4. Participation of AhR in Antioxidant Defense

Aside from the AhR-dependent production of intracellular reactive oxygen species, the AhR signaling pathway modulates the expression of genes of the antioxidant system and thereby regulates cell functions that ensure protection from oxidative stress. Numerous studies indicate that the protective action of antioxidants against oxidative stress is mediated by AhR through a response to such AhR ligands as flavonoids, phytochemicals, and azoles [174-181].

When this type of ligand binds to AhR, the production of reactive oxygen species does not occur because of the induction of the nuclear translocation of AhR; instead, Nrf2 is activated. Nrf2 is a key biomolecule that provides cell protection against the oxidative damage caused by reactive oxygen species: Nrf2 is a transcription factor that regulates the genes encoding enzymes of the antioxidant system [102,182].

4.1. Nrf2 Expression, Functions and Signaling

In a normal physiological state, Nrf2 is located in the cytoplasm and binds to Kelch-like ECH-associated protein 1 (Keap1) [183,184]. In response to stress signals, Keap1 is inactivated, resulting in Nrf2 stabilization. Nrf2 is translocated to the nucleus where it binds to members of the Maf protein family (e.g., MafK, MafF, and MafG). In a sequence-specific manner, the Nrf2–sMaf complex binds to an ARE, 5′-TGACXXXGC-3′, in a promoter region and activates the transcription of target genes of Nrf2 [19,182,185-187].

Nrf2 regulates the transcription of genes encoding components of the antioxidant systems based on glutathione and thioredoxin as well as genes coding for enzymes involved in the phase II detoxification of exogenous and endogenous compounds or in NADPH regeneration and heme metabolism (heme oxygenase 1): GPX4, superoxide dismutase, sulfiredoxin, paraoxonases, NQO1, GSTP1, GSTA1/2, UGT1A6, and various other enzymes that remain to be identified [188-193].

In addition to ensuring redox homeostasis, Nrf2 functions encompass multiple cellular processes, including the regulation of cell survival, metabolic and protein homeostasis, inflammation, and cell proliferation and differentiation [194-198].

Nrf2 is at the center of a complicated regulatory network. Its activity is modulated at several levels, including transcriptional regulation (by NF-κB, AhR, ATF4, and other transcription factors and cofactors), post-transcriptional regulation (by microRNA, RBPs, or alternative splicing), post-translational regulation (by ERK, JNK, PKC, CK2, PERK, GSK3, or p38), and the regulation of Nrf2 protein stability (by KEAP1, βTrCP, HRD1, WDR23, or CRIF1) [182,199].

4.2. Participation of AhR in Mechanisms of Nrf2 Activation

At present, there is some understanding of the mechanisms underlying Nrf2 activation by AhR. (Figure 3) One of them is the transcriptional activation of Nrf2 as a target gene of AhR, and the other is the indirect activation of Nrf2 via CYP1A1-generated reactive oxygen species [200].

Figure 3. The scheme of putative connections between gene batteries of AhR and Nrf2. (1) Nrf2 is a target gene of AhR; (2) indirect activation of Nrf2 by CYP1A1-generated reactive oxygen species (ROS); and (3) direct interaction of complexes AhR–XRE and Nrf2–ARE in a regulatory region of the NQO1 gene.

4.2.1. Nrf2 as a Target Gene of AhR

AhR is one of the transcription factors regulating Nrf2 [200,201]. Research on the Nrf2 promoter indicates that Nrf2 is a target gene of AhR. That Nrf2 gene transcription is directly modulated by AhR activation has been demonstrated by DNA sequence analyses of the mouse Nrf2 promoter; this work revealed one xenobiotic-responsive element-like element (XREL1) located at position 712 and two additional xenobiotic-responsive element-like elements located at positions +755 (XREL2) and +850 (XREL3). In those studies, functional analysis by a luciferase assay revealed that XREL1, XREL2, and XREL3 are all inducible by TCDD treatment, with XREL2 being the most potent [104,201].

There is also confirmation of the functionality of these xenobiotic-responsive element-like elements, and a direct binding of AhR to the Nrf2 promoter has been proven [201]. It has been reported that Nrf2 expression is at least partly regulated by AhR inducers through the activation of multiple xenobiotic-responsive elements in the Nrf2 promoter. This molecular event represents a direct connection between AhR and Nrf2 and places the Nrf2–ARE pathway downstream of AhR–XRE activation in certain scenarios [104].

There is fine-tuned crosstalk between AhR and Nrf2, which mutually enhance or weaken their activation states. The antioxidant response resulting from AhR activation and mediated by Nrf2 depends on the type of AhR ligand. Such AhR ligands as dioxins, BaP, and other polycyclic aromatic hydrocarbons bind to AhR with high affinity and induce extremely high CYP1A1 expression along with reactive oxygen species production [131,202]. Although Nrf2 is also activated in this case [102], the oxidative stress suppresses antioxidant defense [131,178].

Other AhR ligands, such as phytochemicals and flavonoids, bind to AhR less strongly [203-205], and among antioxidant phytochemicals, there are those that activate the AhR signaling pathway without the production of reactive oxygen species. These include ketoconazole and cynaropicrin [174,175].

Antioxidant phytochemicals capable of modulating Nrf2, AhR, and CYP1A1 have been described. By means of epidermal keratinocytes, as an example, it has been revealed that phytochemicals exerting their antioxidant actions through AhR and Nrf2 signaling can be categorized into three groups depending on their ability to increase and decrease AhR and CYP1A1 activities [10]. 1 contains Nrf2 agonists with AhR-agonistic activity. This group includes soybean tar, Opuntia Ficus-Indica extract, Houttuynia cordata extract, Bidens pilosa extract, and cynaropicrin. Group 2 contains Nrf2 agonists with AhR-antagonistic activity. This group includes cinnamaldehyde and epigallocatechin gallate. Group 3 contains Nrf2 agonists with CYP1A1-inhibitory activity. This group includes Z-ligustilide, quercetin, kaempferol, pterostilbene, and resveratrol.

Nonetheless, the ability of phytochemicals to regulate Nrf2, AhR, and CYP1A1 functions may depend on the cell type. The exact mechanisms by which these compounds influence the AhR and Nrf2 pathways differently remain unknown [10,100,200,206].

4.2.2. Indirect Activation of Nrf2 via CYP1A1-Generated Reactive Oxygen Species

Another mechanism of Nrf2 activation by AhR is the indirect activation of Nrf2 via CYP1A1-generated reactive oxygen species. The upregulation of intracellular reactive oxygen species can lead to the oxidation of Keap1 and a release of Nrf2 from its complex [200,207].

4.2.3. Direct Crosstalk between AhR–XRE and Nrf2–ARE Signaling Pathways

AhR and Nrf2 signaling pathways coordinate the expression regulation of genes of phase II xenobiotic metabolism, e.g., GSTA2, UGT1A6, and NQO1 [192,200,201,208-210]. The mechanism of direct crosstalk between the AhR–XRE and Nrf2–ARE signaling cascades has been described for the NQO1 enzyme and involves the close proximity of a xenobiotic-responsive element and ARE in the regulatory region of the NQO1 gene [200,211].

5. AhR in the Pathogenesis of Diseases Related to Oxidative Stress

Although initial studies on AhR were focused on its function as a signaling molecule of a chemical sensor responsive to environmental pollutants, lately, the range of subject areas has widened significantly. Our understanding has expanded regarding the role of the AhR signaling pathway in the regulation of a variety of physiological and pathological phenomena. AhR’s functions cover many cellular processes, including the regulation of cell survival, metabolic and protein homeostasis, inflammation, cell proliferation and differentiation, apoptosis, and cellular adhesion and migration. Reactive oxygen species-induced activation of transcription factors and proinflammatory genes increases inflammation. Accordingly, research on various diseases in which AhR induces an oxidative stress response—by switching on inflammation and antioxidant, prooxidant, and cytochrome P450 enzymes—is now within the scope of the interest of investigators.

It is known that oxidative stress causes inflammation and toxicity, and these problems can lead to such pathologies as cardiovascular, liver, kidney, lung, brain, eye, skin, and joint diseases, as well as aging and cancer [7,212-216]. In recent decades, AhR has been increasingly recognized as an important modulator of disease because of AhR’s role in the regulation of the redox system and of immune and inflammatory responses [121,217].

Below are examples of AhR involvement in the pathogenesis of many human diseases associated with oxidative stress.

5.1. Neurological Diseases

Oxidative stress has been studied in neurological diseases, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis, and in some psychiatric disorders such as depression [214,216,218-221]. It is now proven that AhR is involved in the initiation of oxidative stress in the brain because AhR activation by some ligands shifts the cellular redox balance toward oxidative stress [121,222,223]. In most areas of the brain and in the pituitary gland, AhR activation induces CYP1A1 and CYP1B1 expression [224]. This event can result in the mitochondrial production of reactive oxygen species [125,225] and in the higher production of reactive oxygen species through the activation of the arachidonic acid pathway by CYP enzymes and other intracellular signaling processes [70,226].

AhR plays an important part in the initiation of benign and malignant brain tumors [227,228]. In glioblastoma cells, neuroactive hormone dopamine has been identified as an inducer of enzymes CYP1A1, CYP1B1, and UGT1A1 [229].

It has been proven that AhR signaling pathways (especially after activation by such endogenous AhR ligands as tryptophan metabolites) are implicated in neurodegenerative diseases, in particular in well-known age-related brain diseases (Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, and amyotrophic lateral sclerosis) and other diseases of the central nervous system [230-234]. The hypothesis that AhR is involved in the neurodegenerative processes in Parkinson’s disease and Alzheimer’s disease derives from both human and in vitro studies. An important question addressed in these studies is the contribution of environmental factors to the risk of neurodegenerative diseases [67,234,235].

Parkinson’s disease is an extrapyramidal disorder characterized by decreased motor function due to the loss of dopaminergic neurons. Toxic exogenous ligands such as TCDD enhance the degeneration of dopaminergic neurons in the midbrain owing to enhanced oxidative stress, thereby inducing experimental Parkinson’s disease; in contrast, several phytochemicals such as a flavonoid called tangeretin as well as natural compounds from the plant Withaferin sominifera act via AhR to protect against Parkinson’s symptoms in several models of this disease [236,237]. An experimental murine model of Parkinson’s disease has revealed that AhR activation by BaP may have a protective effect against this pathology [238]. It should be noted that AhR is activated by carbidopa, which is used to treat Parkinson’s disease [239].

AhR is associated with Alzheimer’s disease too, which is a neurodegenerative illness featuring aggregation of b-amyloid plaques, which cause neuroinflammation and promote neuronal loss [240]. In a mouse model of Alzheimer’s disease, AhR activation alleviates cognitive deficits through the upregulation of neprilysin: the main endogenous enzyme of b-amyloid catabolism [240]. Those authors showed that neprilysin expression and enzymatic activity are higher when AhR is activated by endogenous ligands L-kynurenine or 6-formylindolo[3,2-b]carbazole or by exogenous ligands diosmin or indole-3-carbinol; they also found that AhR is a direct transcription factor of the neprilysin gene [240]. Substantial amounts of AhR and indolamine-2,3-dioxygenase 1 (IDO1) are detectable in glial cells in postmortem brain samples from Alzheimer’s patients and in postmortem hippocampus and serum samples from such patients; these amounts are elevated as compared with young people and elderly patients without dementia [231].

It has been established that b-amyloid neurotoxicity depends on AhR activation through the IDO1–kynurenine–AhR cascade, where—via the increased activity of IDO1 (an enzyme responsible for tryptophan degradation)—the production of tryptophan metabolites is accelerated, which can act as AhR ligands and may be neurotoxic [241]. On the contrary, inhibitors of IDO1 attenuate the neurotoxic activity of AhR. Because of the evidence of the neuroprotective effects of AhR against neurodegenerative diseases of the brain, research on non-toxic AhR agonists will be necessary and may help to alleviate the symptoms as a new therapeutic strategy against these diseases.

