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Transcription Mar 2024Aryl hydrocarbon receptor (AhR) is a transcription factor that is primarily known as an intracellular sensor of environmental pollution. After five decades, the list of... (Review)
Review
Aryl hydrocarbon receptor (AhR) is a transcription factor that is primarily known as an intracellular sensor of environmental pollution. After five decades, the list of synthetic and toxic chemicals that activate AhR signaling has been extended to include a number of endogenous compounds produced by various types of cells via their metabolic activity. AhR signaling is active from the very beginning of embryonal development throughout the life cycle and participates in numerous biological processes such as control of cell proliferation and differentiation, metabolism of aromatic compounds of endogenous and exogenous origin, tissue regeneration and stratification, immune system development and polarization, control of stemness potential, and homeostasis maintenance. AhR signaling can be affected by various pharmaceuticals that may help modulate abnormal AhR signaling and drive pathological states. Given their role in immune system development and regulation, AhR antagonistic ligands are attractive candidates for immunotherapy of disease states such as advanced prostate cancer, where an aberrant immune microenvironment contributes to cancer progression and needs to be reeducated. Advanced stages of prostate cancer are therapeutically challenging and characterized by decreased overall survival (OS) due to the metastatic burden. Therefore, this review addresses the role of AhR signaling in the development and progression of prostate cancer and discusses the potential of AhR as a drug target for the treatment of advanced prostate cancer upon entering the phase of drug resistance and failure of first-line androgen deprivation therapy.: ADC: antibody-drug conjugate; ADT: androgen deprivation therapy; AhR: aryl hydrocarbon receptor; AR: androgen receptor; ARE: androgen response element; ARPI: androgen receptor pathway inhibitor; mCRPC: metastatic castration-resistant prostate cancer; DHT: 5a-dihydrotestosterone; FICZ: 6-formylindolo[3,2-b]carbazole; 3-MC: 3-methylcholanthrene; 6-MCDF: 6-methyl-1,3,8-trichlorodibenzofuran; MDSCs: myeloid-derived suppressor cells; PAHs: polycyclic aromatic hydrocarbons; PCa: prostate cancer; TAMs: tumor-associated macrophages; TF: transcription factor; TCDD, 2,3,7,8-tetrachlorodibenzo--dioxin; TME: tumor microenvironment; TRAMP: transgenic adenocarcinoma of the mouse prostate; TROP2: tumor associated calcium signal transducer 2.
PubMed: 38547312
DOI: 10.1080/21541264.2024.2334106 -
Bratislavske Lekarske Listy 2020Skin is the body's first defence against direct exposure to variety of chemicals. Polycyclic aromatic hydrocarbons such as 3-methylcholanthrene (3-MC) are common in...
BACKGROUND
Skin is the body's first defence against direct exposure to variety of chemicals. Polycyclic aromatic hydrocarbons such as 3-methylcholanthrene (3-MC) are common in polluted urban air and have a potential of producing harmful effects. Moreover, their late effects can occur months or years after exposure.
OBJECTIVES
We aimed to investigate the long-term effects of 3-MC induced dermal toxicity on the expression of markers of apoptosis, pleiotropic cytokines, and oxidative stress and to determine the protective effect of cisplatin.
METHODS
Groups were designed as control (group 1), 3-MC applied (group 2) and 3-MC+cisplatin applied mice (group 3). Cutaneous expressions of TGFβ, PDGFA, PDGFC, bFGF, PDGFRα, USP28, and Ki67 were evaluated with qPCR. Total oxidant (TOS), total antioxidant (TAS) and oxidative stress index (OSI) values were determined in liver and kidney tissues.
RESULTS
The expression levels of TGFβ, PDGFRα, USP-28, Ki67, and PDGFA were decreased significantly in MC applied groups. Renal TAS levels were significantly lower in group-3. Liver and kidney OSI values were increased in both groups 2 and 3.
CONCLUSION
The results indicated that low dose 3-MC caused oxidative stress and downregulated apoptotic and cytokine markers in the long term and cisplatin had no ameliorative effects on this degeneration processes (Tab. 3, Fig. 3, Ref. 32). Text in PDF www.elis.sk.
