Aryl Hydrocarbon Receptor Modulators Research Articles

Selective aryl hydrocarbon receptor modulators can act as antidepressants in obese female mice

BackgroundObese females are more likely to suffer from depression and are also more likely to be resistant to current medications. This study examined the potential antidepressant-like effects of 1,4-dihydroxy-2-napthoic acid (DHNA), a selective aryl hydrocarbon receptor modulator (SAhRM), in obese female mice. MethodsObesity was established by feeding C57BL/6N female mice a high fat diet (HFD) for 9–10 weeks. Subsequently, mice were subjected to unpredictable chronic mild stress (UCMS) or remained unstressed. Daily administration of vehicle or 20 mg/kg DHNA began three weeks prior or on the third week of UCMS. Mice were examined for depression-like behaviors (sucrose preference, forced swim test (FST), splash and tape groom tests), anxiety (open-field test, light/dark test, novelty-induced hypophagia), and cognition (object location recognition, novel object recognition, Morris water maze). ResultsUCMS did not alter, and DHNA slightly increased, weight gain in HFD-fed females. HFD decreased sucrose preference, increased FST immobility time, but did not alter splash and tape tests' grooming time. UCMS did not have additional effects on sucrose preference. UCMS further increased FST immobility time and decreased splash and tape tests' grooming time; these effects were prevented and reversed by DHNA treatment. HFD did not affect behaviors in the cognitive tests. UCMS impaired spatial learning; this effect was not prevented nor reversed by DHNA. ConclusionsDHNA protected against UCMS-induced depression-like behaviors in HFD-fed female mice. DHNA neither improved nor worsened UCMS-induced impairment of spatial learning. Our findings indicate that DHNA has high potential to act as an antidepressant in obese females.

Aryl hydrocarbon receptor as a therapeutical target of environmentally induced skin conditions.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, expressed in several tissues and involved in the response to environmental stressors. Studies have already associated exposure to environmental factors, such as organic air pollutants, products of the skin microbiota, and solar radiation, with the development/worsening of skin conditions, mediated by AhR. On the other hand, recent studies have shown that synthetic and natural compounds are able to modulate the activation of some AhR signaling pathways, minimizing the harmful response of these environmental stressors in the skin. Thus, AhR constitutes a new therapeutic target for the prevention or treatment of skin conditions induced by the skin exposome. Here in, an overview of potential AhR ligands and their biological effects in environmentally induced skin conditions are presented. The literature survey pointed out divergences in the mechanism of action from a therapeutic perspective. Although most studies point to the benefits of ligand downregulation of AhR signaling, counteracting the toxic effects of environmental factors on the skin, some studies suggest the AhR ligand activation as a therapeutical mechanism for some skin conditions. Furthermore, both agonist and antagonist profiles were identified in the AhR modulation by the synthetic and natural compounds raised. Despite that, this target is still little explored, and further studies are needed to elucidate the molecular mechanisms involved and identify new AhR ligands with therapeutic potential. Significance Statement The aryl hydrocarbon receptor (AhR) is involved in different skin physiological and pathological processes, including toxic mechanisms of environmental factors. Synthetic and natural AhR ligands have demonstrated therapeutic potential for skin conditions induced by these agents. Thus, a comprehensive understanding of the skin toxicity mechanisms involving the AhR, as well as the use of AhR modulators from a therapeutic perspective provides an alternative approach to the development of new treatments for skin disorders induced by the exposome.

Modulation of the Aryl Hydrocarbon Receptor Signaling Pathway Impacts on Junín Virus Replication.

Junín virus (JUNV), a member of the family Arenaviridae, is the etiological agent of the Argentine hemorrhagic fever, an endemic disease in the rural region of Argentina lacking a specific chemotherapy. Aryl hydrocarbon receptor (AHR) is expressed in several mammalian tissues and has been indicated as a sensor of ligands from variable sources and a modulator of the cell immune response. Interestingly, recent studies have suggested that the activation or depression of the AHR signaling pathway may play a role in the outcome of diverse human viral infections. In the present report, the effect of the pharmacological modulation of AHR on JUNV in vitro infection was analyzed. An initial microarray screening showed that the AHR pathway was overexpressed in JUNV-infected hepatic cells. Concomitantly, the infection of Vero and Huh-7 cells with the JUNV strains IV4454 and Candid#1 was significantly inhibited in a dose-dependent manner by treatment with CH223191, a specific AHR antagonist, as detected by infectivity assays, real-time RT-PCR and immunofluorescence detection of viral proteins. Furthermore, the pro-viral role of AHR in JUNV infection appears to be independent of the IFN-I pathway. Our findings support the promising perspectives of the pharmacological modulation of AHR as a potential target for the control of AHF.