In multiple sclerosis and amyotrophic lateral sclerosis, the enhancement of inflammatory and neurodegenerative processes in the central nervous system is caused by environmental factors, among other reasons. In particular, the risk of multiple sclerosis correlates with smoking, which drives AhR gene demethylation and inhibits AhR signaling pathways, followed by the enhancement of inflammatory processes in the central nervous system in multiple sclerosis [242-244]. Patients with multiple sclerosis have lower levels of circulating AhR than healthy controls do, suggesting that AhR is involved in the pathogenesis of this disorder [245]. AhR may limit the central nervous system-inflammation characteristic of multiple sclerosis by suppressing astrocyte activation [246,247]. In multiple sclerosis, the gut microbiome is altered, which represents an interesting opportunity for investigating the role of the kynurenine–AhR pathway in this pathology [248]. In an animal model of multiple sclerosis (autoimmune encephalomyelitis), it has been shown that AhR may be a therapeutic target in multiple sclerosis too: a knockdown of AhR worsens disease signs, whereas AhR activation by such AhR agonists as TCDD, indole-3-carbinol, or diindolylmethane slows the progression of experimental allergic encephalomyelitis, owing to the overexpression of Forkhead Box P3, greater numbers of anti-inflammatory regulatory T cells, and the attenuation of proinflammatory expansion of T helper 17 (Th17) cells [247,249,250].

6-Formylindolo[3,2-b]carbazole, another AhR agonist, also alleviates disease progression when systemically administered in mouse models [251]. On the other hand, topical administration of 6-formylindolo[3,2-b]carbazole promotes Th17 cell expansion, thus worsening disease signs [250]. Furthermore, in an animal model of multiple sclerosis (autoimmune encephalomyelitis), treatment with laquinimod, which crosses the blood–brain barrier, reduces astrogliosis and prevents the production of downstream proinflammatory cytokines in an AhR-dependent manner [252]. These results suggest that laquinimod is a first-in-class drug that targets AhR for the treatment of multiple sclerosis and other neurodegenerative diseases.

In amyotrophic lateral sclerosis, TDP-43 has been identified as the major pathological protein [253]. Drugs targeting this protein have become a therapeutic approach to this disease. One work on a cell line (induced pluripotent stem cells differentiated into motor neurons) on a mouse brain and on human neuronal cell lines (BE-M17 cells) has revealed that AhR activation by an exogenous ligand (TCDD) or an endogenous ligand (6-formylindolo[3,2-b]carbazole) raises the TDP-43 protein level in human neuronal cell lines and motor neurons [244]. The observed effects were abrogated by AhR antagonists, implying that exposure to the environmental toxic substances that activate AhR may be a risk factor for the onset or progression of amyotrophic lateral sclerosis [244].

Available data suggest that AhR activation may have a bidirectional effect on diseases of the brain. At the same time, only the IDO1-kynurenine-AhR cascade has been clearly shown to be involved in the development of Alzheimer’s disease. AhR function may depend on additional stress events, or cell types. Effects on the AhR signaling pathway may depend on interaction with various coactivators or ligand-selective binding of the AhR complex to nontraditional sequences of XRE [227,254]. Apparently, in different cases, AhR antagonists or agonists can promote or hinder the development of neurodegenerative disorders, as well as exert either pro- or antitumor influence.

5.2. Ocular Diseases

Oxidative stress participates in age-related macular degeneration and cataracts by altering various types of eye cells photochemically or nonphotochemically [255]. Under the action of free radicals, crystalline proteins in the lens can become crosslinked and aggregate, causing the formation of cataracts [256]. In the retina, prolonged exposure to radiation can inhibit mitosis in the retinal pigment epithelium and choroid, may damage outer segments of photoreceptors, and can be implicated in lipid peroxidation [257].

Because environmental factors and metabolites have been shown to affect the central nervous system, researchers have demonstrated a role of AhR in some diseases of the central nervous system and a functional contribution of AhR to the regulation of the behavior of astrocytes, other microglial cells, and neurons; given that the retina is an extension of the brain, a growing area of research deals with the involvement of AhR in ocular diseases [234].

The importance of AhR and AhR signaling in eye development, toxicology, and diseases is currently being uncovered. AhR is expressed in many ocular tissues, including the retina, choroid, cornea, and orbit. A considerable role of AhR in age-related macular degeneration, glaucoma, and other eye diseases has been identified [258].

Glaucoma is caused by an increase in intraocular pressure, which damages the optic nerve and induces vision loss and blindness. CYP1B1, an AhR-inducible gene, is associated with various types of glaucoma, including two main ones: primary open-angle glaucoma and primary congenital glaucoma [259,260]. Mutations correlating with various types of glaucoma have been identified in CYP1B1 and cause a low CYP1B1 enzymatic activity or its absence [259,261].

Additionally, TCDD can induce CYP1B1 expression in non-pigmented human ciliary epithelial cells that constitute the ciliary body, whose main function is the production of aqueous humor in the eye [262]. CYP1B1 takes part in the metabolism of steroids, retinol, retinal, arachidonate, and melatonin. Consequently, CYP1B1 expression, which is elevated during AhR activation, alters the biosynthesis of critical metabolites as well as metabolic pathways that may lead to the initiation and/or progression of glaucoma [259].

Age-related macular degeneration is a complex multifactorial disease of the elderly and has unclear pathogenesis. In age-related macular degeneration, one of the destructive processes is oxidative stress, which gives an imbalance among the processes responsible for the production and detoxification of reactive oxygen species. In the dry type of age-related macular degeneration, there is a thinning and degradation of choroid capillaries, expanding atrophy of the outer retinal part, and irreversible damage to photoreceptors. In wet age-related macular degeneration, the presence of proinflammatory cytokines, in particular vascular endothelial growth factor (VEGF), promotes angiogenesis and vascular permeability.

During an investigation into the AhR function in retinal homeostasis, a loss of AhR signaling was found to increase retinal susceptibility to environmental stressors such as intense light [263]. In the retina of Ahr^-/- mice, there is a subretinal microglia accumulation concurrent with changes in autofluorescence, degeneration of the retinal pigment epithelium, and immune activation [263]. That study implies that AhR plays a protective part in the retina as a sensor of environmental stress, whereas altered AhR function may contribute to the progression of age-related macular degeneration in humans.

The effects of AhR have been analyzed in retinal pigment epithelial and choroid cell lines using AhR small interfering RNA [264]. That paper indicates that the expression of the VEGFA gene and of a proinflammatory chemokine (CC motif ligand 2; CCL2) goes up after AhR depletion in a human retinal pigment epithelial cell line, ARPE-19 [264]. Additionally, in that study, AhR depletion increased collagen IV synthesis and secretion in ARPE-19 cells and choroidal RF/6A cells. The depletion of AhR in RF/6A cells also raised the expression of the macrophage chemotactic factor gene, of secreted phosphoprotein 1 (SPP1), and of transforming growth factor (TGF)-β, while reducing the expression of antiangiogenic factor SERPINF1 [264].

Mice treated with TCDD show elevated VEGFA levels and choroidal vascularization: a hallmark of age-related macular degeneration [265]. These findings suggest that either a loss of AhR expression or AhR activation by TCDD (and/or by other toxic substances in cigarette smoke) promotes angiogenesis, inflammation, and alterations in the extracellular matrix, all of which are seen in the wet type of age-related macular degeneration.

In an experimental model of age-related macular degeneration (OXYS rats with signs of age-related macular-degeneration-like retinopathy of varying severity), it has been found that an imbalance between the prooxidant (AhR-dependent) system and antioxidant (Nrf2-dependent) system may be key to the pathogenesis of age-related macular degeneration and its initiation and/or progression [266]. Moreover, mitochondria-targeted antioxidant SkQ1 has been shown to ameliorate clinical signs of retinopathy in OXYS rats (manifesting signs of age-related macular-degeneration-like retinopathy) by influencing the transcriptional activity of AhR and Nrf2 and mRNA expression levels of CYP1A2 and CYP1B1 in the retina of OXYS and Wistar rats. These data are evidence that the enzymes CYP1A2 and CYP1B1 are implicated in the pathogenesis of age-related macular-degeneration-like retinopathy in OXYS rats and are possible therapeutic targets of SkQ1 [267].

Investigation into the impact of melatonin on mRNA expression of genes of AhR and Nrf2 signaling pathways in OXYS rats has shown that melatonin reduces the mRNA level of AhR-dependent genes of cytochromes CYP1A2 and CYP1B1 in the retina but does not affect mRNA expression of Nrf2-dependent genes in OXYS rats. This means that in age-related macular degeneration, the efficacy of melatonin is attributable to its ability to modulate the expression of AhR signaling pathway genes [268].

The discovery of a new synthetic AhR ligand (2,2¢-aminophenylindole) should also be mentioned regarding the development of therapeutic strategies promoting cell homeostasis during the degeneration of the retinal pigment epithelium layer [269]. This compound protects retinal pigment epithelium cells from lipid peroxidation cytotoxicity in vitro and the retina from light-induced damage in vivo. In addition, metabolic characterization of this agent by liquid chromatography coupled with mass spectrometry suggests that 2,2¢-aminophenylindole alters lipid metabolism in retinal pigment epithelium cells, thereby increasing the intracellular concentration of palmitoleic acid. The latter, as a downstream effector of 2,2¢-aminophenylindole-mediated activation of AhR, has also been reported to protect cells of the retinal pigment epithelium from 4HNE-mediated stress and light-induced retinal degeneration in mice [269].

The synthetic AhR agonist 2,2¢-aminophenylindole also regulates microglial homeostasis, thus making AhR a potential target for immunomodulatory and antioxidant therapies. This notion has been illustrated in a study on the anti-inflammatory and antioxidant effects of 2,2¢-aminophenylindole on microglial reactivity; the results showed that 2,2¢-aminophenylindole strongly represses the expression of proinflammatory genes and induces antioxidant genes in activated human and murine microglial cells, in lipopolysaccharide-stimulated explants of the retina, and in stressed human ARPE-19 cells [270].

5.3. Pulmonary Diseases

There is now firm proof that inflammatory lung disorders such as asthma and chronic obstructive pulmonary disease are characterized by systemic and localized chronic inflammation and oxidative stress [271-274]. Oxidants may contribute to inflammation by activating various kinases and redox transcription factors such as NF-κB and AP-1 [273,274].

The production of an inflammatory mediator called bronchial mucin-containing mucus is usually mediated by a release of cytokines or lipid mediators or by an increase in reactive oxygen species levels [275-278]. AhR is expressed in many lung cells, including macrophages, club cells, type II alveolar cells, and endothelial cells, and plays an important part in lung function modulation [279]. AhR serves as a regulator of mucosal-barrier function and may influence an immune response in the lungs through changes in gene expression, in intercellular adhesion, in mucin production, and in cytokine expression. AhR is expressed in cells of innate immune responses and in cells crucial for adaptive immunity [279].

By means of gene-deficient mice and the administration of AhR agonists and antagonists, numerous researchers have demonstrated that AhR modulates an immune response in various respiratory diseases and that lungs are sensitive to AhR ligands [280-282]. Allergic and inflammatory diseases such as bronchitis, asthma, and chronic obstructive pulmonary disease were recently linked with exposure to environmental toxic compounds. AhR mediates the effects of these substances through the arachidonic acid pathway, cell differentiation, intercellular adhesion interactions, cytokine expression, and mucin production. Human bronchial epithelial cells are reported to express AhR, and AhR activation induces mucin production via reactive oxygen species [278,280,283-285].