Topics: Animals; Antioxidants; Biomarkers; DNA Damage; Methylcholanthrene; Mice; Oxidative Stress
PubMed: 32356428
DOI: No ID Found -
Toxicology Letters May 2022The aryl hydrocarbon receptor (AhR) is a receptor-type transcription factor that is crucial for endocrine disruption and carcinogenesis caused by environment chemicals....
The aryl hydrocarbon receptor (AhR) is a receptor-type transcription factor that is crucial for endocrine disruption and carcinogenesis caused by environment chemicals. Previous studies have indicated that certain intracellular signals are involved in AhR activation by their agonists, but the detailed mechanism remains unclear. In this study, we screened for important molecules for AhR activation using SCAD inhibitor kits. Among 164 kinase inhibitors listed in these kits, tyrphostin AG1024, commonly used as an inhibitor of insulin-like growth factor receptor (IGF1R) and insulin receptor (IR), was identified as a potent inhibitor of 3-methylcholanthrene (MC)-mediated AhR activation. We further investigated the mechanism by which AG1024 suppresses MC-mediated AhR activation. AG1024 decreased AhR-dependent luciferase activity, CYP1A1 gene expression, and its protein expression. However, when IGF1R siRNA and IR siRNA were used, AhR activation was slightly increased, in contrast to AG1024 treatment. In addition, AG1024 treatment downregulated the expression of AhR protein but not AhR gene, and decreased both nucleic and cytosolic AhR proteins. Therefore, AG1024 suppressed AhR activation by downregulating AhR protein expression. The molecular target of AG1024 remains unclear, and should be an important target for the regulation of AhR-dependent toxicity.
Topics: Cytochrome P-450 CYP1A1; Receptor, Insulin; Receptors, Aryl Hydrocarbon; Tyrphostins
PubMed: 35149128
DOI: 10.1016/j.toxlet.2022.02.003 -
Archives of Toxicology Jan 2022Error-corrected sequences (ECSs) that utilize double-stranded DNA sequences are useful in detecting mutagen-induced mutations. However, relatively higher frequencies of...
Error-corrected sequences (ECSs) that utilize double-stranded DNA sequences are useful in detecting mutagen-induced mutations. However, relatively higher frequencies of G:C > T:A (1 × 10 bp) and G:C > C:G (2 × 10 bp) errors decrease the accuracy of detection of rare G:C mutations (approximately 10 bp). Oxidized guanines in single-strand (SS) overhangs generated after shearing could serve as the source of these errors. To remove these errors, we first computationally discarded up to 20 read bases corresponding to the ends of the DNA fragments. Error frequencies decreased proportionately with trimming length; however, the results indicated that they were not sufficiently removed. To efficiently remove SS overhangs, we evaluated three mechanistically distinct SS-specific nucleases (S1 Nuclease, mung bean nuclease, and RecJf exonuclease) and found that they were more efficient than computational trimming. Consequently, we established Jade-Seq™, an ECS protocol with S1 Nuclease treatment, which reduced G:C > T:A and G:C > C:G errors to 0.50 × 10 bp and 0.12 × 10 bp, respectively. This was probably because S1 Nuclease removed SS regions, such as gaps and nicks, depending on its wide substrate specificity. Subsequently, we evaluated the mutation-detection sensitivity of Jade-Seq™ using DNA samples from TA100 cells exposed to 3-methylcholanthrene and 7,12-dimethylbenz[a]anthracene, which contained the rare G:C > T:A mutation (i.e., 2 × 10 bp). Fold changes of G:C > T:A compared to the vehicle control were 1.2- and 1.3-times higher than those of samples without S1 Nuclease treatment, respectively. These findings indicate the potential of Jade-Seq™ for detecting rare mutations and determining the mutagenicity of environmental mutagens.
Topics: DNA; DNA Repair; High-Throughput Nucleotide Sequencing; Mutagens; Mutation
PubMed: 34767040
DOI: 10.1007/s00204-021-03185-y -
Acta Clinica Croatica Jun 2020The role of T regulatory lymphocytes (T) particularly in cancer is well known. The goal of the present study was to determine the contribution of these lymphocytes in...
