Aryl Hydrocarbon
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2022 ◽  
Vol 10 (1) ◽  
pp. 188
Author(s):  
Filomena Fiorito ◽  
Claudia Cerracchio ◽  
Maria Michela Salvatore ◽  
Francesco Serra ◽  
Alessia Pucciarelli ◽  
...  

Bovine herpesvirus type-1 (BoHV-1) is a widespread pathogen that provokes infectious rhinotracheitis and polymicrobial infections in cattle, resulting in serious economic losses to the farm animal industry and trade restrictions. To date, non-toxic active drugs against BoHV-1 are not available. The exploitation of bioactive properties of microbial products is of great pharmaceutical interest. In fact, fungi are a promising source of novel drugs with a broad spectrum of activities and functions, including antiviral properties. Hence, the potential antiviral properties of 3-O-methylfunicone (OMF), a secondary metabolite produced by Talaromyces pinophilus, were evaluated on BoHV-1. In this study, during BoHV-1 infection in bovine cells (MDBK), the non-toxic concentration of 5 µM OMF considerably reduced signs of cell death and increased cell proliferation. Furthermore, OMF significantly decreased the virus titer as well as the cytopathic effect and strongly inhibited the expression of bICP0, the major regulatory protein in the BoHV-1 lytic cycle. These findings were accompanied by a considerable up-regulation in the expression of the aryl hydrocarbon receptor (AhR), a multifunctional transcription factor also linked to the host’s response to a herpesvirus infection. Overall, our results suggest that by involving AhR, OMF shows potential against a BoHV-1 infection.


2022 ◽  
Vol 23 (2) ◽  
pp. 920
Author(s):  
David Hutin ◽  
Karoline Alvik Hagen ◽  
Peng Shao ◽  
Kim Sugamori ◽  
Denis M. Grant ◽  
...  

Poly-ADP-ribose polymerases (PARPs) are important regulators of the immune system, including TCDD-inducible poly-ADP-ribose polymerase (TIPARP), also known as poly-ADP-ribose polymerase 7 (PARP7). PARP7 negatively regulates aryl hydrocarbon receptor (AHR) and type I interferon (IFN-I) signaling, both of which have been implicated in intestinal homeostasis and immunity. Since the loss of PARP7 expression increases AHR and IFN-I signaling, we used a murine dextran sulfate sodium (DSS)-induced colitis model to investigate the effect of PARP7 loss on DSS-induced intestinal inflammation. DSS-exposed Parp7−/− mice had less body weight loss, lower disease index scores, and reduced expression of several inflammation genes, including interleukin IL-6, C-x-c motif chemokine ligand 1 (Cxcl1), and lipocalin-2, when compared with wild-type mice. However, no significant difference was observed between genotypes in the colonic expression of the AHR target gene cytochrome P450 1A1 (Cyp1a1). Moreover, no significant differences in microbial composition were observed between the genotypes. Our findings demonstrate that the absence of PARP7 protein results in an impaired immune response to colonic inflammation and suggests that PARP7 may participate in the recruitment of immune cells to the inflammation site, which may be due to its role in IFN-I signaling rather than AHR signaling.


Antibodies ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 4
Author(s):  
Ashleigh J. Nicaise ◽  
Amye McDonald ◽  
Erin Rushing Sears ◽  
Trell Sturgis ◽  
Barbara L. F. Kaplan

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) is a ligand for the aryl hydrocarbon receptor (AhR). TCDD is well-characterized to produce immunotoxicity, including suppression of antibody production. Previously we showed that TCDD inhibited myelin oligodendrocyte glycoprotein (MOG) peptide-specific IgG and attenuated disease in experimental autoimmune encephalomyelitis (EAE) model in mice. Thus, the purpose of this study was to characterize the effects of TCDD on IgG subclasses in EAE and in vitro and assess effects in B cells derived from various tissues. TCDD modestly suppressed intracellular IgG expression in splenocytes (SPLC), but not bone marrow (BM) or lymph node (LN) cells. To further understand TCDD’s effects on IgG, we utilized LPS and LPS + IL-4 in vitro to stimulate IgG3 and IgG1 production, respectively. TCDD preferentially suppressed IgG1+ cell surface expression, especially in SPLC. However, TCDD was able to suppress IgG1 and IgG3 secretion from SPLC and B cells, but not BM cells. Lastly, we revisited the EAE model and determined that TCDD suppressed MOG-specific IgG1 production. Together these data show that the IgG1 subclass of IgG is a sensitive target of suppression by TCDD. Part of the pathophysiology of EAE involves production of pathogenic antibodies that can recruit cytolytic cells to destroy MOG-expressing cells that comprise myelin, so inhibition of IgG1 likely contributes to TCDD’s EAE disease attenuation.


Toxics ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 26
Author(s):  
Manhai Long ◽  
Maria Wielsøe ◽  
Eva Cecilie Bonefeld-Jørgensen

Exposure to lipophilic persistent organic pollutants (lipPOPs) elicits a number of species- and tissue-specific toxic responses, many of which involve the aryl hydrocarbon receptor (AhR). This study aims to measure the combined serum dioxin-like activity of lipPOPs in Greenlandic Inuit pregnant women and the associations with fetal growth indices. The combined dioxin-like activity of serum lipPOPs extracts was determined using the AhR reporter gene bioassay and expressed as pico-gram (pg) TCDD equivalent (TEQ) per gram serum lipid [AhR-TEQ (pg/g lipid)]. Significant AhR-TEQ was found in > 87% of serum samples with the median level of 86.2 pg TEQ/g lipid. The AhR-TEQ level positively correlated with the marine food intake biomarker n-3/n-6 polyunsaturated fatty acids ratio, while negatively correlated with body mass index and parity. Women giving birth to infants with low birth weight (<2500 g) and length (<50 cm) had higher AhR-TEQ level compared to those with normal weight and length infants. For previous smokers, we found significant inverse associations between maternal AhR-TEQ level and fetal growth indices. In conclusion, exposure of Greenlandic Inuit pregnant women to dioxin-like compounds through traditional marine food can adversely influence the fetal growth via induced AhR activity. Smoking might have modifying effects.