Chronic obstructive pulmonary disease develops as a result of exposure to risk factors that cause oxidative stress, inflammation, and the aberrant proliferation, death, and aging of lung cells, with the consequent destruction of parenchymal tissue [286,287]. AhR has a ligand-specific impact on the lungs and can either aggravate or ameliorate chronic obstructive pulmonary disease. For example, the toxic effects of dioxins and polycyclic aromatic hydrocarbons from tobacco smoke and from particulate matter on the lungs are mediated by AhR signal transduction. These ligands induce inflammation, increase the expression of mucin 5AC and matrix metalloproteinases (MMPs), and damage ciliated cells, club cells, and alveolar macrophages, thereby contributing to the pathogenesis of chronic obstructive pulmonary disease [288-290].

The exact molecular mechanisms behind the pathogenetic effects of endogenous AhR are unclear, but research indicates that the RelB protein (encoded by a target gene of NF-κB) may be partially responsible: AhR is known to interact with RelB and to modulate its expression [291]. Moreover, AhR regulates oxidative stress. When exposed to cigarette smoke, AhR-deficient lung cells show a higher production of reactive oxygen species and a lower expression of antioxidant enzymes (NQO1 and sulfiredoxin) than do lung cells with normal AhR levels, suggesting that cigarette smoke-induced oxidative stress is enhanced in AhR-deficient lungs [292].

AhR activation can influence the inflammatory phase in both asthma and chronic obstructive pulmonary disease through inflammatory and resident cells in the lungs [283,285]. The relation between AhR function and airway inflammation in the initial phase is important not only in chronic obstructive pulmonary disease but also in asthma. Airway Clara cells are sensitive to AhR activation by the ligand TCDD, and these cells are capable of secreting a wide range of glycoproteins such as mucins and SP-D [275,293]. TCDD upregulates inflammatory cytokines, COX2, MUC5AC, and MMPs via AhR signaling in a Clara cell-derived cell line. Research articles about AhR agonists and inhibitors have shown that AhR activation induces the production of such cytokines as TGF-α and tumor necrosis factor and of MMPs through receptors in human hematocytes and epithelial cells [283,293-295]. Thus, typical AhR xenobiotic ligands such as TCDD and BaP may contribute to the development of lung diseases.

Nevertheless, there are observations strongly indicating that AhR signaling can be beneficial in lung diseases mediated by inflammation and oxidative damage [296]. A deficiency of AhR signaling affects immune and nonimmune cells such as neutrophils, macrophages, and fibroblasts in the lungs, thereby resulting in greater pulmonary inflammation after exposure to tobacco smoke, lipopolysaccharide, and hyperoxia [297,298]. Conversely, AhR activation is known to reduce airway inflammation in rodent models of asthma by modulating the production and secretion of Th2 cytokines such as interleukin (IL) 4, IL-5, and IL-15 [299,300]. The activation of AhR by omeprazole alleviates lung inflammation in a model of acute hyperoxic lung injury based on adult mice, while neutrophil infiltration and MCP-1 expression are weaker as compared to vehicle-treated animals [301].

Because AhR takes part in the initiation of the aforementioned lung diseases, the development of biologics and small-molecule compounds that target the AhR signaling pathway is a possible approach to the prevention and treatment of these pathologies. For instance, AhR antagonist resveratrol has been shown to diminish mucin production [280]. AhR antagonist CH223191 attenuates BaP-induced allergic lung inflammation via AhR [302]. This AhR antagonist has also been reported to reverse experimental pulmonary hypertension induced by Sugen 5146 in rats [303].

5.4. Rheumatoid Arthritis

This is an autoimmune disease characterized by the chronic inflammation of the joints and the tissues around the joints along with infiltration by macrophages and activated T cells [126,304]. The pathogenesis of this disease is due to the formation of reactive oxygen and nitrogen species at the site of inflammation. The oxidative damage and inflammation have been confirmed in various rheumatic diseases by means of elevated levels of isoprostane and prostaglandins in serum and synovial fluid as compared with a control group [305]. Environmental factors, especially polycyclic aromatic hydrocarbons, are implicated in the pathogenesis of rheumatoid arthritis; hence, the role of AhR in this pathogenesis is of interest. Many papers indicate that polycyclic aromatic hydrocarbons play a critical part in the development of rheumatoid arthritis in various ways [306-308], primarily by influencing changes in the diversity of immune cells and the related downstream cytokines, and the main route of these effects goes through the AhR signaling pathway.

AhR, a major immunomodulator, is expressed in various cells (T and B cells, natural killers, macrophages, and dendritic cells) involved in rheumatoid arthritis [309]. Of note, in different cells implicated in rheumatoid arthritis, the effects of AhR activation are opposite. For instance, in Th1 and Th17 cells, B cells, dendritic cells, M1 monocytes, natural killers, and osteoclasts, AhR activation has an exacerbating impact on rheumatoid arthritis [310-315]; however, in Th2 cells, regulatory T cells, regulatory dendritic cells, M2 monocytes, and osteoblasts, AhR activation protects against rheumatoid arthritis [312,315-317].

AhR ligands such as 6-formylindolo[3,2-b]carbazole, TCDD and BaP relieve experimental arthritis; nonetheless, the long-term administration of these compounds has serious adverse effects such as high embryonic mortality, hepatotoxicity, and carcinogenicity [318-320], which limit the use of these compounds as therapeutic agents in animals or humans. AhR agonists with fewer adverse effects may be candidate therapeutics for rheumatoid arthritis [309]. Although much basic research has been conducted on the role of polycyclic aromatic hydrocarbon-activated AhR in rheumatoid arthritis, clinical studies on its effects on the mechanism of AhR signaling in rheumatoid arthritis are still lacking, and further research is needed.

5.5. Skin Diseases

These diseases may also be linked with environmental pollutants having high affinity for AhR [84,321]. Low doses of these compounds cause skin irritation or worsen symptoms of diseases [322]. Exposure to high doses of air pollutants leads to such skin pathologies as chloracne and hyperpigmentation [323-326]. AhR participates in many pathological processes in the skin through alterations in the signaling pathways controlled by AhR.

Early studies pointed to a partial role of AhR in the pathogenesis of various skin diseases, including inflammatory diseases, skin pigmentation disorders, and skin cancer [131,180,327], as well as a dependence of the outcome of AhR activation on the cell type and ligand [130,328]. Several papers offer evidence of AhR’s involvement in the pathogenesis of chloracne, hyperpigmentation, and vitiligo, as well as inflammatory diseases such as psoriasis and atopic dermatitis [321,329-332]. Additionally, many different biological responses to AhR stimulation or inhibition are observed in the skin [178].

On the one hand, the activation of AhR by ligands can induce the overexpression of proinflammatory cytokines and the production of reactive oxygen species, yielding an inflammatory disease or carcinogenesis [174]. On the other hand, AhR activity can influence the differentiation of regulatory T cells, thereby promoting immune tolerance [333]. A large class of tryptophan derivatives that are AhR ligands may play a part in the pathogenesis or treatment of many skin diseases [73,334]. Tryptophan derivatives are generated by enzymatic reactions or by exposure to ultraviolet light in various skin cells, and some of these compounds are present in herbs and plant extracts commonly used for skin care and therapies. Their biological activities require further research [100,335].

5.6. Nephropathies

Oxidative stress participates in various renal pathologies such as glomerulonephritis, tubulointerstitial nephritis, proteinuria, uremia, diabetic nephropathy, and chronic renal failure [336]. In chronic kidney disease, especially with uremia, oxidative stress can be explained by high pro-oxidant activity driving the overproduction of reactive oxygen species. The reasons for this phenomenon are complicated and multifactorial, and are mostly linked with elevated NOX activity, markedly upregulated xanthine oxidase, and concomitant mitochondrial dysfunction [337].

The roles of oxidative stress and inflammation in kidney failure lie in their influence on the most common disorders accompanying chronic kidney disease, which progress further via a positive-feedback mechanism, promoting an additional enhancement of oxidative stress and the progression of chronic kidney disease with a full range of complications [337]. Many authors have reported that AhR is associated with chronic kidney disease and its complications. A review of current knowledge on the participation of AhR in chronic kidney disease [338] shows that AhR mediates chronic kidney disease complications, including cardiovascular disorders, anemia, bone disorders, cognitive dysfunction, and malnutrition, and that AhR affects drug metabolism in patients with chronic kidney disease [338].

AhR also helps to reduce the harmful effects of uremic toxins by strengthening intestinal-barrier function [338,339]. In patients with chronic kidney disease, the key AhR ligands are the uremic toxins that arise during the metabolism of tryptophan, which is a precursor of a large number of microbial and host metabolites [339]. Derivatives of kynurenine, of serotonin, and of indole are (by-)products of the three main tryptophan metabolic pathways, which are directly or indirectly modulated by the gut microbiota [339]. The tryptophan metabolites indoxyl sulfate, indole-3-acetic acid, and kynurenine are not only important uremic toxins but are also potent AhR ligands [340-342]. Activated AhR is proven to exacerbate kidney damage [343-345]. An increase in AhR activity—in the periglomerular region and in proximal and distal renal tubules—under the action of adenine and indoxyl sulfate leads to renal fibrosis [346]. Indoxyl sulfate-activated AhR causes podocyte injury, progressive glomerular damage, and a proinflammatory phenotype [347]. Chronic kidney disease may be aggravated by indoxyl sulfate via the OAT3–AhR–STAT3 cascade in proximal tubular cells owing to the downregulation of a receptor called MAS, the subsequent inhibition of the renin–angiotensin system, and TGF-β activation [348]. Renal fibrosis may be mediated by AhR signaling [339,349].

AhR activity in patients with diabetes mellitus positively correlates with the progression of diabetic nephropathy and kidney failure severity [350]. A paper about the function of AhR in the pathophysiological processes of diabetic nephropathy (on the basis of an AhR knockout mouse model and a pharmacological inhibitor, α-naphthoflavone) has revealed that AhR mediates renal oxidative stress in a diabetic mouse model, thereby inducing infiltration by macrophages, extracellular matrix accumulation, and mesangial cell activation [351].

5.7. Cardiovascular Diseases

These diseases have a multifactorial etiology related to various risk factors, including but not limited to hypercholesterolemia, hypertension, tobacco smoking, diabetes mellitus, poor diet, stress, and lack of physical activity. Evidence has been published supporting the participation of oxidative stress in a number of cardiovascular disorders such as atherosclerosis, ischemia, hypertension, cardiomyopathy, cardiac hypertrophy, and congestive heart failure [352-355].

AhR is closely connected with cardiovascular diseases in terms of cardiac function, vascular development, and blood pressure regulation. In some diseases associated with atherosclerosis, AhR can serve as a transmitter of an oxidative stress signal [62,356,357].

There is a strong association between the accumulation of uremic toxic compounds and cardiovascular complications of chronic kidney disease [358]. AhR activation directly correlates with cardiovascular risk, even in the absence of uremia [359,360]. People exposed to AhR agonists are at an increased cardiovascular risk. To give an example, people who were exposed to TCDD as part of Agent Orange during the Vietnam War were more likely to experience relevant cardiovascular complications such as coronary heart disease and stroke [361].