Lead optimization of aryl hydrocarbon receptor ligands for treatment of inflammatory skin disorders

Therapeutic aryl hydrocarbon receptor (AHR) modulating agents gained attention in dermatology as non-steroidal anti-inflammatory drugs that improve skin barrier properties. By exploiting AHR’s known ligand promiscuity, we generated novel AHR modulating agents by lead optimization of a selective AHR modulator (SAhRM; SGA360). Twenty-two newly synthesized compounds were screened yielding two novel derivatives, SGA360f and SGA388, in which agonist activity led to enhanced keratinocyte terminal differentiation. SGA388 showed the highest agonist activity with potent normalization of keratinocyte hyperproliferation, restored expression of skin barrier proteins and dampening of chemokine expression by keratinocytes upon Th2-mediated inflammation in vitro. The topical application of SGA360f and SGA388 reduced acute skin inflammation in vivo by reducing cyclooxygenase levels, resulting in less neutrophilic dermal infiltrates. The minimal induction of cytochrome P450 enzyme activity, lack of cellular toxicity and mutagenicity classifies SGA360f and SGA388 as novel potential therapeutic AHR ligands and illustrates the potential of medicinal chemistry to fine-tune AHR signaling for the development of targeted therapies in dermatology and beyond.

Intestinal epithelium aryl hydrocarbon receptor is involved in stress sensitivity and maintaining depressive symptoms

The aryl hydrocarbon receptor (AhR) is a key regulator in the microbiome-gut-brain axis, and AhR-active microbial metabolites modulate multiple neuronal responses. We recently demonstrated that 3,3’-diindolylmethane (DIM) and 1,4-dihydroxy-2-naphthoic acid (DHNA), two selective AhR modulators (SAhRMs), act as antidepressants in female mice. Thus, to examine the role of intestinal AhR in depression, anxiety, and spatial learning, this study employed transgenic mice in which the AhR was knockout only in the intestinal epithelium (AhRΔIEC). Additionally, this study examined whether the antidepressant effects of dietary DIM and DHNA is mediated by intestinal AhR. AhRΔIEC and WT female mice were fed daily with vehicle, 20 mg/kg DIM or DHNA for three weeks prior to four weeks of unpredictable chronic mild stress (UCMS). Mice were examined for weight gain, anhedonia-like behavior (sucrose preference test), anxiety levels (open field, light/dark, elevated plus maze, novelty-induced hypophagia, and marble burying tests), and spatial learning (Morris water maze). UCMS reduced weight gain in AhRΔIECs, but not WTs. Moreover, UCMS initially reduced sucrose preference in both AhRΔIECs and WTs, but over 4 weeks of UCMS, AhRΔIECs develop resilience to UCMS-induced anhedonia. Additionally, AhRΔIECs exhibit slightly reduced anxiety in certain tests and faster spatial learning. DIM and DHNA acted as antidepressants in both AhRΔIECs and WTs. Thus, this study suggests that intestinal AhR plays differential roles, mitigating stress effects on weight gain, and increasing stress effects on mood. However, the site of antidepressant action of SAhRMs, such as DIM and DHNA, is not dependent on the expression of intestinal AhR.

Proper modulation of AHR signaling is necessary for establishing neural connectivity and oligodendrocyte precursor cell development in the embryonic zebrafish brain.

