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1.
Drugs Today (Barc) ; 56(8): 515-530, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33025947

RESUMO

There is a need for new and effective topical treatment options for psoriasis. Recent phase I and II clinical trials have demonstrated efficacy of the novel nonsteroidal drug tapinarof to treat mild to moderate plaque psoriasis. Tapinarof is an aryl hydrocarbon receptor (AHR) agonist that induces antioxidant, immunomodulatory and epidermal differentiation regulation pathways. In this review, we examine the current preclinical and clinical studies with a focus on the mechanism of action, pharmacokinetics, safety and efficacy of tapinarof to treat psoriasis.


Assuntos
Psoríase/tratamento farmacológico , Resorcinóis/uso terapêutico , Estilbenos/uso terapêutico , Administração Tópica , Ensaios Clínicos como Assunto , Humanos , Receptores de Hidrocarboneto Arílico/agonistas
2.
Chem Biol Interact ; 331: 109284, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33035518

RESUMO

Glutathione S-transferases (GSTs) are a key enzyme superfamily involved in the detoxification and cytoprotection of a wide variety of xenobiotics, such as carcinogens, anticancer drugs, environmental toxicants, and endogenously produced free radicals. In the liver, the hGSTA1 isoenzyme is the most abundant and catalyzes the glutathione conjugation of a wide range of electrophiles and has been the principal GST responsible for xenobiotic detoxification. Given the critical role of this enzyme in several cellular processes, particularly cell detoxification, understanding the molecular mechanisms underlying the regulation of hGSTA1 expression is critical. Therefore, the aim of the present study was to investigate whether AHR is involved in the modulation of hGSTA1 gene expression and to characterize the molecular mechanism through which AHR exerts this regulation. Two xenobiotic response elements (XREs) were located at -602 bp and -1030 bp from the transcription start site at the hGSTA1 gene promoter. After treatment of HepG2 cells with beta-naphthoflavone (ß-NF), an AHR agonist, induction of hGSTA1 mRNA was observed. This effect was mediated by the recruitment of AHR to the hGSTA1 gene promoter and its transactivation, as indicated by the ChIP, EMSA and luciferase activity assays. The increase in hGSTA1 transcription regulated by AHR also resulted in enhanced levels of hGSTA1 protein and activity. Taken together, our data suggest that AHR ligands have the potential to modify xenobiotic and endobiotic metabolism mediated by hGSTA1, thereby altering the detoxification of xenobiotics, steroidogenesis and the efficacy of chemotherapeutic agents.


Assuntos
Glutationa Transferase/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Sequência de Bases , Ensaio de Desvio de Mobilidade Eletroforética , Inibidores Enzimáticos/farmacologia , Glutationa Transferase/genética , Células Hep G2 , Humanos , Regiões Promotoras Genéticas , Receptores de Hidrocarboneto Arílico/agonistas , Sítio de Iniciação de Transcrição , Ativação Transcricional/efeitos dos fármacos , beta-Naftoflavona/farmacologia
3.
PLoS One ; 15(8): e0237163, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764792

RESUMO

In bovine mammary glands, the ABCG2 transporter actively secretes xenobiotics into dairy milk. This can have significant implications when cattle are exposed to pesticide residues in feed. Recent studies indicate that the fungicide prochloraz activates the aryl hydrocarbon receptor (AhR) pathway, increasing bovine ABCG2 (bABCG2) gene expression and efflux activity. This could enhance the accumulation of bABCG2 substrates in dairy milk, impacting pesticide risk assessment. We therefore investigated whether 13 commonly used pesticides in Europe are inducers of AhR and bABCG2 activity. MDCKII cells expressing mammary bABCG2 were incubated with pesticides for up to 72 h. To reflect an in vivo situation, applied pesticide concentrations corresponded to the maximum residue levels (MRLs) permitted in bovine fat or muscle. AhR activation was ascertained through CYP1A mRNA expression and enzyme activity, measured by qPCR and 7-ethoxyresorufin-Ο-deethylase (EROD) assay, respectively. Pesticide-mediated increase of bABCG2 efflux activity was assessed using the Hoechst 33342 accumulation assay. For all assays, the known AhR-activating pesticide prochloraz served as a positive control, while the non-activating tolclofos-methyl provided the negative control. At 10-fold MRL concentrations, chlorpyrifos-methyl, diflufenican, ioxynil, rimsulfuron, and tebuconazole significantly increased CYP1A1 mRNA levels, CYP1A activity, and bABCG2 efflux activity compared to the vehicle control. In contrast, dimethoate, dimethomorph, glyphosate, iprodione, methiocarb and thiacloprid had no impact on AhR-mediated CYP1A1 mRNA levels, CYP1A activity or bABCG2 efflux. In conclusion, the MDCKII-bABCG2 cell model proved an appropriate tool for identifying AhR- and bABCG2-inducing pesticides. This provides an in vitro approach that could reduce the number of animals required in pesticide approval studies.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Alternativas aos Testes com Animais/métodos , Fungicidas Industriais/toxicidade , Receptores de Hidrocarboneto Arílico/agonistas , Testes de Toxicidade Crônica/métodos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/agonistas , Animais , Bovinos , Cães , Alemanha , Lactação/efeitos dos fármacos , Células Madin Darby de Rim Canino , Receptores de Hidrocarboneto Arílico/metabolismo , Proteínas Recombinantes/metabolismo
4.
Ecotoxicol Environ Saf ; 201: 110808, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32516676