Environmental pollutants that are AhR ligands promote the onset and progression of atherosclerosis, indicating that AhR may partake in the regulation of atherosclerosis [362-364]. Inflammatory responses contribute to AhR-regulated atherosclerosis. There are three hypotheses based on the AhR signaling pathways that mediate inflammation and promote atherosclerosis. The first hypothesis involves downstream inflammatory signaling factors such as VCAM-1 acting through the AhR–NF-κB signaling pathway, resulting in monocyte chemotaxis. Macrophages and monocytes are targets of polycyclic aromatic hydrocarbons, which are implicated in the physiological and pathological processes of atherosclerosis [365,366]. The second hypothesis postulates that AhR promotes absorption of oxidized low-density lipoprotein by macrophages giving rise to foam cells with the help of endogenous and exogenous ligands such as oxidized low-density lipoprotein, lipopolysaccharides, and TCDD. In vitro experiments have revealed that cholesterol accumulation in foam cells under the influence of particulate matter-induced inflammation is an early sign of cardiovascular diseases. Nonetheless, the suppressive action of AhR inhibitors on foam cells and on inflammation has not been investigated. It is believed that these mechanisms will be clarified by extensive studies on AhR [367,368]. The third hypothesis is the accelerated proliferation of vascular smooth muscle cells, which is key to the initiation of vascular complications according to the finding that indoxyl sulfate induces the proliferation of vascular smooth muscle cells through AhR activation, NF-κB signal transduction, and the production of reactive oxygen species [369]. It should be said that the division of the pathological involvement of AhR in the development of atherosclerosis into three hypotheses is largely arbitrary. These processes are related, and this division can only reflect the structuring and emphasis in future studies that should clarify the activity of this complex molecular network.

The regulation of AhR at the AhR transcription level in humans has not been elucidated yet. AhR is connected with other signaling pathways, including Wnt and E2 cascades, and further research is needed to clarify the function of AhR and identify new endogenous ligands in order to elucidate the role, regulation, and possible usefulness of AhR in the treatment of atherosclerosis [370]. AhR is reported to be a major participant in the pathogenesis of such cardiovascular pathologies as myocarditis, hypertension, coronary heart disease, and pulmonary arterial hypertension [62]. The pathogenesis driven by AhR varies among cardiovascular diseases, but includes inflammatory responses, immune responses, oxidative stress, and endothelial dysfunction. The molecular mechanisms behind AhR signaling and behind the crosstalk between AhR signaling and other signal transduction cascades still require further investigation [62].

6. Conclusions

Major breakthroughs were recently made in the biology of redox modulation by AhR. Despite all the gained knowledge, the remaining intriguing questions concern the mechanism underlying the cell- and tissue-specific effects of AhR ligands and the dependence of responses on the type of ligands. The function of AhR is complicated because the outcome of its activation depends on a wide range of endogenous and exogenous ligands (which are characterized by different affinity values and diverse combinatorial effects) and on different AhR functions in many physiological and pathological processes in cells and tissues. The molecular mechanisms of AhR signaling and of the crosstalk between AhR signaling and other signal transduction cascades require further research. It is mostly the inconsistency of scientific findings that makes it difficult to determine the signaling pathways through which AhR can exert its beneficial or detrimental actions. There is growing evidence that AhR activation can have multidirectional effects on many aspects of human physiology and pathology, and that these may depend on cell and tissue types, or on the interaction of the AhR complex with non-traditional XRE sequences, or interaction with various coactivators and corepressors. Depending on many factors, the action of AhR agonists or antagonists can cause positive or negative effects on human health (Figure 4).

Figure 4. Pro-oxidant and antioxidant effects of AhR results in wide range of physiological and pathological processes in cells and tissues.

 The recognition that AhR is implicated in the pathogenesis of many human diseases has arisen in conjunction with numerous examples of diseases in which AhR modulates disease activity through interaction with environmental factors. The pathogenesis driven by AhR often includes oxidative stress and immune and inflammatory responses. The weight of evidence indicates that, in diseases of various organs and tissues, AhR activation can be beneficial or detrimental. The ultimate effect depends both on the context of the disease and on the nature of AhR ligands. In this context, AhR activation aggravates the symptoms of some diseases, but alleviates the symptoms of other diseases.

Currently, in the literature, there are few examples of disorders where the molecular mechanisms of AhR’s involvement in the pathogenesis are clear. More numerous are findings about various biological responses to the stimulation or inhibition of AhR in various diseases. At the current stage of our insight into AhR’s biology and its role in the pathogenesis of diverse diseases, the utility of AhR as a therapeutic target has already been established, and a foundation has been laid for the selection and design of effective AhR ligands as new treatments of various diseases. Although much basic research has been conducted on the functions of AhR in pathological processes, clinical studies about the effects on the mechanism of the AhR signaling pathway in different pathologies are still scarce, and further investigation is necessary.

Conceptualization, AYG; writing—original draft preparation, AYG and MLP; writing—review and editing, AYG and MLP; project administration, AYG; funding acquisition, AYG; All authors have read and agreed to the published version of the manuscript.

Funding: The work was supported by budgetary financing project FGMU-2022-0004, N1021050601082-2-1.6.4;3.1.6.

Acknowledgments: The authors thank N.A. for language help and for proofreading the article.

Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations
AhR aryl hydrocarbon receptor
AhRR aryl hydrocarbon receptor repressor
AKR aldo–keto reductase
ARE antioxidant response element
ARNT aryl hydrocarbon receptor nuclear translocator
Int. J. Mol. Sci. 2022, 23, 6719 21 of 36
BAFF B-cell-activating factor of the tumor necrosis factor family
BaP benzo[a]pyrene
bHLH basic helix–loop–helix
BLC B-lymphocyte chemoattractant
CCL1 CC-chemokine ligand 1
COX cyclooxygenase
CYP cytochrome P450
E2F1 E2 promoter binding factor 1
EGF epidermal growth factor
GPx glutathione peroxidase
GST glutathione S-transferase
HSP90 heat shock protein 90
IDO1 indolamine-2,3-dioxygenase 1
IFR3 interferon responsive factor
IL interleukin
Keap1 Kelch-like ECH-associated protein 1
KLF6 Kruppel-like Factor 6
MAPK mitogen-activated protein kinase
MMP matrix metalloproteinase
NADPH nicotinamide adenine dinucleotide phosphate
NF-B nuclear factor B
NOX NADPH oxidase
NQO1 NADPH:quinone oxidoreductase-1
Nrf2 nuclear factor erythroid 2-related factor 2
PAS Per–ARNT–Sim
pRB retinoblastoma protein
TAD transactivation domain
TCDD 2,3,7,8-tetrachlorodibenzo-p-dioxin
TDP-43 TAR DNA-binding protein 43 kDa
TGF transforming growth factor
UGT UDP glucuronosyltransferase
VEGF vascular endothelial growth factor
XRE xenobiotic-responsive element
XREL1 XRE-like element