2,3,7,8-tetrachlorodibenzo-[p]-dioxin (TCDD) is a persistent global pollutant that exhibits a high affinity for the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor. Epidemiological studies have associated AHR agonist exposure with multiple human neuropathologies. Consistent with the human data, research studies using laboratory models have linked pollutant-induced AHR activation to disruptions in learning and memory as well as motor impairments. Our understanding of endogenous AHR functions in brain development is limited and, correspondingly, scientists are still determining which cell types and brain regions are sensitive to AHR modulation. To identify novel phenotypes resulting from pollutant-induced AHR activation and ahr2 loss of function, we utilized the optically transparent zebrafish model. Early embryonic TCDD exposure impaired embryonic brain morphogenesis, resulted in ventriculomegaly, and disrupted neural connectivity in the optic tectum, habenula, cerebellum, and olfactory bulb. Altered neural network formation was accompanied by reduced expression of synaptic vesicle 2. Loss of ahr2 function also impaired nascent network development, but did not affect gross brain or ventricular morphology. To determine whether neural AHR activation was sufficient to disrupt connectivity, we used the Gal4/UAS system to express a constitutively active AHR specifically in differentiated neurons and observed disruptions only in the cerebellum; thus, suggesting that the phenotypes resulting from global AHR activation likely involve multiple cell types. Consistent with this hypothesis, we found that TCDD exposure reduced the number of oligodendrocyte precursor cells and their derivatives. Together, our findings indicate that proper modulation of AHR signaling is necessary for the growth and maturation of the embryonic zebrafish brain.

Mercury and methylmercury differentially modulate hepatic cytochrome P450 1A1 and 1A2 in vivo and in vitro.

The cytochrome P450 1 A (CYP1A) subfamily enzymes are involved in the metabolic activation of several xenobiotics to toxic metabolites and reactive intermediates, resulting ultimately in carcinogenesis. Mercury and halogenated aromatic hydrocarbons (HAHs), typified by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are persistent environmental pollutants involved in the modulation of aryl hydrocarbon receptor (AHR) gene battery, including cytochrome P450 (CYP) genes. We previously investigated the effect of coexposure to either inorganic or organic mercury (Hg+2 and MeHg) with TCDD on CYP1A1 in vitro. Thus, we examined the impact of coexposure to Hg+2 or MeHg and TCDD on AHR-regulated genes (Cyp1a1/1a2) in vivo and in vitro. Therefore, male C57BL/6 mice were injected intraperitoneally with MeHg or Hg+2 (2.5 mg/kg) in the absence and presence of TCDD (15 μg/kg) for 6 or 24 h. The concentration-dependent effect of MeHg was examined in murine hepatoma Hepa1c1c7 cells. In vivo, both MeHg and Hg2+ inhibited the TCDD-mediated induction of Cyp1a1/1a2 mRNA levels. However, Only Hg2+ was able to inhibit the TCDD-mediated induction at posttranscriptional levels of CYP1A1/1A2 protein and catalytic activity, suggesting differential modulation effects by Hg+2 and MeHg. In addition, the inhibitory role of HO-1 (Heme oxygenase-1) on CYP1A activity induced by TCDD was investigated using a HO-1 competitive inhibitor, tin-mesoporphyrin, that partially restored the MeHg-mediated decrease in CYP1A1 activity. This study demonstrates that MeHg, alongside Hg2+ , can differentially modulate the TCDD-induced AHR-regulated genes (Cyp1a1/1a2) at different expression levels in C57BL/6 mice liver and Hepa1c1c7 cells.

Sex-dependent differences in the stress mitigating and antidepressant effects of selective aryl hydrocarbon receptor modulators

BackgroundOur recent study demonstrated that selective aryl hydrocarbon receptor modulators (SAhRMs), such as 1,4-dihydroxy-2-napthoic acid (DHNA) act as antidepressants in female mice. Given that some effects of certain SAhRMs are known to also be mediated via estrogen receptor signaling, this study examined whether the effects of SAhRMs on mood, emotional state, and cognition are sex-dependent. MethodsC57BL/6N mice were fed with vehicle or 20 mg/kg DHNA for three weeks prior to four weeks of unpredictable chronic mild stress (UCMS). Mice were examined for depression-like behaviors (sucrose preference, forced swim test (FST), splash test, tape groom test), emotional state (open-field test, light/dark test, marble burying, novelty-induced hypophagia, elevated-plus maze), and cognition (object location recognition, novel object recognition, Morris water maze). ResultsIn females, UCMS decreased sucrose preference and increased FST immobility time; both effects were prevented by DHNA. In males, UCMS increased FST immobility time, and increased the latency to groom in the splash test. These effects were not mitigated by DHNA. However, in males, UCMS induced an increase in novelty-induced locomotion, an increase in the time spent in the light compartment in the L/D test, and an increase in the time spent with an object in a novel location. These effects were prevented by DHNA. ConclusionsOur findings indicate that DHNA has high potential to act as antidepressants in females. However, given classical interpretation, DHNA did not appear to act as an antidepressant in males. Nonetheless, our findings indicate that DHNA can mitigate stress effects and reactivity in males.