RESUMO

Cyprodinil is a broad-spectrum pyrimidine amine fungicide that has been reportedly used worldwide. However, toxicity studies of cyprodinil on aquatic organisms, specifically zebrafish (Danio rerio), are lacking. In our present study, we predicted cyprodinil binding to the aryl hydrocarbon receptor (AhR) by using molecular docking simulation. Then, we used recombinant HepG2 cells and Tg(cyp1a1-12DRE:egfp) transgenic zebrafish to further assess the AhR agonistic activity of cyprodinil. Besides, the significant upregulation of cyp1a1 further verified that statement. Moreover, we found that zebrafish exposure to cyprodinil induced developmental toxicity in the larvae, particularly during cardiac development. The expression levels of cardiac development-related genes, namely tbx5, nkx2.5, gata4, and tnnt2, were markedly altered, which might cause the adverse effects of cyprodinil on cardiac function and development. In summary, we found that cyprodinil, as an AhR agonist, induced development toxicity in zebrafish larvae, especially on cardiac. Data here can assess the potential effects on organisms in the aquatic environment and promote the regulation and safe use of cyprodinil.


Assuntos
Animais Geneticamente Modificados/metabolismo , Larva/efeitos dos fármacos , Pirimidinas/toxicidade , Receptores de Hidrocarboneto Arílico/agonistas , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Animais , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Fungicidas Industriais/metabolismo , Coração/efeitos dos fármacos , Coração/embriologia , Células Hep G2 , Humanos , Larva/genética , Larva/metabolismo , Simulação de Acoplamento Molecular , Organogênese/efeitos dos fármacos , Organogênese/genética , Ligação Proteica , Peixe-Zebra/genética
5.
Proc Natl Acad Sci U S A ; 117(27): 15837-15845, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571957

RESUMO

Despite broad appreciation of their clinical utility, it has been unclear how vitamin B12 and folic acid (FA) function at the molecular level to directly prevent their hallmark symptoms of deficiency like anemia or birth defects. To this point, B12 and FA have largely been studied as cofactors for enzymes in the one-carbon (1C) cycle in facilitating the de novo generation of nucleotides and methylation of DNA and protein. Here, we report that B12 and FA function as natural antagonists of aryl hydrocarbon receptor (AhR). Our studies indicate that B12 and FA bind AhR directly as competitive antagonists, blocking AhR nuclear localization, XRE binding, and target gene induction mediated by AhR agonists like 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and 6-formylindolo[3,2-b]carbazole (FICZ). In mice, TCDD treatment replicated many of the hallmark symptoms of B12/FA deficiency and cotreatment with aryl hydrocarbon portions of B12/FA rescued mice from these toxic effects. Moreover, we found that B12/FA deficiency in mice induces AhR transcriptional activity and accumulation of erythroid progenitors and that it may do so in an AhR-dependent fashion. Consistent with these results, we observed that human cancer samples with deficient B12/FA uptake demonstrated higher transcription of AhR target genes and lower transcription of pathways implicated in birth defects. In contrast, there was no significant difference observed between samples with mutated and intact 1C cycle proteins. Thus, we propose a model in which B12 and FA blunt the effect of natural AhR agonists at baseline to prevent the symptoms that arise with AhR overactivation.