The role of T regulatory lymphocytes (T) particularly in cancer is well known. The goal of the present study was to determine the contribution of these lymphocytes in the regulation of anti-tumor immunity of CBA/HZgr mice against MC-2 fibrosarcoma (4 generation of methylcholanthrene induced tumor). The levels of T lymphocytes (CD4+, CD8+ and CD4+CD25+) were determined 8 and 20 days after tumor transplantation. Further, the role of CD4+CD25+ (T) in tumor-host interaction was evaluated and by using specific monoclonal antibodies. We found that splenocytes of both control and T depleted tumor bearing mice strongly but differently inhibited growth of tumor cells . While splenocytes of untreated mice exhibited significant decrease of this activity (from 74.4% to 62.6% and 32.95%), the splenocytes of T depleted mice showed increase of this activity (from 79.5% to 84.3% and 86.2%) from day 6 to day 13 and day 21 after tumor grafting, respectively. Further, upon i.v. injecting specific monoclonal anti-T antibody tumor immediately prior to tumor cell intracutaneous transplantation, the tumor was rejected after initial growth. In treated mice, the incidence of T cells was very low initially, reaching normal values two weeks later. These animals were shown to be resistant to tumor transplantation four months later.
Topics: Animals; Antibodies, Monoclonal; Fibrosarcoma; Humans; Mice; Mice, Inbred CBA; T-Lymphocytes, Regulatory
PubMed: 33456124
DOI: 10.20471/acc.2020.59.02.20 -
Food Research International (Ottawa,... Jul 2022Food-derived biopeptides can interact with genes and proteins to preserve health and prevent the development of diseases. Lunasin is a soybean cancer-preventive peptide...
Food-derived biopeptides can interact with genes and proteins to preserve health and prevent the development of diseases. Lunasin is a soybean cancer-preventive peptide that has been well characterized; however, few studies have been carried out to characterize the function of amaranth lunasin-like peptide (AhLun). The aim of this work was to analyze the proteomic profile changes in NIH-3T3 cells when they are chemically transformed with the carcinogen 3-methylcholanthrene (3MC) in the absence or presence of AhLun. The addition of AhLun into the culture medium did not affect the cell morphology; however, as a chemopreventive agent, it significantly reduced anisokaryosis formation when cells were treated with 3MC. Changes in protein accumulation in NIH-3T3 cells were evaluated by gel-based proteomics analysis. Differentially accumulated protein spots that exhibited at least a twofold change in spot intensity (p < 0.05), when compared with control cells, were analyzed by LC-MS/MS. Successfully identified proteins were grouped into six main categories according to their localization and function (nuclear, ribosomal, mitochondrial, metabolism, cytoskeletal, and miscellaneous). The gel-based proteomic approach for the evaluation of the chemopreventive potential of AhLun reveals novel pathways of action and provides new clues about the possible mechanisms of action of this bioactive peptide present in amaranth seeds.
Topics: Animals; Chromatography, Liquid; Mice; NIH 3T3 Cells; Peptides; Proteomics; Tandem Mass Spectrometry
PubMed: 35761629
DOI: 10.1016/j.foodres.2022.111374 -
Drug Metabolism and Disposition: the... Aug 2022[4-(4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazole-5-yl)pyrimidine-2-amine] (JNJ-2482272), under investigation as an anti-inflammatory agent, was orally administered to...
Characterization of JNJ-2482272 [4-(4-Methyl-2-(4-(Trifluoromethyl)Phenyl)Thiazole-5-yl) Pyrimidine-2-Amine] As a Strong Aryl Hydrocarbon Receptor Activator in Rat and Human.