Natural Compounds Tapinarof and Galactomyces Ferment Filtrate Downregulate IL-33 Expression via the AHR/IL-37 Axis in Human Keratinocytes.

Interleukin (IL)-37 suppresses systemic and local inflammation. It is expressed in the epidermis, the external layer of the skin, and is decreased in inflammatory skin diseases including atopic dermatitis (AD) and psoriasis. Therefore, an agent applied topically on the skin that can increase IL-37 could be promising for treating AD and psoriasis; however, the mechanism regulating IL-37 remains largely unknown. Given that IL-37 expression is induced in differentiated keratinocytes, a major component of the epidermis, and that activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, promotes keratinocyte differentiation, we hypothesized that AHR might be involved in the IL-37 expression in human keratinocytes. We analyzed normal epidermal human keratinocytes (NHEKs) treated with tapinarof and Galactomyces ferment filtrate (GFF), which are potent AHR modulators. We found that tapinarof and GFF upregulated IL-37 in NHEKs, which was canceled by the knockdown of AHR using siRNA transfection, indicating that AHR mediates IL-37 expression in NHEKs. Furthermore, we found that the knockdown of IL-37 resulted in the upregulation of IL-33, an alarmin cytokine with crucial roles in the pathogenesis of AD and psoriasis. These findings suggest that IL-37 negatively regulates IL-33 expression in NHEKs. Finally, we examined whether tapinarof and GFF treatment modulates IL-33 expression in NHEKs. Such treatment inhibited IL-33 expression, which was partially reversed by the knockdown of either AHR or IL-37. Taken together, our findings provide the first evidence that tapinarof and GFF could have potential to prevent IL-33-overexpressing disorders such as AD and psoriasis via the AHR/IL-37 axis.

Ginsenoside Rg1 protects mice against 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced liver injury by inhibiting CYP1A1 through the aryl hydrocarbon receptor

Ethnopharmacological relevancePanax ginseng C. A. Meyer (ginseng) is a widely used traditional Chinese medicine that has played a beneficial role in the treatment of various diseases, including liver diseases. Ginsenoside Rg1 is a saponin isolated and purified from ginseng that exerts protective effects on the liver in some liver injury models. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a ubiquitous dioxin found mostly in food products that causes liver injury and other human diseases. Although significant efforts have been made to reduce the burden of liver disease, there is still a lack of effective treatment methods.Aim of the study: Although ginsenoside Rg1 was reported to inhibit TCDD-mediated cytochrome P450 1A1 (CYP1A1) induction in HepG2 cells, we sought to verify its hepatoprotective effects and elucidate its mechanism in a TCDD-induced liver injury model in mice. Material and methodsThe mouse liver injury model was established by intraperitoneal TCDD injection, followed by treatment with various doses of ginsenoside Rg1 (50, 100, and 200 mg/kg). Clinical indicators of liver injury, such as an increase in serum aspartate aminotransferase and alanine aminotransferase levels, as well as histopathological changes were evaluated. ResultsThe common clinical indicators of liver injury were detected following TCDD injection, including an increase in serum alanine aminotransferase and aspartate aminotransferase levels, increased relative liver weight, and histopathological changes. Following treatment with ginsenoside Rg1, the levels of aspartate aminotransferase and alanine aminotransferase decreased significantly, and the liver histology was improved. In addition, ginsenoside Rg1 competitively inhibited TCDD-induced Cyp1a1 mRNA transcription through the modulation of aryl hydrocarbon receptor (AhR) nuclear translocation. ConclusionGinsenoside Rg1 is a potent partial AhR agonist that has potential as an effective medication for protecting against TCDD-associated liver injury.