Assuntos
Ácido Fólico/metabolismo , Desnutrição/metabolismo , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/metabolismo , Vitamina B 12/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Carbazóis/farmacologia , Anormalidades Congênitas , Feminino , Deficiência de Ácido Fólico/tratamento farmacológico , Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias , Dibenzodioxinas Policloradas/farmacologia , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/genética , Deficiência de Vitamina B 12/tratamento farmacológico
6.
Int J Mol Sci ; 21(4)2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32085612

RESUMO

Recent studies strongly support the use of the aryl hydrocarbon receptor (AhR) as a therapeutic target in breast cancer. Glyceollins, a group of soybean phytoalexins, are known to exert therapeutic effects in chronic human diseases and also in cancer. To investigate the interaction between glyceollin I (GI), glyceollin II (GII) and AhR, a computational docking analysis, luciferase assays, immunofluorescence and transcriptome analyses were performed with different cancer cell lines. The docking experiments predicted that GI and GII can enter into the AhR binding pocket, but their interactions with the amino acids of the binding site differ, in part, from those interacting with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Both GI and GII were able to weakly and partially activate AhR, with GII being more potent. The results from the transcriptome assays showed that approximately 10% of the genes regulated by TCDD were also modified by both GI and GII, which could have either antagonistic or synergistic effects upon TCDD activation. In addition, we report here, on the basis of phenotype, that GI and GII inhibit the migration of triple-negative (ER-, PgR-, HER2NEU-) MDA-MB-231 breast cancer cells, and that they inhibit the expression of genes which code for important regulators of cell migration and invasion in cancer tissues. In conclusion, GI and GII are AhR ligands that should be further investigated to determine their usefulness in cancer treatments.


Assuntos
Movimento Celular/efeitos dos fármacos , Pterocarpanos/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Sítios de Ligação , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Pterocarpanos/química , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores Estrogênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transcriptoma/genética
7.
Sci Adv ; 6(3): eaay8230, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31998845

RESUMO

Aryl hydrocarbon receptor (AHR) is an essential regulator of gut immunity and a promising therapeutic target for inflammatory bowel disease (IBD). Current AHR agonists are inadequate for clinical translation due to low activity, inadequate pharmacokinetics, or toxicity. We synthesized a structurally diverse library and used integrated computational and experimental studies to discover mechanisms governing ligand-receptor interaction and to design potent drug leads PY109 and PY108, which display physiochemical drug-likeness properties, desirable pharmacokinetic profiles, and low toxicity. In a murine model of dextran sulfate sodium-induced colitis, orally administered compounds increase interleukin-22 (IL-22) production and accelerate mucosal healing by modulating mucosal adaptive and innate lymphoid cells. AHR and IL-22 pathway induction was confirmed using RNA sequencing and characterization of the lymphocyte protein-protein interaction network. Significant induction of IL-22 was also observed using human T cells from patients with IBD. Our findings support rationally designed AHR agonists for IBD therapy.


Assuntos
Desenho de Fármacos , Imunomodulação/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Receptores de Hidrocarboneto Arílico/agonistas , Cicatrização/efeitos dos fármacos , Cicatrização/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Peptídeos Catiônicos Antimicrobianos/farmacologia , Colite/etiologia , Colite/metabolismo , Colite/patologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Estabilidade de Medicamentos , Expressão Gênica , Humanos , Interleucinas/biossíntese , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Ligantes , Linfócitos/imunologia , Camundongos , Modelos Moleculares , Conformação Molecular , Receptores de Hidrocarboneto Arílico/química , Regeneração , Relação Estrutura-Atividade , Linfócitos T/imunologia , Linfócitos T/metabolismo , Cicatrização/genética
8.
J Invest Dermatol ; 140(2): 415-424.e10, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31344386

RESUMO

Skin colonization by Staphylococcus aureus and its relative abundance is associated with atopic dermatitis (AD) disease severity and treatment response. Low levels of antimicrobial peptides in AD skin may be related to the microbial dysbiosis. Therapeutic targeting of the skin microbiome and antimicrobial peptide expression can, therefore, restore skin homeostasis and combat AD. In this study, we analyzed the cutaneous microbiome composition in 7 patients with AD and 10 healthy volunteers upon topical coal tar or vehicle treatment. We implemented and validated a Staphylococcus-specific single-locus sequence typing approach combined with classic 16S ribosomal RNA marker gene sequencing to study the bacterial composition. During coal tar treatment, Staphylococcus abundance decreased, and Propionibacterium abundance increased, suggesting a shift of the microbiota composition toward that of healthy controls. We, furthermore, identified a hitherto unknown therapeutic mode of action of coal tar, namely the induction of keratinocyte-derived antimicrobial peptides via activation of the aryl hydrocarbon receptor. Restoring antimicrobial peptide levels in AD skin via aryl hydrocarbon receptor-dependent transcription regulation can be beneficial by creating a (anti)microbial milieu that is less prone to infection and inflammation. This underscores the importance of coal tar in the therapeutic aryl hydrocarbon receptor armamentarium and highlights the aryl hydrocarbon receptor as a target for drug development.