2022 ◽  
Author(s):  
Eva-Lena Stange ◽  
Franziska Rademacher ◽  
Katharina Antonia Drerup ◽  
Nina Heinemann ◽  
Lena Möbus ◽  
...  

Staphylococcus (S.) aureus is an important pathogen causing various infections including - as most frequently isolated bacterium - cutaneous infections. Keratinocytes as the first barrier cells of the skin respond to S. aureus by the release of defense molecules such as cytokines and antimicrobial peptides. Although several pattern recognition receptors expressed in keratinocytes such as Toll-like and NOD-like receptors have been reported to detect the presence of S. aureus, the mechanisms underlying the interplay between S. aureus and keratinocytes are still emerging. Here we report that S. aureus induced gene expression of CYP1A1 and CYP1B1, responsive genes of the aryl hydrocarbon receptor (AhR). AhR activation by S. aureus was further confirmed by AhR gene reporter assays. AhR activation was mediated by factor(s) < 2 kDa secreted by S. aureus. Whole transcriptome analyses and real-time PCR analyses identified IL-24, IL-6 and IL-1beta as cytokines induced in an AhR-dependent manner in S. aureus-treated keratinocytes. AhR inhibition in a 3D organotypic skin equivalent confirmed the crucial role of the AhR in mediating the induction of IL-24, IL-6 and IL-1beta upon stimulation with living S. aureus. Taken together, we further highlight the important role of the AhR in cutaneous innate defense and identified the AhR as a novel receptor mediating the sensing of the important skin pathogen S. aureus in keratinocytes.


2022 ◽  
pp. 026988112110558
Author(s):  
K Fehsel ◽  
K Schwanke ◽  
BA Kappel ◽  
E Fahimi ◽  
E Meisenzahl-Lechner ◽  
...  

Background: The superior therapeutic benefit of clozapine is often associated with metabolic disruptions as obesity, insulin resistance, tachycardia, higher blood pressure, and even hypertension. Aims: These adverse vascular/ metabolic events under clozapine are similar to those caused by polycyclic aromatic hydrocarbons (PAHs), and clozapine shows structural similarity to well-known ligands of the aryl hydrocarbon receptor (AhR). Therefore, we speculated that the side effects caused by clozapine might rely on AhR signaling. Methods: We examined clozapine-induced AhR activation by luciferase reporter assays in hepatoma HepG2 cells and we proved upregulation of the prototypical AhR target gene Cyp1A1 by realtime-PCR (RT-PCR) analysis and enzyme activity. Next we studied the physiological role of AhR in clozapine’s effects on human preadipocyte differentiation and on vasodilatation by myography in wild-type and AhR-/- mice. Results: In contrast to other antipsychotic drugs (APDs), clozapine triggered AhR activation and Cyp1A1 expression in HepG2 cells and adipocytes. Clozapine induced adipogenesis via AhR signaling. After PGF2α-induced constriction of mouse aortic rings, clozapine strongly reduced the maximal vasorelaxation under acetylcholine in rings from wild-type mice, but only slightly in rings from AhR-/- mice. The reduction was also prevented by pretreatment with the AhR antagonist CH-223191. Conclusion: Identification of clozapine as a ligand for the AhR opens new perspectives to explain common clozapine therapy-associated adverse effects at the molecular level.


2022 ◽  
Author(s):  
Courtney R. Rivet-Noor ◽  
Andrea R. Merchak ◽  
Sihan Li ◽  
Rebecca M. Beiter ◽  
Sangwoo Lee ◽  
...  

Abstract Current treatments for major depressive disorder are limited to neuropharmacological approaches and are ineffective for large numbers of patients. Recently, alternative means have been explored to understand the etiology of depression. Specifically, changes in the microbiome and immune system have been observed in both clinical settings and in mouse models. As such, microbial supplements and probiotics have become a target for potential therapeutics. A current hypothesis for the mechanism of action of these supplements is via the aryl hydrocarbon receptor’s (AHR) modulation of the T helper 17 cell (Th17) and T regulatory cell axis. As inflammatory RORgt+ CD4+ Th17 T cells and their primary cytokine IL-17 have been implicated in the development of stress-induced depression, the connection between stress, the AHR, Th17s and depression remains critical to disease understanding. Here, we utilize genetic knockouts to examine the role of the microbial sensor AHR in the development of stress induced despair behavior. We observe an AHR-independent increase in gut-associated Th17s in stressed mice, indicating that AHR is not responsible for this communication. Further, we utilized a CD4-specific Rorc knockout line to disrupt the production of Th17s. Mice lacking Rorc induced IL-17 did not show any differences in behavior from controls before or after stress. Finally, we utilize an unsupervised machine learning system to examine minute differences in behavior that could not be observed in traditional behavioral assays. Our data demonstrate that neither CD4 specific Ahr nor Rorc are necessary for the development of stress-induced anxiety-or depressive-like behaviors. These data suggest that research approaches should focus on other sources or sites of IL-17 production in stress-induced depression.


Author(s):  
Josiane Fernandes Silva ◽  
Juliana A. Bolsoni ◽  
Rafael M. Costa ◽  
Juliano V. Alves ◽  
Alecsander F. M. Bressan ◽  
...  

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