The aryl hydrocarbon receptor pathway plays a central role in the cutaneous response to pollutants

Short- and long-term exposure to atmospheric pollution has significant health effects. The skin is the organ directly in contact with pollutants and is responsible for protection of the organism. Particulate matter (PM) such as polycyclic aromatic hydrocarbons (PAHs) are the basis of certain pulmonary as well as dermatological complications. Pollution exacerbates certain illnesses such as atopic dermatitis and cancer, and it may also participate in delaying wound healing and in the occurrence of chronic ailments such as diabetes. The aryl hydrocarbon receptor (AhR) transcription factor, at the core of these responses to pollutants, is expressed by all cells of the skin. The AhR is subject to tight regulation that depends on its ligand. Pollutants act in a deleterious manner via the AhR, influencing the behaviour of keratinocytes as well as fibroblasts. Natural ligands, on the other hand, allow the noxious effects of pollution to be countered. This non-systematic review of the literature shows that modulation of AhR appears to be an excellent therapeutic approach to improve or stop the cutaneous problems linked to pollution.

Neuroprotective effect of 3,3'-diindolylmethane and ɑ-naphthoflavone, aryl hydrocarbon receptor modulators in an experimental model of ischemic stroke.

The aryl hydrocarbon receptor (AhR) mediated signaling pathway is being emerged as a current target for neuromodulation. The present study was conducted to characterize the neuroprotective action of AhR modulators, i.e., 3,3'-diindolylmethane (DIM) and ɑ-naphthoflavone (ANF) in an experimental model of stroke using transient middle cerebral artery occlusion (MCAO) in Wistar rats. The animals were treated with respective AhR modulators via intraperitoneal (i.p) injection 3 hrs after MCAO for 4 days (at 24 h interval). Following transient MCAO, the brain infarct volume, ND scoring, and various neuro behavioural tests were conducted to confirm the ischemic stroke. Further, oxidative stress parameters, inflammatory cytokines, and apoptotic mRNA expression were assessed. The histopathological changes in the brain of the rats were assessed using H&E staining and the results obtained were correlated with the molecular parameters. Treatment with AhR modulators had significantly decreased the brain infarct volume, ND scoring and improved neuro-behivoral deficits in animals following MCAO. A significant decrease was also observed in the oxidative stress, pro-inflammatory cytokines, and apoptotic mRNA expression in the AhR ligand treated groups. Moreover, a significant improvement was observed in the neuronal damage following MCAO in the treatment groups. AhR pathway modulation may be taken as a valuable therapeutic target for treating acute ischemic stroke (AIS).

Influence of aryl hydrocarbon receptor and sulfotransferase 1A1 on bisphenol AF-induced clastogenesis in human hepatoma cells

Bisphenol compounds (BPs) are ubiquitously existing pollutants. Recent evidence shows that they may be activated by human CYP1A1 for clastogenic effects; however, factors that influence/mediate CYP1A1-activated 4,4′-(hexafluoroisopropylidene)diphenol (BPAF) toxicity, particularly the aryl hydrocarbon receptor (AhR), sulfotransferase (SULT) 1A1 [known to conjugate 2,2-bis(4-hydroxyphenol)-propane (BPA)] and reactive oxygen species (ROS), remain unclear. In this study, a human hepatoma (HepG2) cell line was genetically engineered for the expression of human CYP1A1 and SULT1A1, producing HepG2-hCYP1A1 and HepG2-hSULT1A1, respectively. They were used in the micronucleus test and γ-H2AX analysis (Western blot) (indicating double-strand DNA breaks) with BPAF; the role of AhR in mediating BPAF toxicity was investigated by coexposure of AhR modulators in HepG2 and its derivative C3A (with no genetic modifications but enhanced CYP expression). The results indicated induction of micronuclei by BPAF (≥ 2.5 µM, for 2-cell cycle) in HepG2-hCYP1A1 and C3A, while inactive in HepG2 and HepG2-hSULT1A1; however, BPAF induced micronuclei in HepG2 pretreated with 3,3′,4,4′,5-pentachlorobiphenyl (PCB126, AhR activator), and BAY-218 (AhR inhibitor) blocked the effect of BPAF in C3A. In HepG2-hCYP1A1 BPAF selectively induced centromere-free micronuclei (immunofluorescent assay) and double-strand DNA breaks. In HepG2 cells receiving conditional medium from BPAF-HepG2-hCYP1A1 incubation micronuclei were formed, while negative in HepG2-hSULT1A1. Finally, the intracellular levels of ROS, superoxide dismutase and reduced glutathione in C3A and HepG2-hCYP1A1 exposed to BPAF were all moderately increased, while unchanged in HepG2 cells. In conclusion, like other BPs BPAF is activated by human CYP1A1 for potent clastogenicity, and this effect is enhanced by AhR while alleviated by SULT1A1.