Assuntos
Anti-Infecciosos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Alcatrão/farmacologia , Dermatite Atópica/tratamento farmacológico , Disbiose/tratamento farmacológico , Microbiota/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/agonistas , Pele/microbiologia , Administração Cutânea , Adulto , Anti-Infecciosos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/imunologia , Peptídeos Catiônicos Antimicrobianos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Biópsia , Linhagem Celular , Alcatrão/uso terapêutico , Dermatite Atópica/imunologia , Dermatite Atópica/microbiologia , Dermatite Atópica/patologia , Disbiose/imunologia , Disbiose/microbiologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Voluntários Saudáveis , Humanos , Queratinócitos , Masculino , Microbiota/imunologia , Pessoa de Meia-Idade , Cultura Primária de Células , Propionibacterium/imunologia , Propionibacterium/isolamento & purificação , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Creme para a Pele/farmacologia , Creme para a Pele/uso terapêutico , Staphylococcus aureus/imunologia , Staphylococcus aureus/isolamento & purificação , Adulto Jovem
9.
Toxicol Lett ; 320: 37-45, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31778776

RESUMO

As a major toxicant which is abundant in tobacco smoking, benzo(a)pyrene (BaP) is considered as a strong carcinogen of lung cancer. In spite of the intensive research, the role that BaP plays in lung cancer still lacks a comprehensive and precise understanding. Recently, a long non-coding RNA, linc00673, has emerged as a central player in different kinds of malignancies, including non-small cell lung cancer (NSCLC). In the present study, we found that BaP with the concentration of no more than 8 µM did not affect cell proliferation in the NSCLC cell line A549, while it significantly enhanced A549 cell migration and invasion. Further results revealed that BaP promoted mesenchymal biomarkers expression and inhibited the major epithelial biomarker E-cadherin in a time and dose dependent manner, which indicated epithelial-mesenchymal transition (EMT) was induced by BaP in A549 cells. Through quantitative real-time PCR, we observed that BaP significantly elevated the expression level of linc00673. While after the knockdown of aryl hydrocarbon receptor (AHR), the up-regulating effect of BaP on linc00673 was reversed. Furthermore, silencing linc00673 significantly suppressed the BaP-induced migration, invasion, and EMT in A549 cells. In summary, our study demonstrates that BaP promotes A549 cell migration, invasion and EMT through up-regulating the expression of linc00673 in an AHR-dependent manner.


Assuntos
Benzo(a)pireno/toxicidade , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , RNA Longo não Codificante/metabolismo , Células A549 , Antígenos CD/genética , Antígenos CD/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Caderinas/genética , Caderinas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Invasividade Neoplásica , RNA Longo não Codificante/genética , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Fatores de Tempo , Regulação para Cima
10.
Toxicol Lett ; 319: 85-94, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31730885

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a chronic hepatic disease associated with the excessive accumulation of lipids in the liver. Premenopausal women are protected from the liver metabolic complications of obesity compared with body mass index (BMI)-matched men. This protection may be related to estrogen's ability to limit liver fat accumulation. Aryl hydrocarbon receptor (AhR), a novel regulator of NAFLD, may be an important target for regulating estrogen homeostasis. In present study, we used benzo[a]pyrene (BaP), a classic and potent ligand of AhR, to activate AhR pathway causes overexpression of the estrogen-metabolizing enzyme cytochrome P450 1A1 (CYP1A1) and affects the expression of important genes involved in hepatic lipid regulation. BaP induces CYP1A1 expression through AhR signaling and inhibits the protective effect of 17ß-estradiol (E2) on hepatic steatosis, characterized by triglyceride accumulation, and markers of liver damage are significantly elevated. The expression of adipogenic genes involved in the hepatic lipid metabolism of sterol regulatory element-binding protein-1c (SREBP-1c) was increased compared with that in the control group. Furthermore, the mRNA and protein levels of peroxisome proliferator-activated receptor alpha (PPARα), which is involved in fatty acid oxidation, were significantly reduced. Taken together, our results revealed that the steatotic effect of AhR is likely due to overexpression of the E2 metabolic enzyme CYP1A1, which affects the estrogen signaling pathway, leading to the suppression of fatty acid oxidation, inhibition of the hepatic export of triglycerides, and an increase in peripheral fat mobilization. The results from this study may help establish AhR as a novel therapeutic and preventive target for fatty liver disease.