Referencs

1. Chen, L.; Hu, J.Y.; Wang, S.Q. The role of antioxidants in photoprotection: a critical review. J Am Acad Dermatol 2012, 67, 1013-1024, doi:10.1016/j.jaad.2012.02.009.
2. Murphy, M.P. How mitochondria produce reactive oxygen species. Biochem J 2009, 417, 1-13, doi:10.1042/BJ20081386.
3. Cadenas, E. Mitochondrial free radical production and cell signaling. Mol Aspects Med 2004, 25, 17-26, doi:10.1016/j.mam.2004.02.005.
4. Di Meo, S.; Reed, T.T.; Venditti, P.; Victor, V.M. Role of ROS and RNS Sources in Physiological and Pathological Conditions. Oxid Med Cell Longev 2016, 2016, 1245049, doi:10.1155/2016/1245049.
5. Dandekar, A.; Mendez, R.; Zhang, K. Cross talk between ER stress, oxidative stress, and inflammation in health and disease. Methods Mol Biol 2015, 1292, 205-214, doi:10.1007/978-1-4939-2522-3_15.
6. Finkel, T.; Holbrook, N.J. Oxidants, oxidative stress and the biology of ageing. Nature 2000, 408, 239-247, doi:10.1038/35041687.
7. Reuter, S.; Gupta, S.C.; Chaturvedi, M.M.; Aggarwal, B.B. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med 2010, 49, 1603-1616, doi:10.1016/j.freeradbiomed.2010.09.006.
8. Haghi Aminjan, H.; Abtahi, S.R.; Hazrati, E.; Chamanara, M.; Jalili, M.; Paknejad, B. Targeting of oxidative stress and inflammation through ROS/NF-kappaB pathway in phosphine-induced hepatotoxicity mitigation. Life Sci 2019, 232, 116607, doi:10.1016/j.lfs.2019.116607.
9. Sharifi-Rad, M.; Anil Kumar, N.V.; Zucca, P.; Varoni, E.M.; Dini, L.; Panzarini, E.; Rajkovic, J.; Tsouh Fokou, P.V.; Azzini, E.; Peluso, I.; et al. Lifestyle, Oxidative Stress, and Antioxidants: Back and Forth in the Pathophysiology of Chronic Diseases. Front Physiol 2020, 11, 694, doi:10.3389/fphys.2020.00694.
10. Furue, M.; Uchi, H.; Mitoma, C.; Hashimoto-Hachiya, A.; Chiba, T.; Ito, T.; Nakahara, T.; Tsuji, G. Antioxidants for Healthy Skin: The Emerging Role of Aryl Hydrocarbon Receptors and Nuclear Factor-Erythroid 2-Related Factor-2. Nutrients 2017, 9, doi:10.3390/nu9030223.
11. Rodriguez, R.; Redman, R. Balancing the generation and elimination of reactive oxygen species. Proc Natl Acad Sci U S A 2005, 102, 3175-3176, doi:10.1073/pnas.0500367102.
12. Curi, R.; Newsholme, P.; Marzuca-Nassr, G.N.; Takahashi, H.K.; Hirabara, S.M.; Cruzat, V.; Krause, M.; de Bittencourt, P.I., Jr. Regulatory principles in metabolism-then and now. Biochem J 2016, 473, 1845-1857, doi:10.1042/BCJ20160103.
13. Griendling, K.K.; Sorescu, D.; Ushio-Fukai, M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 2000, 86, 494-501, doi:10.1161/01.res.86.5.494.
14. To, E.E.; Vlahos, R.; Luong, R.; Halls, M.L.; Reading, P.C.; King, P.T.; Chan, C.; Drummond, G.R.; Sobey, C.G.; Broughton, B.R.S.; et al. Endosomal NOX2 oxidase exacerbates virus pathogenicity and is a target for antiviral therapy. Nat Commun 2017, 8, 69, doi:10.1038/s41467-017-00057-x.
15. Zangar, R.C.; Davydov, D.R.; Verma, S. Mechanisms that regulate production of reactive oxygen species by cytochrome P450. Toxicol Appl Pharmacol 2004, 199, 316-331, doi:10.1016/j.taap.2004.01.018.
16. Agostinelli, E.; Tempera, G.; Viceconte, N.; Saccoccio, S.; Battaglia, V.; Grancara, S.; Toninello, A.; Stevanato, R. Potential anticancer application of polyamine oxidation products formed by amine oxidase: a new therapeutic approach. Amino Acids 2010, 38, 353-368, doi:10.1007/s00726-009-0431-8.
17. Ng, M.P.; Lee, J.C.; Loke, W.M.; Yeo, L.L.; Quek, A.M.; Lim, E.C.; Halliwell, B.; Seet, R.C. Does influenza A infection increase oxidative damage? Antioxid Redox Signal 2014, 21, 1025-1031, doi:10.1089/ars.2014.5907.
18. Masella, R.; Di Benedetto, R.; Vari, R.; Filesi, C.; Giovannini, C. Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes. J Nutr Biochem 2005, 16, 577-586, doi:10.1016/j.jnutbio.2005.05.013.
19. Gegotek, A.; Skrzydlewska, E. The role of transcription factor Nrf2 in skin cells metabolism. Arch Dermatol Res 2015, 307, 385-396, doi:10.1007/s00403-015-1554-2.
20. McIntosh, B.E.; Hogenesch, J.B.; Bradfield, C.A. Mammalian Per-Arnt-Sim proteins in environmental adaptation. Annu Rev Physiol 2010, 72, 625-645, doi:10.1146/annurev-physiol-021909-135922.
21. Nebert, D.W. Aryl hydrocarbon receptor (AHR): "pioneer member" of the basic-helix/loop/helix per-Arnt-sim (bHLH/PAS) family of "sensors" of foreign and endogenous signals. Prog Lipid Res 2017, 67, 38-57, doi:10.1016/j.plipres.2017.06.001.
22. Schulte, K.W.; Green, E.; Wilz, A.; Platten, M.; Daumke, O. Structural Basis for Aryl Hydrocarbon Receptor-Mediated Gene Activation. Structure 2017, 25, 1025-1033 e1023, doi:10.1016/j.str.2017.05.008.
23. Dolwick, K.M.; Schmidt, J.V.; Carver, L.A.; Swanson, H.I.; Bradfield, C.A. Cloning and expression of a human Ah receptor cDNA. Mol Pharmacol 1993, 44, 911-917.
24. Kawajiri, K.; Fujii-Kuriyama, Y. The aryl hydrocarbon receptor: a multifunctional chemical sensor for host defense and homeostatic maintenance. Exp Anim 2017, 66, 75-89, doi:10.1538/expanim.16-0092.
25. Tsuji, N.; Fukuda, K.; Nagata, Y.; Okada, H.; Haga, A.; Hatakeyama, S.; Yoshida, S.; Okamoto, T.; Hosaka, M.; Sekine, K.; et al. The activation mechanism of the aryl hydrocarbon receptor (AhR) by molecular chaperone HSP90. FEBS Open Bio 2014, 4, 796-803, doi:10.1016/j.fob.2014.09.003.
26. Yamamoto, J.; Ihara, K.; Nakayama, H.; Hikino, S.; Satoh, K.; Kubo, N.; Iida, T.; Fujii, Y.; Hara, T. Characteristic expression of aryl hydrocarbon receptor repressor gene in human tissues: organ-specific distribution and variable induction patterns in mononuclear cells. Life Sci 2004, 74, 1039-1049, doi:10.1016/j.lfs.2003.07.022.
27. Fujisawa-Sehara, A.; Sogawa, K.; Yamane, M.; Fujii-Kuriyama, Y. Characterization of xenobiotic responsive elements upstream from the drug-metabolizing cytochrome P-450c gene: a similarity to glucocorticoid regulatory elements. Nucleic Acids Res 1987, 15, 4179-4191, doi:10.1093/nar/15.10.4179.
28. Fujii-Kuriyama, Y.; Kawajiri, K. Molecular mechanisms of the physiological functions of the aryl hydrocarbon (dioxin) receptor, a multifunctional regulator that senses and responds to environmental stimuli. Proc Jpn Acad Ser B Phys Biol Sci 2010, 86, 40-53, doi:10.2183/pjab.86.40.
29. Gargaro, M.; Scalisi, G.; Manni, G.; Mondanelli, G.; Grohmann, U.; Fallarino, F. The Landscape of AhR Regulators and Coregulators to Fine-Tune AhR Functions. Int J Mol Sci 2021, 22, doi:10.3390/ijms22020757.
30. Abel, J.; Haarmann-Stemmann, T. An introduction to the molecular basics of aryl hydrocarbon receptor biology. Biol Chem 2010, 391, 1235-1248, doi:10.1515/BC.2010.128.
31. Hao, N.; Whitelaw, M.L. The emerging roles of AhR in physiology and immunity. Biochem Pharmacol 2013, 86, 561-570, doi:10.1016/j.bcp.2013.07.004.
32. Poland, A.; Palen, D.; Glover, E. Tumour promotion by TCDD in skin of HRS/J hairless mice. Nature 1982, 300, 271-273, doi:10.1038/300271a0.
33. Murray, I.A.; Patterson, A.D.; Perdew, G.H. Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat Rev Cancer 2014, 14, 801-814, doi:10.1038/nrc3846.
34. Denison, M.S.; Soshilov, A.A.; He, G.; DeGroot, D.E.; Zhao, B. Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. Toxicol Sci 2011, 124, 1-22, doi:10.1093/toxsci/kfr218.
35. Hoffman, E.C.; Reyes, H.; Chu, F.F.; Sander, F.; Conley, L.H.; Brooks, B.A.; Hankinson, O. Cloning of a factor required for activity of the Ah (dioxin) receptor. Science 1991, 252, 954-958, doi:10.1126/science.1852076.
36. Sherr, D.H. Another important biological function for the aryl hydrocarbon receptor. Arterioscler Thromb Vasc Biol 2011, 31, 1247-1248, doi:10.1161/ATVBAHA.111.227553.
37. Zablon, H.A.; Ko, C.I.; Puga, A. Converging Roles of the Aryl Hydrocarbon Receptor in Early Embryonic Development, Maintenance of Stemness, and Tissue Repair. Toxicol Sci 2021, 182, 1-9, doi:10.1093/toxsci/kfab050.
38. Schneider, A.J.; Branam, A.M.; Peterson, R.E. Intersection of AHR and Wnt signaling in development, health, and disease. Int J Mol Sci 2014, 15, 17852-17885, doi:10.3390/ijms151017852.
39. Guarnieri, T.; Abruzzo, P.M.; Bolotta, A. More than a cell biosensor: aryl hydrocarbon receptor at the intersection of physiology and inflammation. Am J Physiol Cell Physiol 2020, 318, C1078-C1082, doi:10.1152/ajpcell.00493.2019.
40. Mulero-Navarro, S.; Fernandez-Salguero, P.M. New Trends in Aryl Hydrocarbon Receptor Biology. Front Cell Dev Biol 2016, 4, 45, doi:10.3389/fcell.2016.00045.
41. Lamorte, S.; Shinde, R.; McGaha, T.L. Nuclear receptors, the aryl hydrocarbon receptor, and macrophage function. Mol Aspects Med 2021, 78, 100942, doi:10.1016/j.mam.2021.100942.
42. Kung, T.; Murphy, K.A.; White, L.A. The aryl hydrocarbon receptor (AhR) pathway as a regulatory pathway for cell adhesion and matrix metabolism. Biochem Pharmacol 2009, 77, 536-546, doi:10.1016/j.bcp.2008.09.031.
43. Bock, K.W. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-mediated deregulation of myeloid and sebaceous gland stem/progenitor cell homeostasis. Arch Toxicol 2017, 91, 2295-2301, doi:10.1007/s00204-017-1965-2.
44. Casado, F.L. The Aryl Hydrocarbon Receptor Relays Metabolic Signals to Promote Cellular Regeneration. Stem Cells Int 2016, 2016, 4389802, doi:10.1155/2016/4389802.
45. Zaragoza-Ojeda, M.; Apatiga-Vega, E.; Arenas-Huertero, F. Role of aryl hydrocarbon receptor in central nervous system tumors: Biological and therapeutic implications. Oncol Lett 2021, 21, 460, doi:10.3892/ol.2021.12721.
46. Bock, K.W. Aryl hydrocarbon receptor (AHR): From selected human target genes and crosstalk with transcription factors to multiple AHR functions. Biochem Pharmacol 2019, 168, 65-70, doi:10.1016/j.bcp.2019.06.015.
47. de Tomaso Portaz, A.C.; Caimi, G.R.; Sanchez, M.; Chiappini, F.; Randi, A.S.; Kleiman de Pisarev, D.L.; Alvarez, L. Hexachlorobenzene induces cell proliferation, and aryl hydrocarbon receptor expression (AhR) in rat liver preneoplastic foci, and in the human hepatoma cell line HepG2. AhR is a mediator of ERK1/2 signaling, and cell cycle regulation in HCB-treated HepG2 cells. Toxicology 2015, 336, 36-47, doi:10.1016/j.tox.2015.07.013.
48. Barhoover, M.A.; Hall, J.M.; Greenlee, W.F.; Thomas, R.S. Aryl hydrocarbon receptor regulates cell cycle progression in human breast cancer cells via a functional interaction with cyclin-dependent kinase 4. Mol Pharmacol 2010, 77, 195-201, doi:10.1124/mol.109.059675.
49. Nebert, D.W.; Roe, A.L.; Dieter, M.Z.; Solis, W.A.; Yang, Y.; Dalton, T.P. Role of the aromatic hydrocarbon receptor and [Ah] gene battery in the oxidative stress response, cell cycle control, and apoptosis. Biochem Pharmacol 2000, 59, 65-85, doi:10.1016/s0006-2952(99)00310-x.
50. Hatherell, S.; Baltazar, M.T.; Reynolds, J.; Carmichael, P.L.; Dent, M.; Li, H.; Ryder, S.; White, A.; Walker, P.; Middleton, A.M. Identifying and Characterizing Stress Pathways of Concern for Consumer Safety in Next-Generation Risk Assessment. Toxicol Sci 2020, 176, 11-33, doi:10.1093/toxsci/kfaa054.
51. Formosa, R.; Borg, J.; Vassallo, J. Aryl hydrocarbon receptor (AHR) is a potential tumour suppressor in pituitary adenomas. Endocr Relat Cancer 2017, 24, 445-457, doi:10.1530/ERC-17-0112.
52. Zhu, P.; Zhou, K.; Lu, S.; Bai, Y.; Qi, R.; Zhang, S. Modulation of aryl hydrocarbon receptor inhibits esophageal squamous cell carcinoma progression by repressing COX2/PGE2/STAT3 axis. J Cell Commun Signal 2020, 14, 175-192, doi:10.1007/s12079-019-00535-5.
53. Naseri-Nosar, P.; Nogalski, M.T.; Shenk, T. The aryl hydrocarbon receptor facilitates the human cytomegalovirus-mediated G1/S block to cell cycle progression. Proc Natl Acad Sci U S A 2021, 118, doi:10.1073/pnas.2026336118.
54. Mohammadi, S.; Seyedhosseini, F.S.; Behnampour, N.; Yazdani, Y. Indole-3-carbinol induces G1 cell cycle arrest and apoptosis through aryl hydrocarbon receptor in THP-1 monocytic cell line. J Recept Signal Transduct Res 2017, 37, 506-514, doi:10.1080/10799893.2017.1360351.
55. Sahebnasagh, A.; Hashemi, J.; Khoshi, A.; Saghafi, F.; Avan, R.; Faramarzi, F.; Azimi, S.; Habtemariam, S.; Sureda, A.; Khayatkashani, M.; et al. Aromatic hydrocarbon receptors in mitochondrial biogenesis and function. Mitochondrion 2021, 61, 85-101, doi:10.1016/j.mito.2021.09.012.
56. Chopra, M.; Schrenk, D. Dioxin toxicity, aryl hydrocarbon receptor signaling, and apoptosis-persistent pollutants affect programmed cell death. Crit Rev Toxicol 2011, 41, 292-320, doi:10.3109/10408444.2010.524635.
57. Zhang, W.; Xie, H.Q.; Li, Y.; Zhou, M.; Zhou, Z.; Wang, R.; Hahn, M.E.; Zhao, B. The aryl hydrocarbon receptor: A predominant mediator for the toxicity of emerging dioxin-like compounds. J Hazard Mater 2022, 426, 128084, doi:10.1016/j.jhazmat.2021.128084.
58. Duarte-Hospital, C.; Tete, A.; Brial, F.; Benoit, L.; Koual, M.; Tomkiewicz, C.; Kim, M.J.; Blanc, E.B.; Coumoul, X.; Bortoli, S. Mitochondrial Dysfunction as a Hallmark of Environmental Injury. Cells 2021, 11, doi:10.3390/cells11010110.
59. Gearhart-Serna, L.M.; Davis, J.B.; Jolly, M.K.; Jayasundara, N.; Sauer, S.J.; Di Giulio, R.T.; Devi, G.R. A polycyclic aromatic hydrocarbon-enriched environmental chemical mixture enhances AhR, antiapoptotic signaling and a proliferative phenotype in breast cancer cells. Carcinogenesis 2020, 41, 1648-1659, doi:10.1093/carcin/bgaa047.
60. Gutierrez-Vazquez, C.; Quintana, F.J. Regulation of the Immune Response by the Aryl Hydrocarbon Receptor. Immunity 2018, 48, 19-33, doi:10.1016/j.immuni.2017.12.012.