Pharmaceutically Active Microbial AhR Agonists as Innovative Biodrugs in Inflammation.

Alterations of the microbiome occur in inflammatory and autoimmune diseases, a finding consistent with the role of the microbiome in the maintenance of the immune system homeostasis. In this regard, L-tryptophan (Trp) metabolites, of both host and microbial origin, act as important regulators of host–microbial symbiosis by acting as aryl hydrocarbon receptor (AhR) ligands. The intestinal and respiratory barriers are very sensitive to AhR activity, suggesting that AhR modulation could be a therapeutic option to maintain the integrity of the epithelial barrier, which has substantial implications for health even beyond the mucosal site. A number of studies have highlighted the capacity of AhR to respond to indoles and indolyl metabolites, thus positioning AhR as a candidate indole receptor. However, the context-and ligand-dependent activity of AhR requires one to resort to suitable biopharmaceutical formulations to enable site-specific drug delivery in order to achieve therapeutic effectiveness, decrease unwanted toxicities and prevent off-target effects. In this review, we highlight the dual activity of the microbial metabolite indole-3-aldehyde at the host–microbe interface and its ability to orchestrate host pathophysiology and microbial symbiosis and discuss how its proper clinical development may turn into a valuable therapeutic strategy in local and distant inflammatory diseases.

Phytochemicals From Vicia faba Beans as Ligands of the Aryl Hydrocarbon Receptor to Regulate Autoimmune Diseases.

Legumes are associated with gut health benefits, and increasing evidence indicates that their consumption reduces the risk of chronic diseases that include autoimmunity. Beans are rich sources of compounds with health-promoting effects, and recent metabolomic approaches have enabled the comprehensive characterization of the chemical composition of Vicia faba L. This article reviewed whether the phytocompounds in broad beans might modulate the aryl hydrocarbon receptor (AhR), which plays an essential role in autoantigen tolerance as a potential dietary strategy for autoimmune disease management. Therefore, thirty molecules present in Vicia faba of the chemical classes of flavonoids, chalcones, stilbenes, jasmonates, alkaloids, and amino acids, and either a human- or microbiome-derived product of biotransformation, retrieved from the literature or predicted in silico were evaluated by docking for affinity against the ligand-binding domain of AhR. Most analyzed compounds showed high affinity even after their metabolism which indicate that some AhR modulators remain active despite several steps in their biotransformation. Hence, our results suggest that in similitude with the gut metabolism of the tryptophan, phytocompounds mainly polyphenols also lead to metabolites that induce the AhR pathway. Furthermore, wyerone acid, wyerone epoxide, jasmonic acid, stizolamine, vicine, and convicine and their metabolite derivatives are reported for the first time as potential AhR ligands. Overall, chronic consumption of phytochemicals in Vicia faba L. and their gut biotransformation may protect against autoimmune disease pathogenesis by AhR modulation.

Advancements in topical therapy

AbstractAtopic dermatitis (AD) is a common dermatologic ailment with a large variety of treatment options ranging from topical to systemic medications. First‐line treatment for AD often involves topical therapy using agents such as emollients, topical corticosteroids, phosphodiesterase‐4 (PDE4) inhibitors, and calcineurin inhibitors. Despite these therapeutic options, there are numerous emerging topical therapies in the pipeline for AD. This review will discuss novel and emerging topical medications for AD including PDE4 inhibitors, janus kinase inhibitors, aryl hydrocarbon receptor modulators, and other miscellaneous agents.