Assuntos
Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Animais , Benzo(a)pireno/farmacologia , Citocromo P-450 CYP1A1/biossíntese , Citocromo P-450 CYP1A1/genética , Estradiol/farmacologia , Estrogênios/metabolismo , Feminino , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , PPAR alfa/biossíntese , PPAR alfa/genética , Receptores de Hidrocarboneto Arílico/agonistas , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/biossíntese , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Triglicerídeos/metabolismo
11.
Eur J Med Chem ; 185: 111842, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31727470

RESUMO

Aryl Hydrocarbon Receptor (AhR) constitutes a major network hub of genomic and non-genomic signaling pathways, connecting host's immune cells to environmental factors. It shapes innate and adaptive immune processes to environmental stimuli with species-, cell- and tissue-type dependent specificity. Although an ever increasing number of studies has thrust AhR into the limelight as attractive target for the development of next-generation immunotherapies, concerns exist on potential safety issues associated with small molecule modulation of the receptor. Selective AhR modulators (SAhRMs) and rapidly metabolized AhR ligands (RMAhRLs) are two classes of receptor agonists that are emerging as interesting lead compounds to bypass AhR-related toxicity in favor of therapeutic effects. In this article, we discuss SAhRMs and RMAhRLs reported in literature, covering concepts underlying their definitions, specific binding modes, structure-activity relationships and AhR-mediated functions.


Assuntos
Doenças do Sistema Imunitário/terapia , Imunoterapia , Receptores de Hidrocarboneto Arílico/agonistas , Animais , Humanos , Doenças do Sistema Imunitário/imunologia , Ligantes , Estrutura Molecular
12.
Toxicol Lett ; 321: 114-121, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31830554

RESUMO

Despite numerous studies on the toxicities of planar polycyclic aromatic hydrocarbons (PAHs), very little is known about the toxicological profiles of non-planar PAHs. In the present study, the cytotoxicity of corannulene (COR), a typical bowl-shaped PAH with a myriad of applications in the area of material chemistry, and benzo[a]pyrene (BaP), a typical planar PAH with similar molecular weight, were systematically compared in various cell lines. Compared with BaP, exposure to COR resulted in less cytotoxic responses in both human (HepG2) and murine (Hepa1-6) hepatoma cells, which was characterized with a slower cellular accumulation as well as a weaker induction of cytochrome P450 1 (CYP1/Cyp1) isozymes. Knockdown of aryl hydrocarbon receptor (AhR) by siRNA attenuated the inductive effect of COR on CYP1A/Cyp1a mRNA levels in these two cell lines. Further analysis revealed that derivatization greatly influenced the cytotoxicity of COR, which was positively correlated with their binding affinities to the AhR, as demonstrated by in silico molecular docking. Overall, these results suggest that AhR appears to be involved in the cytotoxic responses of COR and its derivatives, providing a fundamental understanding of the biological effects of bowl-like PAHs.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Hepatócitos/efeitos dos fármacos , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Receptores de Hidrocarboneto Arílico/agonistas , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Sítios de Ligação , Citocromo P-450 CYP1A1/biossíntese , Citocromo P-450 CYP1A1/genética , Indução Enzimática , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Camundongos , Simulação de Acoplamento Molecular , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Ligação Proteica , Conformação Proteica , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade
13.
Environ Int ; 133(Pt B): 105199, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31675573

RESUMO

This study utilized effect-directed analysis (EDA) combined with full-scan screening analysis (FSA) to identify aryl hydrocarbon receptor (AhR)-active compounds in sediments of inland creeks flowing into Lake Sihwa, South Korea. The specific objectives were to (i) investigate the major AhR-active fractions of organic extracts of sediments by using H4IIE-luc in vitro bioassay (4 h and 72 h exposures), (ii) quantify known AhR agonists, such as polycyclic aromatic hydrocarbons (PAHs) and styrene oligomers (SOs), (iii) identify unknown AhR agonists by use of gas chromatography-quadrupole time-of-flight mass spectrometry (GC-QTOFMS), and (iv) determine contributions of AhR agonists to total potencies measured by use of the bioassay. FSA was conducted on fractions F2.6 and F2.7 (aromatics with log Kow 5-7) in extracts of sediment from Siheung Creek (industrial area). Those fractions exhibited significant AhR-mediated potency as well as relatively great concentrations of PAHs and SOs. FSA detected 461 and 449 compounds in F2.6 and F2.7, respectively. Of these, five tentative candidates of AhR agonist were selected based on NIST library matching, aromatic structures and numbers of rings, and available standards. Benz[b]anthracene, 11H-benzo[a]fluorene, and 4,5-methanochrysene exhibited significant AhR-mediated potency in the H4IIE-luc bioassay, and relative potencies of these compounds were determined. Potency balance analysis demonstrated that these three newly identified AhR agonists explained 1.1% to 67% of total induced AhR-mediated potencies of samples, which were particularly great for industrial sediments. Follow-up studies on sources and ecotoxicological effects of these compounds in coastal environments would be required.