61. Ebert, B.; Seidel, A.; Lampen, A. Identification of BCRP as transporter of benzo[a]pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists. Carcinogenesis 2005, 26, 1754-1763, doi:10.1093/carcin/bgi139.
62. Yi, T.; Wang, J.; Zhu, K.; Tang, Y.; Huang, S.; Shui, X.; Ding, Y.; Chen, C.; Lei, W. Aryl Hydrocarbon Receptor: A New Player of Pathogenesis and Therapy in Cardiovascular Diseases. Biomed Res Int 2018, 2018, 6058784, doi:10.1155/2018/6058784.
63. Poland, A.; Knutson, J.C. 2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Annu Rev Pharmacol Toxicol 1982, 22, 517-554, doi:10.1146/annurev.pa.22.040182.002505.
64. Quattrochi, L.C.; Tukey, R.H. Nuclear uptake of the Ah (dioxin) receptor in response to omeprazole: transcriptional activation of the human CYP1A1 gene. Mol Pharmacol 1993, 43, 504-508.
65. Ciolino, H.P.; Daschner, P.J.; Yeh, G.C. Dietary flavonols quercetin and kaempferol are ligands of the aryl hydrocarbon receptor that affect CYP1A1 transcription differentially. Biochem J 1999, 340 ( Pt 3), 715-722.
66. Goya-Jorge, E.; Jorge Rodriguez, M.E.; Veitia, M.S.; Giner, R.M. Plant Occurring Flavonoids as Modulators of the Aryl Hydrocarbon Receptor. Molecules 2021, 26, doi:10.3390/molecules26082315.
67. Rothhammer, V.; Quintana, F.J. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat Rev Immunol 2019, 19, 184-197, doi:10.1038/s41577-019-0125-8.
68. Hubbard, T.D.; Murray, I.A.; Perdew, G.H. Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation. Drug Metab Dispos 2015, 43, 1522-1535, doi:10.1124/dmd.115.064246.
69. Phelan, D.; Winter, G.M.; Rogers, W.J.; Lam, J.C.; Denison, M.S. Activation of the Ah receptor signal transduction pathway by bilirubin and biliverdin. Arch Biochem Biophys 1998, 357, 155-163, doi:10.1006/abbi.1998.0814.
70. Larigot, L.; Juricek, L.; Dairou, J.; Coumoul, X. AhR signaling pathways and regulatory functions. Biochim Open 2018, 7, 1-9, doi:10.1016/j.biopen.2018.05.001.
71. Schaldach, C.M.; Riby, J.; Bjeldanes, L.F. Lipoxin A4: a new class of ligand for the Ah receptor. Biochemistry 1999, 38, 7594-7600, doi:10.1021/bi982861e.
72. Stejskalova, L.; Dvorak, Z.; Pavek, P. Endogenous and exogenous ligands of aryl hydrocarbon receptor: current state of art. Curr Drug Metab 2011, 12, 198-212, doi:10.2174/138920011795016818.
73. Wirthgen, E.; Hoeflich, A.; Rebl, A.; Gunther, J. Kynurenic Acid: The Janus-Faced Role of an Immunomodulatory Tryptophan Metabolite and Its Link to Pathological Conditions. Front Immunol 2017, 8, 1957, doi:10.3389/fimmu.2017.01957.
74. Smirnova, A.; Wincent, E.; Vikstrom Bergander, L.; Alsberg, T.; Bergman, J.; Rannug, A.; Rannug, U. Evidence for New Light-Independent Pathways for Generation of the Endogenous Aryl Hydrocarbon Receptor Agonist FICZ. Chem Res Toxicol 2016, 29, 75-86, doi:10.1021/acs.chemrestox.5b00416.
75. Jin, U.H.; Lee, S.O.; Sridharan, G.; Lee, K.; Davidson, L.A.; Jayaraman, A.; Chapkin, R.S.; Alaniz, R.; Safe, S. Microbiome-derived tryptophan metabolites and their aryl hydrocarbon receptor-dependent agonist and antagonist activities. Mol Pharmacol 2014, 85, 777-788, doi:10.1124/mol.113.091165.
76. Miller, C.A., 3rd. Expression of the human aryl hydrocarbon receptor complex in yeast. Activation of transcription by indole compounds. J Biol Chem 1997, 272, 32824-32829, doi:10.1074/jbc.272.52.32824.
77. Minzaghi, D.; Pavel, P.; Dubrac, S. Xenobiotic Receptors and Their Mates in Atopic Dermatitis. Int J Mol Sci 2019, 20, doi:10.3390/ijms20174234.
78. Guzman-Navarro, G.; Leon, M.B.; Martin-Estal, I.; Duran, R.C.; Villarreal-Alvarado, L.; Vaquera-Vazquez, A.; Cuevas-Cerda, T.; Garza-Garcia, K.; Cuervo-Perez, L.E.; Barbosa-Quintana, A.; et al. Prenatal indole-3-carbinol administration activates aryl hydrocarbon receptor-responsive genes and attenuates lung injury in a bronchopulmonary dysplasia model. Exp Biol Med (Maywood) 2021, 246, 695-706, doi:10.1177/1535370220963789.
79. Moorthy, B.; Chu, C.; Carlin, D.J. Polycyclic aromatic hydrocarbons: from metabolism to lung cancer. Toxicol Sci 2015, 145, 5-15, doi:10.1093/toxsci/kfv040.
80. Becker, A.; Klapczynski, A.; Kuch, N.; Arpino, F.; Simon-Keller, K.; De La Torre, C.; Sticht, C.; van Abeelen, F.A.; Oversluizen, G.; Gretz, N. Gene expression profiling reveals aryl hydrocarbon receptor as a possible target for photobiomodulation when using blue light. Sci Rep 2016, 6, 33847, doi:10.1038/srep33847.
81. Dere, E.; Lee, A.W.; Burgoon, L.D.; Zacharewski, T.R. Differences in TCDD-elicited gene expression profiles in human HepG2, mouse Hepa1c1c7 and rat H4IIE hepatoma cells. BMC Genomics 2011, 12, 193, doi:10.1186/1471-2164-12-193.
82. Carlson, E.A.; McCulloch, C.; Koganti, A.; Goodwin, S.B.; Sutter, T.R.; Silkworth, J.B. Divergent transcriptomic responses to aryl hydrocarbon receptor agonists between rat and human primary hepatocytes. Toxicol Sci 2009, 112, 257-272, doi:10.1093/toxsci/kfp200.
83. Farmahin, R.; Crump, D.; O'Brien, J.M.; Jones, S.P.; Kennedy, S.W. Time-dependent transcriptomic and biochemical responses of 6-formylindolo[3,2-b]carbazole (FICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are explained by AHR activation time. Biochem Pharmacol 2016, 115, 134-143, doi:10.1016/j.bcp.2016.06.005.
84. Esser, C.; Rannug, A. The aryl hydrocarbon receptor in barrier organ physiology, immunology, and toxicology. Pharmacol Rev 2015, 67, 259-279, doi:10.1124/pr.114.009001.
85. Zhang, N.; Walker, M.K. Crosstalk between the aryl hydrocarbon receptor and hypoxia on the constitutive expression of cytochrome P4501A1 mRNA. Cardiovasc Toxicol 2007, 7, 282-290, doi:10.1007/s12012-007-9007-6.
86. Schmidt, J.V.; Bradfield, C.A. Ah receptor signaling pathways. Annu Rev Cell Dev Biol 1996, 12, 55-89, doi:10.1146/annurev.cellbio.12.1.55.
87. Denison, M.S.; Fisher, J.M.; Whitlock, J.P., Jr. The DNA recognition site for the dioxin-Ah receptor complex. Nucleotide sequence and functional analysis. J Biol Chem 1988, 263, 17221-17224.
88. Soshilov, A.A.; Motta, S.; Bonati, L.; Denison, M.S. Transitional States in Ligand-Dependent Transformation of the Aryl Hydrocarbon Receptor into Its DNA-Binding Form. Int J Mol Sci 2020, 21, doi:10.3390/ijms21072474.
89. Puga, A.; Barnes, S.J.; Dalton, T.P.; Chang, C.; Knudsen, E.S.; Maier, M.A. Aromatic hydrocarbon receptor interaction with the retinoblastoma protein potentiates repression of E2F-dependent transcription and cell cycle arrest. J Biol Chem 2000, 275, 2943-2950, doi:10.1074/jbc.275.4.2943.
90. Go, R.E.; Hwang, K.A.; Choi, K.C. Cytochrome P450 1 family and cancers. J Steroid Biochem Mol Biol 2015, 147, 24-30, doi:10.1016/j.jsbmb.2014.11.003.
91. Kuramoto, N.; Baba, K.; Gion, K.; Sugiyama, C.; Taniura, H.; Yoneda, Y. Xenobiotic response element binding enriched in both nuclear and microsomal fractions of rat cerebellum. J Neurochem 2003, 85, 264-273, doi:10.1046/j.1471-4159.2003.01679.x.
92. Denison, M.S.; Faber, S.C. And Now for Something Completely Different: Diversity in Ligand-Dependent Activation of Ah Receptor Responses. Curr Opin Toxicol 2017, 2, 124-131, doi:10.1016/j.cotox.2017.01.006.
93. Wilson, S.R.; Joshi, A.D.; Elferink, C.J. The tumor suppressor Kruppel-like factor 6 is a novel aryl hydrocarbon receptor DNA binding partner. J Pharmacol Exp Ther 2013, 345, 419-429, doi:10.1124/jpet.113.203786.
94. Vogel, C.F.; Wu, D.; Goth, S.R.; Baek, J.; Lollies, A.; Domhardt, R.; Grindel, A.; Pessah, I.N. Aryl hydrocarbon receptor signaling regulates NF-kappaB RelB activation during dendritic-cell differentiation. Immunol Cell Biol 2013, 91, 568-575, doi:10.1038/icb.2013.43.
95. Jackson, D.P.; Joshi, A.D.; Elferink, C.J. Ah Receptor Pathway Intricacies; Signaling Through Diverse Protein Partners and DNA-Motifs. Toxicol Res (Camb) 2015, 4, 1143-1158, doi:10.1039/c4tx00236a.
96. Zhang, Q.; Lenardo, M.J.; Baltimore, D. 30 Years of NF-kappaB: A Blossoming of Relevance to Human Pathobiology. Cell 2017, 168, 37-57, doi:10.1016/j.cell.2016.12.012.
97. Ishihara, Y.; Kado, S.Y.; Hoeper, C.; Harel, S.; Vogel, C.F.A. Role of NF-kB RelB in Aryl Hydrocarbon Receptor-Mediated Ligand Specific Effects. Int J Mol Sci 2019, 20, doi:10.3390/ijms20112652.
98. Kim, D.W.; Gazourian, L.; Quadri, S.A.; Romieu-Mourez, R.; Sherr, D.H.; Sonenshein, G.E. The RelA NF-kappaB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells. Oncogene 2000, 19, 5498-5506, doi:10.1038/sj.onc.1203945.
99. Kimura, A.; Naka, T.; Nohara, K.; Fujii-Kuriyama, Y.; Kishimoto, T. Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells. Proc Natl Acad Sci U S A 2008, 105, 9721-9726, doi:10.1073/pnas.0804231105.
100. Szelest, M.; Walczak, K.; Plech, T. A New Insight into the Potential Role of Tryptophan-Derived AhR Ligands in Skin Physiological and Pathological Processes. Int J Mol Sci 2021, 22, doi:10.3390/ijms22031104.
101. Lamas, B.; Natividad, J.M.; Sokol, H. Aryl hydrocarbon receptor and intestinal immunity. Mucosal Immunol 2018, 11, 1024-1038, doi:10.1038/s41385-018-0019-2.
102. Yeager, R.L.; Reisman, S.A.; Aleksunes, L.M.; Klaassen, C.D. Introducing the "TCDD-inducible AhR-Nrf2 gene battery". Toxicol Sci 2009, 111, 238-246, doi:10.1093/toxsci/kfp115.
103. Shin, S.; Wakabayashi, N.; Misra, V.; Biswal, S.; Lee, G.H.; Agoston, E.S.; Yamamoto, M.; Kensler, T.W. NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis. Mol Cell Biol 2007, 27, 7188-7197, doi:10.1128/MCB.00915-07.
104. Miao, W.; Hu, L.; Scrivens, P.J.; Batist, G. Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes. J Biol Chem 2005, 280, 20340-20348, doi:10.1074/jbc.M412081200.
105. Swedenborg, E.; Pongratz, I. AhR and ARNT modulate ER signaling. Toxicology 2010, 268, 132-138, doi:10.1016/j.tox.2009.09.007.
106. Watabe, Y.; Nazuka, N.; Tezuka, M.; Shimba, S. Aryl hydrocarbon receptor functions as a potent coactivator of E2F1-dependent trascription activity. Biol Pharm Bull 2010, 33, 389-397, doi:10.1248/bpb.33.389.
107. Levine-Fridman, A.; Chen, L.; Elferink, C.J. Cytochrome P4501A1 promotes G1 phase cell cycle progression by controlling aryl hydrocarbon receptor activity. Mol Pharmacol 2004, 65, 461-469, doi:10.1124/mol.65.2.461.
108. Ge, N.L.; Elferink, C.J. A direct interaction between the aryl hydrocarbon receptor and retinoblastoma protein. Linking dioxin signaling to the cell cycle. J Biol Chem 1998, 273, 22708-22713, doi:10.1074/jbc.273.35.22708.
109. Marlowe, J.L.; Knudsen, E.S.; Schwemberger, S.; Puga, A. The aryl hydrocarbon receptor displaces p300 from E2F-dependent promoters and represses S phase-specific gene expression. J Biol Chem 2004, 279, 29013-29022, doi:10.1074/jbc.M404315200.
110. Lawrence, B.P.; Vorderstrasse, B.A. New insights into the aryl hydrocarbon receptor as a modulator of host responses to infection. Semin Immunopathol 2013, 35, 615-626, doi:10.1007/s00281-013-0395-3.
111. Stockinger, B.; Di Meglio, P.; Gialitakis, M.; Duarte, J.H. The aryl hydrocarbon receptor: multitasking in the immune system. Annu Rev Immunol 2014, 32, 403-432, doi:10.1146/annurev-immunol-032713-120245.
112. Frauenstein, K.; Tigges, J.; Soshilov, A.A.; Kado, S.; Raab, N.; Fritsche, E.; Haendeler, J.; Denison, M.S.; Vogel, C.F.; Haarmann-Stemmann, T. Activation of the aryl hydrocarbon receptor by the widely used Src family kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine (PP2). Arch Toxicol 2015, 89, 1329-1336, doi:10.1007/s00204-014-1321-8.
113. Backlund, M.; Johansson, I.; Mkrtchian, S.; Ingelman-Sundberg, M. Signal transduction-mediated activation of the aryl hydrocarbon receptor in rat hepatoma H4IIE cells. J Biol Chem 1997, 272, 31755-31763, doi:10.1074/jbc.272.50.31755.
114. Matsumura, F. The significance of the nongenomic pathway in mediating inflammatory signaling of the dioxin-activated Ah receptor to cause toxic effects. Biochem Pharmacol 2009, 77, 608-626, doi:10.1016/j.bcp.2008.10.013.
115. Canga, L.; Paroli, L.; Blanck, T.J.; Silver, R.B.; Rifkind, A.B. 2,3,7,8-tetrachlorodibenzo-p-dioxin increases cardiac myocyte intracellular calcium and progressively impairs ventricular contractile responses to isoproterenol and to calcium in chick embryo hearts. Mol Pharmacol 1993, 44, 1142-1151.
116. Esser, C.; Bargen, I.; Weighardt, H.; Haarmann-Stemmann, T.; Krutmann, J. Functions of the aryl hydrocarbon receptor in the skin. Semin Immunopathol 2013, 35, 677-691, doi:10.1007/s00281-013-0394-4.
117. Dong, H.; Bonala, R.R.; Suzuki, N.; Johnson, F.; Grollman, A.P.; Shibutani, S. Mutagenic potential of benzo[a] pyrene-derived DNA adducts positioned in codon 273 of the human P53 gene. Biochemistry-Us 2004, 43, 15922-15928, doi:10.1021/bi0482194.
118. Landvik, N.E.; Arlt, V.M.; Nagy, E.; Solhaug, A.; Tekpli, X.; Schmeiser, H.H.; Refsnes, M.; Phillips, D.H.; Lagadic-Gossmann, D.; Holme, J.A. 3-Nitrobenzanthrone and 3-aminobenzanthrone induce DNA damage and cell signalling Hepa1c1c7 cells. Mutat Res-Fund Mol M 2010, 684, 11-23, doi:10.1016/j.mrfmmm.2009.11.004.
119. Phillips, T.D.; Richardson, M.; Cheng, Y.S.L.; He, L.Y.; McDonald, T.J.; Cizmas, L.H.; Safe, S.H.; Donnelly, K.C.; Wang, F.; Moorthy, B.; et al. Mechanistic relationships between hepatic genotoxicity and carcinogenicity in male B6C3F1 mice treated with polycyclic aromatic hydrocarbon mixtures. Arch Toxicol 2015, 89, 967-977, doi:10.1007/s00204-014-1285-8.
120. Rossner, P.; Strapacova, S.; Stolcpartova, J.; Schmuczerova, J.; Milcova, A.; Neca, J.; Vlkova, V.; Brzicova, T.; Machala, M.; Topinka, J. Toxic Effects of the Major Components of Diesel Exhaust in Human Alveolar Basal Epithelial Cells (A549). Int J Mol Sci 2016, 17, doi:ARTN 1393