[4-(4-Methyl-2-(4-(trifluoromethyl)phenyl)thiazole-5-yl)pyrimidine-2-amine] (JNJ-2482272), under investigation as an anti-inflammatory agent, was orally administered to rats once daily at 60 mg/kg for 6 consecutive days. Despite high plasma exposure after single administration (C of 7.1 M), JNJ-2482272 had plasma concentrations beneath the lower limit of quantification (3 ng/ml) after 6 consecutive days of dosing. To determine if JNJ-2482272 is an autoinducer in rats, plated rat hepatocytes were treated with JNJ-2482272 for 2 days. The major hydroxylated metabolites of JNJ-2482272 were isolated and characterized by mass spectrometry and NMR analyses. Compared with the vehicle-treated cells, a concentration-dependent increase was observed in the formation of phase I- and II-mediated metabolites coinciding with greater expression of cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs) in rat hepatocytes. CYP1A1, CYP1A2, CYP1B1, and UGT1A6 transcripts were predominantly induced, suggesting that JNJ-2482272 is an activator of the aryl hydrocarbon receptor (AhR). In a human AhR reporter assay, JNJ-2482272 demonstrated potent AhR activation with an EC value of 0.768 nM, a potency more comparable to the strong AhR activator and toxin 2,3,7,8-tetrachloro-dibenzodioxin than to weaker AhR activators 3-methylcholanthrene, -naphthoflavone, and omeprazole. In plated human hepatocytes, JNJ-2482272 induced CYP1A1 gene expression with an EC of 20.4 nM and increased CYP1A activity >50-fold from basal levels. In human recombinant P450s, JNJ-2482272 was exclusively metabolized by the CYP1 family of enzymes and most rapidly by CYP1A1. The summation of these in vitro findings bridges the in vivo conclusion that JNJ-2482272 is a strong autoinducer in rats and potentially in humans through potent AhR activation. SIGNIFICANCE STATEMENT: Drugs that induce their own metabolism (autoinducers) can lack sustained exposures for pharmacology and safety assessment hindering their development. JNJ-2482272 is demonstrated herein as a strong aryl hydrocarbon receptor (AhR) activator and CYP1A autoinducer, explaining its near complete loss of exposure after repeat administration in rat, which is likely translatable to human (if progressed further) considering its nanomolar potency comparable to "classical" AhR ligands like 2,3,7,8-tetrachloro-dibenzo-dioxin despite bearing a "nonclassical" drug structure.
Topics: Amines; Animals; Cytochrome P-450 CYP1A1; Humans; Pyrimidines; Rats; Receptors, Aryl Hydrocarbon; Thiazoles
PubMed: 35680134
DOI: 10.1124/dmd.121.000825 -
Journal of the American Heart... Oct 2021Background Hyperglycemia is associated with greater hematoma expansion (HE) and worse clinical prognosis after intracerebral hemorrhage (ICH). However, the clinical...
Background Hyperglycemia is associated with greater hematoma expansion (HE) and worse clinical prognosis after intracerebral hemorrhage (ICH). However, the clinical benefits of intensive glucose normalization remain controversial, and there are no approved therapies for reducing HE. The aryl hydrocarbon receptor (AHR) has been shown to participate in hyperglycemia-induced blood-brain barrier (BBB) dysfunction and brain injury after stroke. Herein, we investigated the role of AHR in hyperglycemia-induced HE in a male mouse model of ICH. Methods and Results CD1 mice (n=387) were used in this study. Mice were subjected to ICH by collagenase injection. Fifty percent dextrose was injected intraperitoneally 3 hours after ICH. AHR knockout clustered regularly interspaced short palindromic repeat was administered intracerebroventricularly to evaluate the role of AHR after ICH. A selective AHR inhibitor, 6,2',4'-trimethoxyflavone, was administered intraperitoneally 2 hours or 6 hours after ICH for outcome study. To evaluate the effect of AHR on HE, 3-methylcholanthrene, an AHR agonist, was injected intraperitoneally 2 hours after ICH. The results showed hyperglycemic ICH upregulated AHR accompanied by greater HE. AHR inhibition provided neurological benefits by restricting HE and preserving BBB function after hyperglycemic ICH. In vivo knockdown of AHR further limited HE and enhanced the BBB integrity. Hyperglycemia directly activated AHR as a physiological stimulus in vivo. The thrombospondin-1/transforming growth factor-β/vascular endothelial growth factor axis partly participated in AHR signaling after ICH, which inhibited the expressions of BBB-related proteins, ZO-1 and Claudin-5. Conclusions AHR may serve as a potential therapeutic target to attenuate hyperglycemia-induced hematoma expansion and to preserve the BBB in patients with ICH.
Topics: Animals; Cerebral Hemorrhage; Disease Models, Animal; Hematoma; Hyperglycemia; Male; Mice; Receptors, Aryl Hydrocarbon
PubMed: 34622690
DOI: 10.1161/JAHA.121.022701 -
In Vitro Cellular & Developmental... Jan 2020Hepatocyte-derived cell lines provide useful experimental systems for studying liver metabolism. Unlike human and rodents, few hepatocyte-derived cell lines have been...