Assuntos
Sedimentos Geológicos/análise , Receptores de Hidrocarboneto Arílico/agonistas , Poluentes Químicos da Água/farmacologia , Animais , Bioensaio/métodos , Linhagem Celular Tumoral , Monitoramento Ambiental/métodos , Cromatografia Gasosa-Espectrometria de Massas , Lagos/química , Hidrocarbonetos Policíclicos Aromáticos/análise , Hidrocarbonetos Policíclicos Aromáticos/farmacologia , Ratos , República da Coreia , Estireno/análise , Estireno/farmacologia , Poluentes Químicos da Água/análise
14.
Front Immunol ; 10: 2364, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681274

RESUMO

Vulvovaginal candidiasis (VVC) is a common mucosal infection caused by Candida spp., most frequently by Candida albicans, which may become recurrent and severely impacting the quality of life of susceptible women. Although it is increasingly being recognized that mucosal damage is mediated by an exaggerated inflammatory response, current therapeutic approaches are only based on antifungals that may relieve the symptomatology, but fail to definitely prevent recurrences. The unrestrained activation of the NLRP3 inflammasome with continuous production of IL-1ß and recruitment of neutrophils is recognized as a pathogenic factor in VVC. We have previously shown that IL-22 is required to dampen pathogenic inflammasome activation in VVC via the NLRC4/IL-1Ra axis. However, IL-22 also regulates IL-18, a product of the inflammasome activity that regulates IL-22 expression. Here we describe a cross-regulatory circuit between IL-18 and IL-22 in murine VVC that is therapeutically druggable. We found that IL-18 production was dependent on IL-22 and NLRC4, and that IL-18, in turn, contributes to IL-22 activity. Like in IL-22 deficiency, IL-18 deficiency was associated with an increased susceptibility to VVC and unbalanced Th17/Treg response, suggesting that IL-18 can regulate both the innate and the adaptive responses to the fungus. Administration of the microbial metabolite indole-3-aldehyde, known to stimulate the production of IL-22 via the aryl hydrocarbon receptor (AhR), promoted IL-18 expression and protection against Candida infection. Should low levels of IL-18 be demonstrated in the vaginal fluids of women with recurrent VVC, targeting the AhR/IL-22/IL-18 pathway could be exploited for future therapeutic approaches in VVC. This study suggests that a deeper understanding of the mechanisms regulating inflammasome activity may lead to the identification of novel targets for intervention in VVC.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Candida albicans/imunologia , Candidíase Vulvovaginal , Indóis/farmacologia , Interleucina-18/imunologia , Interleucinas/imunologia , Receptores de Hidrocarboneto Arílico/agonistas , Transdução de Sinais/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Candidíase Vulvovaginal/tratamento farmacológico , Candidíase Vulvovaginal/genética , Candidíase Vulvovaginal/imunologia , Candidíase Vulvovaginal/patologia , Feminino , Inflamassomos/genética , Inflamassomos/imunologia , Interleucina-18/genética , Interleucinas/genética , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Células Th17/imunologia , Células Th17/patologia
15.
Chem Res Toxicol ; 32(11): 2353-2364, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31621310

RESUMO

Many of the protective responses observed for flavonoids in the gastrointestinal track resemble aryl hydrocarbon receptor (AhR)-mediated effects. Therefore, we examined the structure-activity relationships of isoflavones and isomeric flavone and flavanones as AhR ligands on the basis of their induction of CYP1A1, CYP1B1, and UGT1A1 gene expression in colon cancer Caco2 cells and young adult mouse colonocyte (YAMC) cells. Caco2 cells were significantly more Ah-responsive than YAMC cells, and this was due, in part, to flavonoid-induced cytotoxicity in the latter cell lines. The structure-activity relationships for the flavonoids were complex and both response and cell context specific; however, there was significant variability in the AhR activities of the isomeric substituted isoflavones and flavones. For example, 4',5,7-trihydroxyisoflavone (genistein) was AhR-inactive whereas 4',5,7-trihydroxyflavone (apigenin) induced CYP1A1, CYP1B1, and UGT1A1 in Caco2 cells. In contrast, both 5,7-dihydroxy-4-methoxy substituted isoflavone (biochanin A) and flavone (acacetin) induced all three AhR-responsive genes; 4',5,7-trimethoxyisoflavone was a potent AhR agonist, and the isomeric flavone was AhR-inactive. These results coupled with simulation studies modeling flavonoid interaction within the AhR binding pocket demonstrate that the orientation of the substituted phenyl ring at C-2 (flavones) or C-3 (isoflavones) on the common 4-H-chromen-4-one ring strongly influences the activities of isoflavones and flavones as AhR agonists.