10.3390/ijms17091393.

121. Vogel, C.F.A.; Van Winkle, L.S.; Esser, C.; Haarmann-Stemmann, T. The aryl hydrocarbon receptor as a target of environmental stressors - Implications for pollution mediated stress and inflammatory responses. Redox Biol 2020, 34, 101530, doi:10.1016/j.redox.2020.101530.
122. Burczynski, M.E.; Lin, H.K.; Penning, T.M. Isoform-specific induction of a human aldo-keto reductase by polycyclic aromatic hydrocarbons (PAHs), electrophiles, and oxidative stress: implications for the alternative pathway of PAH activation catalyzed by human dihydrodiol dehydrogenase. Cancer Res 1999, 59, 607-614.
123. Hockley, S.L.; Arlt, V.M.; Brewer, D.; Giddings, I.; Phillips, D.H. Time- and concentration-dependent changes in gene expression induced by benzo(a)pyrene in two human cell lines, MCF-7 and HepG2. BMC Genomics 2006, 7, 260, doi:10.1186/1471-2164-7-260.
124. Yamashita, N.; Kanno, Y.; Saito, N.; Terai, K.; Sanada, N.; Kizu, R.; Hiruta, N.; Park, Y.; Bujo, H.; Nemoto, K. Aryl hydrocarbon receptor counteracts pharmacological efficacy of doxorubicin via enhanced AKR1C3 expression in triple negative breast cancer cells. Biochem Biophys Res Commun 2019, 516, 693-698, doi:10.1016/j.bbrc.2019.06.119.
125. Albertolle, M.E.; Guengerich, F.P. The relationships between cytochromes P450 and H2O2: Production, reaction, and inhibition. Journal of Inorganic Biochemistry 2018, 186, 228-234, doi:10.1016/j.jinorgbio.2018.05.014.
126. Valko, M.; Leibfritz, D.; Moncol, J.; Cronin, M.T.; Mazur, M.; Telser, J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007, 39, 44-84, doi:10.1016/j.biocel.2006.07.001.
127. Veith, A.; Moorthy, B. Role of Cytochrome P450s in the Generation and Metabolism of Reactive Oxygen Species. Curr Opin Toxicol 2018, 7, 44-51, doi:10.1016/j.cotox.2017.10.003.
128. Kuthan, H.; Ullrich, V. Oxidase and Oxygenase Function of the Microsomal Cytochrome-P450 Mono-Oxygenase System. Eur J Biochem 1982, 126, 583-588, doi:DOI 10.1111/j.1432-1033.1982.tb06820.x.
129. Kukielka, E.; Cederbaum, A.I. Nadph-Dependent and Nadh-Dependent Oxygen Radical Generation by Rat-Liver Nuclei in the Presence of Redox Cycling Agents and Iron. Arch Biochem Biophys 1990, 283, 326-333, doi:Doi 10.1016/0003-9861(90)90650-N.
130. Wincent, E.; Bengtsson, J.; Bardbori, A.M.; Alsberg, T.; Luecke, S.; Rannug, U.; Rannug, A. Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor. Proceedings of the National Academy of Sciences of the United States of America 2012, 109, 4479-4484, doi:10.1073/pnas.1118467109.
131. Tsuji, G.; Takahara, M.; Uchi, H.; Takeuchi, S.; Mitoma, C.; Moroi, Y.; Furue, M. An environmental contaminant, benzo(a)pyrene, induces oxidative stress-mediated interleukin-8 production in human keratinocytes via the aryl hydrocarbon receptor signaling pathway. J Dermatol Sci 2011, 62, 42-49, doi:10.1016/j.jdermsci.2010.10.017.
132. Haarmann-Stemmann, T.; Bothe, H.; Abel, J. Growth factors, cytokines and their receptors as downstream targets of arylhydrocarbon receptor (AhR) signaling pathways. Biochem Pharmacol 2009, 77, 508-520, doi:10.1016/j.bcp.2008.09.013.
133. Puga, A.; Ma, C.; Marlowe, J.L. The aryl hydrocarbon receptor cross-talks with multiple signal transduction pathways. Biochem Pharmacol 2009, 77, 713-722, doi:10.1016/j.bcp.2008.08.031.
134. Bedard, K.; Krause, K.H. The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology. Physiol Rev 2007, 87, 245-313, doi:10.1152/physrev.00044.2005.
135. Smith, J.; Neupane, R.; McAmis, W.; Singh, U.; Chatterjee, S.; Raychoudhury, S. Toxicity of polycyclic aromatic hydrocarbons involves NOX2 activation. Toxicol Rep 2019, 6, 1176-1181, doi:10.1016/j.toxrep.2019.11.006.
136. Pinel-Marie, M.L.; Sparfel, L.; Desmots, S.; Fardel, O. Aryl hydrocarbon receptor-dependent induction of the NADPH oxidase subunit NCF1/p47(phox) expression leading to priming of human macrophage oxidative burst. Free Radical Bio Med 2009, 47, 825-834, doi:10.1016/j.freeradbiomed.2009.06.025.
137. Lee, C.W.; Lin, Z.C.; Hu, S.C.S.; Chiang, Y.C.; Hsu, L.F.; Lin, Y.C.; Lee, I.T.; Tsai, M.H.; Fang, J.Y. Urban particulate matter down-regulates filaggrin via COX2 expression/PGE2 production leading to skin barrier dysfunction. Sci Rep-Uk 2016, 6, doi:ARTN 27995

10.1038/srep27995.