Aryl Hydrocarbon Receptor (AHR) Gene Expression in AML Is Associated with FLT3-ITD+ AML and HLA-E Induced Immune Resistance Reversed By Ik-364

Background: The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor critical for cellular metabolism, stem cell differentiation and immune control. HLA-E is a non-classical HLA molecule that is critical for NK cell activation. HLA-E is expressed on some AML blasts but genomic characterization is limited. IK-364, a tool compound generated by Ikena Oncology, is an AHR inhibitor in preclinical investigation. We set out to identify the genomic signatures associated with activation of the AHR pathway in AML samples utilizing the Beat AML dataset.Methods: Whole bone marrow or peripheral blood samples were procured from AML patients under IRB-approved protocol (eIRB# 4422). Utilizing the Beat AML database, all samples were examined based on RNA AHR expression levels (RPKM) and correlated with genomic expression. High vs. low AHR expression was based on 90 th and 10 th percentiles. Pathway enrichment from upregulated genes was identified and compared between high vs. low AHR expression. Single cell RNA sequencing by 10x genomics Chromium system by the Massively Parallel Sequencing Shared Resource at OHSU was performed with previously frozen FLT3 positive AML samples (4 high AHR and 4 low AHR). Immunophenotyping was conducted by flow cytometry. The AHR antagonist IK-364 was utilized to study the in vitro effects of AHR modulation. Cytotoxicity was measured by flow cytometric detection of caspase-3/7 and SytoxAAD activation.Results: The highest and lowest 10% expression levels of AHR in all samples in Beat AML were evaluated for mutation profiles. Ranking the top 18 mutations based on frequency we found an enrichment of FLT3 mutations in the high AHR expression group compared to the lower expression group (Figure 1A). ELN risk did not correlate with AHR expression however FAB classification M0/M1 and M4/M5 monocytic subtypes had higher AHR expression than M3 FAB subtype (Figure 2A). AHR gene expression was highly correlated with FLT3-ITD mutations (p=0.0007) (Figure 2B) and HLA-E expression (p=<0.0001) (Figure 3A). High AHR and high HLA-E joint expression in AML was associated with pathway upregulation in translocation of ZAP70 to immunological synapse, upregulation of HLA class II antigen presentation, phosphorylation of CD3 and TCR zeta chain and PD-1 signaling (p-value-1.11E-16), which are critical for innate and adaptive immune responses. AHR low and HLA-E low AML samples showed pathway enrichment for down-regulated genes including Hedgehog on state and neurexins and neuroligins (p value-0.001 and 7.61E-04 respectively). Genes upregulated in AHR high samples included CD14, CD86, HLA-DR, LILRB4, MAFB which are associated with monocytic phenotype. AHR high FLT3+ AML samples had higher protein expression of HLA-E on CD45+ blasts (p=0.03) compared to AHR low FLT3+ AML samples. Pretreatment of FLT3+ AML primary patient samples with IK-364 for 48 hours downregulates HLA-E on blasts (p=0.007) and, in a FLT3 positive AML cell line, Molm14, enhanced susceptibility to NK-cell-mediated killing (Figure 3B, 3C).Discussion: Overall, we found that high AHR gene expression in AML correlates with FLT3-ITD expression and HLA-E as well as monocytic subtype. Pathway enrichment highlight the important role of AHR in immune regulation. Furthermore, AHR antagonism by IK-364, downregulates HLA-E on AML blasts and augments NK cell mediated killing of a mutant FLT3-ITD positive AML cell line. Our results highlight a continued interest in targeting the AHR pathway to augment immune-based therapies in AML.uture studies are underway to determine the mechanism behind this critical immune regulation. [Display omitted] DisclosuresSaultz: IKENA: Research Funding. Lind: IKENA: Research Funding. Tyner: Seattle Genetics: Research Funding; Constellation: Research Funding; Agios: Research Funding; Incyte: Research Funding; Petra: Research Funding; Gilead: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Array: Research Funding; Schrodinger: Research Funding; Astrazeneca: Research Funding. Kosaka: IKENA: Research Funding. McGovern: IKENA: Current Employment. Wang: IKENA: Current Employment. Sanchez-Martin: IKENA: Current Employment.

New Topical Therapies for Psoriasis.