Assuntos
Flavonoides/farmacologia , Receptores de Hidrocarboneto Arílico/agonistas , Animais , Linhagem Celular , Colo/citologia , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/metabolismo , Flavonoides/química , Glucuronosiltransferase/metabolismo , Humanos , Camundongos , Modelos Moleculares , Relação Estrutura-Atividade
16.
Int J Mol Sci ; 20(18)2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31540101

RESUMO

Sesquiterpenes, the main components of plant essential oils, are bioactive compounds with numerous health-beneficial activities. Sesquiterpenes can interact with concomitantly administered drugs due to the modulation of drug-metabolizing enzymes (DMEs). The aim of this study was to evaluate the modulatory effects of six sesquiterpenes (farnesol, cis-nerolidol, trans-nerolidol, α-humulene, ß-caryophyllene, and caryophyllene oxide) on the expression of four phase I DMEs (cytochrome P450 3A4 and 2C, carbonyl reductase 1, and aldo-keto reductase 1C) at both the mRNA and protein levels. For this purpose, human precision-cut liver slices (PCLS) prepared from 10 patients and transfected HepG2 cells were used. Western blotting, quantitative real-time PCR and reporter gene assays were employed in the analyses. In the reporter gene assays, all sesquiterpenes significantly induced cytochrome P450 3A4 expression via pregnane X receptor interaction. However in PCLS, their effects on the expression of all the tested DMEs at the mRNA and protein levels were mild or none. High inter-individual variabilities in the basal levels as well as in modulatory efficacy of the tested sesquiterpenes were observed, indicating a high probability of marked differences in the effects of these compounds among the general population. Nevertheless, it seems unlikely that the studied sesquiterpenes would remarkably influence the bioavailability and efficacy of concomitantly administered drugs.


Assuntos
Aldo-Ceto Redutases/metabolismo , Carbonil Redutase (NADPH)/metabolismo , Citocromo P-450 CYP3A/metabolismo , Família 2 do Citocromo P450/metabolismo , Receptor de Pregnano X/agonistas , Sesquiterpenos/farmacologia , Idoso , Idoso de 80 Anos ou mais , Sistema Enzimático do Citocromo P-450/metabolismo , Farneseno Álcool/farmacologia , Feminino , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Fígado/enzimologia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Sesquiterpenos Monocíclicos/farmacologia , Sesquiterpenos Policíclicos/farmacologia , Receptor de Pregnano X/metabolismo , RNA Mensageiro/metabolismo , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/metabolismo
17.
J Immunol ; 203(7): 1830-1844, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31492743

RESUMO

The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant, is a potent ligand for aryl hydrocarbon receptor (AhR). In the current study, we made an exciting observation that naive C57BL/6 mice that were exposed i.p. to TCDD showed massive mobilization of myeloid-derived suppressor cells (MDSCs) in the peritoneal cavity. These MDSCs were highly immunosuppressive and attenuated Con A-induced hepatitis upon adoptive transfer. TCDD administration in naive mice also led to induction of several chemokines and cytokines in the peritoneal cavity and serum (CCL2, CCL3, CCL4, CCL11, CXCL1, CXCL2, CXCL5, CXCL9, G-CSF, GM-CSF, VEGF, and M-CSF) and chemokine receptors on MDSCs (CCR1, CCR5, and CXCR2). Treatment with CXCR2 or AhR antagonist in mice led to marked reduction in TCDD-induced MDSCs. TCDD-induced MDSCs had high mitochondrial respiration and glycolytic rate and exhibited differential microRNA (miRNA) expression profile. Specifically, there was significant downregulation of miR-150-5p and miR-543-3p. These two miRNAs targeted and enhanced anti-inflammatory and MDSC-regulatory genes, including IL-10, PIM1, ARG2, STAT3, CCL11 and its receptors CCR3 and CCR5 as well as CXCR2. The role of miRs in MDSC activation was confirmed by transfection studies. Together, the current study demonstrates that activation of AhR in naive mice triggers robust mobilization of MDSCs through induction of chemokines and their receptors and MDSC activation through regulation of miRNA expression. AhR ligands include diverse compounds from environmental toxicants, such as TCDD, that are carcinogenic to dietary indoles that are anti-inflammatory. Our studies provide new insights on how such ligands may regulate health and disease through induction of MDSCs.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Regulação da Expressão Gênica/imunologia , Tolerância Imunológica , Células Supressoras Mieloides/imunologia , Receptores de Hidrocarboneto Arílico/imunologia , Receptores de Interleucina-8B/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Quimiocinas/imunologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/patologia , Camundongos , MicroRNAs , Células Supressoras Mieloides/patologia , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/agonistas
18.
Environ Pollut ; 254(Pt B): 113098, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31479813

