the other pSS subgroups showed 67 common canonical pathways showed among all the pSS subgroups. Focusing on pSS-associated lymphoma versus healthy controls, 94.9% of the canonical pathways in this comparison were in common with the canonical pathways identified when comparing pSS-associated lymphoma with pSS. The Interferon Signaling pathway was the top pathway for all pSS subgroups comparing with healthy controls. In addition, all the non-lymphoma pSS subgroups showed similar patterns in the downstream analysis ...
Unlike induced \(Foxp3^+\) regulatory T cells (\(Foxp3^+\) \(iT_{reg}\)) that have been shown to play an essential role in the development of protective immunity to the ubiquitous mold Aspergillus fumigatus, type-(1)-regulatory T cells (Tr1) cells have, thus far, not been implicated in this process. Here, we evaluated the role of Tr1 cells specific for an epitope derived from the cell wall glucanase Crf-1 of A. fumigatus (Crf-1/p41) in antifungal immunity. We identified Crf-1/p41-specific latent-associated \(peptide^+\) Tr1 cells in healthy humans and mice after vaccination with Crf-1/p41+zymosan. These cells produced high amounts of interleukin (IL)-10 and suppressed the expansion of antigen-specific T cells in vitro and in vivo. In mice, in vivo differentiation of Tr1 cells was dependent on the presence of the aryl hydrocarbon receptor, c-Maf and IL-27. Moreover, in comparison to Tr1 cells, \(Foxp3^+\) \(iT_{reg}\) that recognize the same epitope were induced in an interferon gamma-type ...
Probiotics have been used to ameliorate gastrointestinal symptoms since ancient times. Over the past 40 years, probiotics have been shown to exert major effects on the immune system, both in vivo and in vitro.  This interaction is clearly linked to gut microbes, their polysaccharide antigens, and key metabolites produced by these bacteria.  At least four metabolic pathways have been implicated in mechanistic studies of probiotics, based on carefully studied animal models.  Microbial-immune system crosstalk has been linked to short chain fatty acid production and signaling, tryptophan metabolism and the activation of aryl hydrocarbon receptors, nucleoside signaling in the gut, and activation of the intestinal histamine-2 receptor.  Several randomized controlled trials have now shown that microbial modification by probiotics may improve gastrointestinal symptoms and multi-organ inflammation in rheumatoid arthritis, ulcerative colitis, and multiple sclerosis.  Future work will need
A green fluorescent protein based recombinaant cell bioassay for the detection of activators of the aryl hydrocarbon receptor: application for screening of a 1,
Current data suggests that most cases of isolated acromegaly are not due to an underlying hereditary (genetic) cause that gets passed through a family. However, when acromegaly begins in childhood or adolescence the gene aryl hydrocarbon receptor interacting protein, [i]AIP[/i], is thought to be a s
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Fingerprint Dive into the research topics of Deciphering Dimerization Modes of PAS Domains: Computational and Experimental Analyses of the AhR:ARNT Complex Reveal New Insights Into the Mechanisms of AhR Transformation. Together they form a unique fingerprint. ...
Covid-19 is the acute illness caused by SARS-CoV-2 with initial clinical symptoms such as cough, fever, malaise, headache, and anosmia. After entry into
AhR ligands are a structurally diverse group of natural and synthetic compounds that elicit a broad range of biological effects (13, 14, 25). Here, we analyze two AhR ligands, DIM and TCDD, which have opposing effects on human and animal health. DIM is a beneficial dietary constituent that suppresses breast tumors in rodents (9, 10) and may decrease breast cancer risk in humans (6). TCDD is a highly toxic, man-made environmental contaminant that is implicated in birth defects, infertility, and cancer (14, 15, 26). We find that DIM and TCDD differ in their ability to activate the two distinct AhR-controlled pathways: transcriptional activation and hormone receptor degradation. TCDD is better than DIM at activating CYP1 expression. DIM is better than TCDD at suppressing ER-α expression and estrogen signaling. This finding, that AhR ligands can preferentially activate the distinct AhR-controlled pathways, implies that the biological effects of different AhR ligands may vary considerably. This may ...
The c1 (B6NLxv1c2) line was derived from Hepa-1c1c7 (ATCC CRL-2026). Hepa-1c1c7 has high CYP1A1-dependent aryl hydrocarbon hydroxylase (AHH) activity. N-methyl-N-nitro-N-nitrosoguanidine (MNNS) mutated colonies were selected for benzo[a]pyrene resistance. The c1 (B6NLxv1c2) cell line lacks cytochrome P4501A1 dependent aryl hydrocarbon hydroylase (AHH) activity due to a single point mutation in CYP1A1 leading to premature termination of the translated protein (Asn-414; 56 kDa to 45 kDa). The line may be used to study xenobiotic (and carcinogenic) metabolism in the absence of cytochrome P4501A1 activity, which is known to metabolize cytotoxic and carcinogenic intermediates. It is also a tool to study the putative natural ligand for the induction of this enzyme.
294629575 - EP 1086212 A2 2001-03-28 - METHOD AND REAGENTS FOR THE TREATMENT OF DISEASES OR CONDITIONS RELATED TO MOLECULES INVOLVED IN ANGIOGENIC RESPONSES - [origin: WO9950403A2] Nucleic acid molecule which modulate the synthesis, expression and/or stability of an mRNA encoding for angiogenic factors selected from aryl hydrocarbon nuclear transport (ARNT), intergrin subunit beta 3 ( beta 3), integrin subunit alpha 6 ( alpha 6) and tie - 2 RNA. This invention further provides a treatment for indications related to angiogenesis using the nucleic acid molecules.[origin: WO9950403A2] Nucleic acid molecule which modulates the synthesis, expression and/or stability of an mRNA encoding for angiogenic factors selected from aryl hydrocarbon nuclear transport (ARNT), intergrin subunit beta 3 ( beta 3), integrin subunit alpha 6 ( alpha 6) and tie - 2RNA. This invention further provides a treatment for indications related to angiogenesis using the nucleic acid molecules.[origin: WO9950403A2] Nucleic acid molecule