Hepatocyte-derived cell lines provide useful experimental systems for studying liver metabolism. Unlike human and rodents, few hepatocyte-derived cell lines have been generated from cattle. Here, we established two immortalized bovine hepatocyte-derived cell lines (BH4 and BH5) via transfection with a SV40 large T-antigen construct. Morphological and immunocytochemical analyses revealed that BH4 and BH5 originated from hepatocytes and biliary-epithelial cells, respectively. A potent carcinogen, 3-methylcholanthrene (3-MC), upregulated gene expression of cytochrome P450 (CYP)1A1, CYP1A2, and CYP1B1 in BH4 and BH5, but only to levels less than one-fifteenth of those in primary cultured bovine hepatocytes. Phenobarbital (PB) also increased expression levels of CYP2B6, CYP2C18, and CYP3A4 in BH4 and BH, but at a lower level than 3-MC. By contrast, when BH4 or BH5 was co-cultured with previously established bovine liver sinusoidal cell lines and treated with 3-MC, the gene expression levels of CYP1A1, CYP1A2, and CYP1B1 increased by 38~290%, compared with those in BH4 or BH5 cells cultured alone. PB-treated co-cultures of BH4 or BH5 cells and liver sinusoidal cell lines also showed synergistic increases in CYP2B6 and CYP2C18 expression. Together, the results suggest that these co-cultures could provide an in vitro model for investigations into pharmacological and toxicological properties of drugs in cattle liver.
Topics: Animals; Cattle; Cell Line; Coculture Techniques; Cytochrome P-450 Enzyme System; Gene Expression Regulation, Enzymologic; Hepatocytes; Liver; Pharmaceutical Preparations; RNA, Messenger
PubMed: 31722089
DOI: 10.1007/s11626-019-00408-6 -
Toxicological Sciences : An Official... Oct 2020In 2019, lung cancer was estimated to be the leading cause of cancer deaths in humans. Polycyclic aromatic hydrocarbons (PAHs) are known to increase the risk of lung...
In 2019, lung cancer was estimated to be the leading cause of cancer deaths in humans. Polycyclic aromatic hydrocarbons (PAHs) are known to increase the risk of lung cancer. PAHs are metabolized by the cytochrome P450 (CYP)1A subfamily, comprised of the CYP1A1 and 1A2 monooxygenases. These enzymes bioactivate PAHs into reactive metabolites that induce mutagenic DNA adducts, which can lead to cancer. Past studies have investigated the role of CYP1A1 in PAH bioactivation; however, the individual roles of each CYP1A enzyme are still unknown. In this investigation, we tested the hypothesis that mice lacking the genes for Cyp1a1 or Cyp1a2 will display altered susceptibilities to PAH-induced pulmonary carcinogenesis. Wild-type, Cyp1a1-null (Cyp1a1-/-), and Cyp1a2-null (Cyp1a2-/-) male and female mice were treated with 3-methylcholanthrene for cancer initiation and tumor formation studies. In wild-type mice, CYP1A1 and 1A2 expression was induced by 3-methylcholanthrene. Cyp1a1-/- and Cyp1a2-/- mice treated with PAHs displayed a compensatory pattern, where knocking out 1 Cyp1a gene led to increased expression of the other. Cyp1a1-/- mice were resistant to DNA adduct and tumor formation, whereas Cyp1a2-/- mice displayed increased levels of both. UALCAN analysis revealed that lung adenocarcinoma patients with high levels of CYP1A2 expression survive significantly better than patients with low/medium expression. In conclusion, Cyp1a1-/- mice were less susceptible to PAH-induced pulmonary carcinogenesis, whereas Cyp1a2-/- mice were more susceptible. In addition, high CYP1A2 expression was found to be protective for lung adenocarcinoma patients. These results support the need to develop novel CYP1A1 inhibitors to mitigate human lung cancer.
Topics: Animals; Carcinogenesis; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Cytochrome P-450 Enzyme System; Female; Humans; Male; Mice; Mice, Inbred C57BL; Polycyclic Aromatic Hydrocarbons
PubMed: 32726451
DOI: 10.1093/toxsci/kfaa107