Psoriasis is a chronic immune-mediated skin disease with a significant impact on patients' quality of life. Mild-to-moderate forms of the disease usually require long-term topical treatment, but prolonged use of corticosteroids and vitamin D analogues is limited by adverse effects. With further understanding of psoriasis pathogenesis, new molecules are emerging aiming to fulfil these clinical needs. Tapinarof, an aryl hydrocarbon receptor modulator, has completed a phase III study and demonstrated good efficacy results, even in long treatment courses, with a favourable safety profile. It additionally appears to have a promising remitting effect as patients presented with an average relapsing time of over 3 months. Roflumilast, a phosphodiesterase type 4 inhibitor, also underwent a phase III study with significant lesion improvement and notable pruritus management, and with no reported side effects. Roflumilast was evaluated as an option for intertriginous areas with good outcomes in a small sample, but larger trials are required. The Janus kinase-signal transducer and activator of transcription pathway has been targeted in recent clinical investigations with promising options, currently with brepocitinib pending phase IIb results. Ongoing preclinical studies involving interleukin-2 inhibition, RNA modulators and amygdalin analogues may lead to forthcoming clinical trials. New topical drugs are successfully emerging and future research comparing them to classical options will dictate their clinical role in the treatment of psoriasis.

Indoles Derived From Glucobrassicin: Cancer Chemoprevention by Indole-3-Carbinol and 3,3'-Diindolylmethane.

Hydrolysis of glucobrassicin by plant or bacterial myrosinase produces multiple indoles predominantly indole-3-carbinol (I3C). I3C and its major in vivo product, 3,3'-diindolylmethane (DIM), are effective cancer chemopreventive agents in pre-clinical models and show promise in clinical trials. The pharmacokinetics/pharmacodynamics of DIM have been studied in both rodents and humans and urinary DIM is a proposed biomarker of dietary intake of cruciferous vegetables. Recent clinical studies at Oregon State University show surprisingly robust metabolism of DIM in vivo with mono- and di-hydroxylation followed by conjugation with sulfate or glucuronic acid. DIM has multiple mechanisms of action, the most well-characterized is modulation of aryl hydrocarbon receptor (AHR) signaling. In rainbow trout dose-dependent cancer chemoprevention by dietary I3C is achieved when given prior to or concurrent with aflatoxin B1, polycyclic aromatic hydrocarbons, nitrosamines or direct acting carcinogens such as N-methyl-N'-nitro-nitrosoguanidine. Feeding pregnant mice I3C inhibits transplacental carcinogenesis. In humans much of the focus has been on chemoprevention of breast and prostate cancer. Alteration of cytochrome P450-dependent estrogen metabolism is hypothesized to be an important driver of DIM-dependent breast cancer prevention. The few studies done to date comparing glucobrassicin-rich crucifers such as Brussels sprouts with I3C/DIM supplements have shown the greater impact of the latter is due to dose. Daily ingestion of kg quantities of Brussels sprouts is required to produce in vivo levels of DIM achievable by supplementation. In clinical trials these supplement doses have elicited few if any adverse effects. Sulforaphane from glucoraphanin can act synergistically with glucobrassicin-derived DIM and this may lead to opportunities for combinatorial approaches (supplement and food-based) in the clinic.

Current approaches to the treatment of atopic dermatitis: a review of the literature

Atopic dermatitis (AtD) ― one of the most common inflammatory skin diseases often characterized by limited or short-time efficacy of traditional treatment options.&#x0D; The PubMed and eLibrary databases were searched for full text articles and reviews about novel approaches to the treatment of this skin disorder published between 2015 and 2021.&#x0D; This review aims to provide an overview of the recent pathogenetic pathways which are considered as main immunologic targets in the development of novel therapeutic strategies and discovering of future opportunities in the treatment of AtD. There are analysed and systematized novel data about systemic medications such as Dupilumab and a number of other monoclonal antibodies and JAK-inhibitors recently implemented in the practice and currently are clinical expertising in the different phases of trials of their efficacy and safety. Novel topical medications are considered separately including JAK-inhibitors, phosphodiesterase 4 inhibitor and aryl hydrocarbon receptor modulator. AtD is a complex disease characterized by different underlying molecular mechanisms/endotypes and phenotypes. This heterogeneity advocates against the traditional one-size-fits-all therapeutic approaches still used to manage AtD.&#x0D; Therapies targeting different cytokine axes and other mechanisms involved in disease pathogenesis will expand our ability of control of AtD including his therapy-refractory cases. Recent research advancements about clinical and immunological diseases variability and different endotypes indicate that control of this disorder must be based on pathogenetic approaches and therefore on the concept of individualized therapy.