RESUMO

While humans are exposed to mixtures of persistent organic pollutants (POPs), their risk assessment is usually based on a chemical-by-chemical approach. To assess the health effects associated with mixed exposures, knowledge on mixture toxicity is required. Several POPs are potential ligands of the Aryl hydrocarbon receptor (AhR), which involves in xenobiotic metabolism and controls many biological pathways. This study assesses AhR agonistic and antagonistic activities of 29 POPs individually and in mixtures by using Chemical-Activated LUciferase gene eXpression bioassays with 3 transgenic cell lines (rat hepatoma DR-H4IIE, human hepatoma DR-Hep G2 and human mammary gland carcinoma DR-T47-D). Among the 29 POPs, which were selected based on their abundance in Scandinavian human blood, only 4 exerted AhR agonistic activities, while 16 were AhR antagonists in DR-H4IIE, 5 in DR-Hep G2 and 7 in DR-T47-D when tested individually. The total POP mixture revealed to be AhR antagonistic. It antagonized EC50 TCDD inducing AhR transactivation at a concentration of 125 and 250 and 500 fold blood levels in DR-H4IIE, DR-T47-D and DR-Hep G2, respectively, although each compound was present at these concentrations lower than their LOEC values. Such values could occur in real-life in food contamination incidents or in exposed populations. In DR-H4IIE, the antagonism of the total POP mixture was due to chlorinated compounds and, in particular, to PCB-118 and PCB-138 which caused 90% of the antagonistic activity in the POP mixture. The 16 active AhR antagonists acted additively. Their mixed effect was predicted successfully by concentration addition or generalized concentration addition models, rather than independent action, with only two-fold IC50 underestimation. We also attained good predictions for the full dose-response curve of the antagonistic activity of the total POP mixture.


Assuntos
Poluentes Ambientais/farmacologia , Bifenilos Policlorados/farmacologia , Receptores de Hidrocarboneto Arílico/química , Ativação Transcricional/efeitos dos fármacos , Animais , Linhagem Celular , Humanos , Bifenilos Policlorados/química , Ratos , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores
19.
Cancer Invest ; 37(8): 367-375, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31462083

RESUMO

The aryl hydrocarbon receptor (AhR) is activated by the ligand, benzo[a]pyrene (B[a]P), a component of smoke that is implicated in lung carcinogenesis in humans. However, the role of B[a]P and AhR in lung cancer malignancy is not well known. In this study, we analyzed the effects of B[a]P and AhR in the 3 D spheroids of human lung cancer cells in vitro. In these spheroids, B[a]P and AhR enhanced cancer cell proliferation. These results suggest that the AhR-dependent effects of B[a]P on cell proliferation may contribute to the adverse effects of continuous smoking with respect to lung cancer malignancy.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Benzo(a)pireno/toxicidade , Proliferação de Células/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Receptores de Hidrocarboneto Arílico/agonistas , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Esferoides Celulares
20.
Mol Cell Biol ; 39(20)2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31358547

RESUMO

Transgenic mice expressing a constitutively active form of the aryl hydrocarbon receptor in keratinocytes (AhR-CA mice) develop severe dermatitis that substantially recapitulates the pathology of human atopic dermatitis. The neurotrophic factor artemin (Artn) is highly expressed in the epidermis of AhR-CA mice and causes hypersensitivity to itch (alloknesis) by elongating nerves into the epidermis. However, whether the Artn gene is regulated directly by AhR or indirectly through complex regulation associated with AhR remains unclear. To this end, we previously conducted chromatin immunoprecipitation-sequencing analyses of the Artn locus and found a xenobiotic response element (XRE) motif located far upstream (52 kb) of the gene. Therefore, in this study, we addressed whether the XRE actually regulates the Artn gene expression by deleting the region containing the motif. We generated two lines of ArtnΔXRE mice. In the mouse epidermis, inducible expression of the Artn gene by the AhR agonist 3-methylcholanthrene was substantially suppressed compared to that in wild-type mice. Importantly, in AhR-CA::ArtnΔXRE mice, Artn expression was significantly suppressed, and alloknesis was improved. These results demonstrate that the Artn gene is indeed regulated by the distal XRE-containing enhancer, and alloknesis in AhR-CA mice is provoked by the AhR-mediated direct induction of the Artn gene.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Dermatite Atópica , Proteínas do Tecido Nervoso/genética , Receptores de Hidrocarboneto Arílico/genética , Poluentes Atmosféricos/toxicidade , Animais , Anticorpos Neutralizantes/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/patologia , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Metilcolantreno/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/metabolismo , Elementos de Resposta , Pele/metabolismo , Xenobióticos/toxicidade
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