138. Amara, N.; Bachoual, R.; Desmard, M.; Golda, S.; Guichard, C.; Lanone, S.; Aubier, M.; Ogier-Denis, E.; Boczkowski, J. Diesel exhaust particles induce matrix metalloprotease-1 in human lung epithelial cells via a NADP(H) oxidase/NOX4 redox-dependent mechanism. Am J Physiol-Lung C 2007, 293, L170-L181, doi:10.1152/ajplung.00445.2006.
139. Ryu, Y.S.; Kang, K.A.; Piao, M.J.; Ahn, M.J.; Yi, J.M.; Hyun, Y.M.; Kim, S.H.; Ko, M.K.; Park, C.O.; Hyun, J.W. Particulate matter induces inflammatory cytokine production via activation of NF kappa B by TLR5-NOX4-ROS signaling in human skin keratinocyte and mouse skin. Redox Biol 2019, 21, doi:ARTN 101080

10.1016/j.redox.2018.101080.

140. Wada, T.; Sunaga, H.; Ohkawara, R.; Shimba, S. Aryl Hydrocarbon Receptor Modulates NADPH Oxidase Activity via Direct Transcriptional Regulation of p40(phox) Expression. Mol Pharmacol 2013, 83, 1133-1140, doi:10.1124/mol.112.083303.
141. Fisher, A.B. Redox Signaling Across Cell Membranes. Antioxid Redox Sign 2009, 11, 1349-1356, doi:10.1089/ars.2008.2378.
142. Geiszt, M.; Leto, T.L. The Nox family of NAD(P)H oxidases: host defense and beyond. J Biol Chem 2004, 279, 51715-51718, doi:10.1074/jbc.R400024200.
143. Leavey, P.J.; Gonzalez-Aller, C.; Thurman, G.; Kleinberg, M.; Rinckel, L.; Ambruso, D.W.; Freeman, S.; Kuypers, F.A.; Ambruso, D.R. A 29-kDa protein associated with p67phox expresses both peroxiredoxin and phospholipase A2 activity and enhances superoxide anion production by a cell-free system of NADPH oxidase activity. J Biol Chem 2002, 277, 45181-45187, doi:10.1074/jbc.M202869200.
144. Hennig, B.; Hammock, B.D.; Slim, R.; Toborek, M.; Saraswathi, V.; Robertson, L.W. PCB-induced oxidative stress in endothelial cells: modulation by nutrients. Int J Hyg Envir Heal 2002, 205, 95-102, doi:Doi 10.1078/1438-4639-00134.
145. Watanabe, I.; Tatebe, J.; Namba, S.; Koizumi, M.; Yamazaki, J.; Morita, T. Activation of Aryl Hydrocarbon Receptor Mediates Indoxyl Sulfate-Induced Monocyte Chemoattractant Protein-1 Expression in Human Umbilical Vein Endothelial Cells. Circ J 2013, 77, 224-230, doi:10.1253/circj.CJ-12-0647.
146. Masai, N.; Tatebe, J.; Yoshino, G.; Morita, T. Indoxyl Sulfate Stimulates Monocyte Chemoattractant Protein-1 Expression in Human Umbilical Vein Endothelial Cells by Inducing Oxidative Stress Through Activation of the NADPH Oxidase-Nuclear Factor-kappa B Pathway. Circ J 2010, 74, 2216-2224, doi:10.1253/circj.CJ-10-0117.
147. Mohammadi-Bardbori, A.; Bergander, L.V.; Rannug, U.; Rannug, A. NADPH Oxidase-Dependent Mechanism Explains How Arsenic and Other Oxidants Can Activate Aryl Hydrocarbon Receptor Signaling. Chem Res Toxicol 2015, 28, 2278-2286, doi:10.1021/acs.chemrestox.5b00415.
148. Anwar-Mohamed, A.; Elshenawy, O.H.; Soshilov, A.A.; Denison, M.S.; Le, X.C.; Klotz, L.O.; El-Kadi, A.O.S. Methylated pentavalent arsenic metabolites are bifunctional inducers, as they induce cytochrome P450 1A1 and NAD(P)H:quinone oxidoreductase through AhR- and Nrf2-dependent mechanisms. Free Radical Bio Med 2014, 67, 171-187, doi:10.1016/j.freeradbiomed.2013.10.810.
149. Wu, J.P.; Chang, L.W.; Yao, H.T.; Chang, H.; Tsai, H.T.; Tsai, M.H.; Yeh, T.K.; Lin, P. Involvement of Oxidative Stress and Activation of Aryl Hydrocarbon Receptor in Elevation of CYP1A1 Expression and Activity in Lung Cells and Tissues by Arsenic: An In Vitro and In Vivo Study. Toxicol Sci 2009, 107, 385-393, doi:10.1093/toxsci/kfn239.
150. Kubli, S.P.; Bassi, C.; Roux, C.; Wakeham, A.; Gobl, C.; Zhou, W.J.; Jafari, S.M.; Snow, B.; Jones, L.; Palomero, L.; et al. AhR controls redox homeostasis and shapes the tumor microenvironment in BRCA1-associated breast cancer. P Natl Acad Sci USA 2019, 116, 3604-3613, doi:10.1073/pnas.1815126116.
151. Seibert, K.; Zhang, Y.; Leahy, K.; Hauser, S.; Masferrer, J.; Perkins, W.; Lee, L.; Isakson, P. Pharmacological and Biochemical Demonstration of the Role of Cyclooxygenase-2 in Inflammation and Pain. P Natl Acad Sci USA 1994, 91, 12013-12017, doi:DOI 10.1073/pnas.91.25.12013.
152. Hussain, T.; Gupta, S.; Mukhtar, H. Cyclooxygenase-2 and prostate carcinogenesis. Cancer Lett 2003, 191, 125-135, doi:10.1016/S0304-3835(02)00524-4.
153. Eling, T.E.; Thompson, D.C.; Foureman, G.L.; Curtis, J.F.; Hughes, M.F. Prostaglandin-H Synthase and Xenobiotic Oxidation. Annu Rev Pharmacol 1990, 30, 1-45, doi:DOI 10.1146/annurev.pa.30.040190.000245.
154. Freyberger A., S.R., Schiffmann D., Degen G.H. . Prostaglandin-H-synthase competent cells derived from ram seminal vesicles: a tool for studying cooxidation of xenobiotics. Mol. Toxicol. 1987, 1, 503–512.
155. Vogel, C.; Schuhmacher, U.S.; Degen, G.H.; Bolt, H.M.; Pineau, T.; Abel, J. Modulation of prostaglandin H synthase-2 mRNA expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice. Arch Biochem Biophys 1998, 351, 265-271, doi:DOI 10.1006/abbi.1997.0555.
156. Vogel, C. Prostaglandin H synthases and their importance in chemical toxicity. Curr Drug Metab 2000, 1, 391-404, doi:Doi 10.2174/1389200003338884.
157. Jones, D.A.; Carlton, D.P.; Mcintyre, T.M.; Zimmerman, G.A.; Prescott, S.M. Molecular-Cloning of Human Prostaglandin Endoperoxide Synthase Type-Ii and Demonstration of Expression in Response to Cytokines. J Biol Chem 1993, 268, 9049-9054.
158. Seibert, K.; Masferrer, J.L. Role of Inducible Cyclooxygenase (Cox-2) in Inflammation. Receptor 1994, 4, 17-23.
159. Prescott, S.M.; Fitzpatrick, F.A. Cyclooxygellase-2 and carcinogenesis. Bba-Rev Cancer 2000, 1470, M69-M78, doi:Doi 10.1016/S0304-419x(00)00006-8.
160. Vogel, C.F.A.; Li, W.; Sciullo, E.; Newman, J.; Hammock, B.; Reader, J.R.; Tuscano, J.; Matsumura, F. Pathogenesis of aryl hydrocarbon receptor-mediated development of lymphoma is associated with increased cyclooxygenase-2 expression. Am J Pathol 2007, 171, 1538-1548, doi:DOI 10.2353/ajpath.2007.070406.
161. Pathak, S.K.; Sharma, R.A.; Steward, W.P.; Mellon, J.K.; Griffiths, T.R.L.; Gescher, A.J. Oxidative stress and cyclooxygenase activity in prostate carcinogenesis: targets for chemopreventive strategies. Eur J Cancer 2005, 41, 61-70, doi:10.1016/j.ejca.2004.09.028.
162. Vogel, C.; Boerboom, A.M.J.F.; Baechle, C.; El-Bahay, C.; Kahl, R.; Degen, G.H.; Abel, J. Regulation of prostaglandin endoperoxide H synthase-2 induction by dioxin in rat hepatocytes: possible c-Src-mediated pathway. Carcinogenesis 2000, 21, 2267-2274, doi:DOI 10.1093/carcin/21.12.2267.
163. Fritsche, E.; Schafer, C.; Calles, C.; Bernsmann, T.; Bernshausen, T.; Wurm, M.; Hubenthal, U.; Cline, J.E.; Hajimiragha, H.; Schroeder, P.; et al. Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation. P Natl Acad Sci USA 2007, 104, 8851-8856, doi:10.1073/pnas.0701764104.
164. Munoz, M.; Sanchez, A.; Martinez, M.P.; Benedito, S.; Lopez-Oliva, M.E.; Garcia-Sacristan, A.; Hernandez, M.; Prieto, D. COX-2 is involved in vascular oxidative stress and endothelial dysfunction of renal interlobar arteries from obese Zucker rats. Free Radical Bio Med 2015, 84, 77-90, doi:10.1016/j.freeradbiomed.2015.03.024.
165. Hernanz, R.; Briones, A.M.; Alonso, M.A.J.; Vila, E.; Salaices, M. Hypertension alters role of iNOS, COX-2, and oxidative stress in bradykinin relaxation impairment after LPS in rat cerebral arteries. Am J Physiol-Heart C 2004, 287, H225-H234, doi:10.1152/ajpheart.00548.2003.
166. Penning, T.M. Human Aldo-Keto Reductases and the Metabolic Activation of Polycyclic Aromatic Hydrocarbons. Chem Res Toxicol 2014, 27, 1901-1917, doi:10.1021/tx500298n.
167. Park, J.H.; Troxel, A.B.; Harvey, R.G.; Penning, T.M. Polycyclic aromatic hydrocarbon (PAH) o-quinones produced by the aldo-keto-reductases (AKRs) generate abasic sites, oxidized pyrimidines, and 8-oxo-dGuo via reactive oxygen species. Chem Res Toxicol 2006, 19, 719-728, doi:10.1021/tx0600245.
168. Burczynski, M.E.; Harvey, R.G.; Penning, T.M. Expression and characterization of four recombinant human dihydrodiol dehydrogenase isoforms: Oxidation of trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene to the activated o-quinone metabolite benzo[a]pyrene-7,8-dione (vol 37, pg 6781, 1998). Biochemistry-Us 1999, 38, 10626-10626, doi:DOI 10.1021/bi995085z.
169. Palackal, N.T.; Burczynski, M.E.; Harvey, R.G.; Penning, T.M. The ubiquitous aldehyde reductase (AKR1A1) oxidizes proximate carcinogen trans-dihydrodiols to o-quinones: Potential role in polycyclic aromatic hydrocarbon activation. Biochemistry-Us 2001, 40, 10901-10910, doi:DOI 10.1021/bi010872t.
170. Gelboin, H.V. Benzo[a]Pyrene Metabolism, Activation, and Carcinogenesis - Role and Regulation of Mixed-Function Oxidases and Related Enzymes. Physiol Rev 1980, 60, 1107-1166, doi:DOI 10.1152/physrev.1980.60.4.1107.
171. Penning, T.M.; Ohnishi, S.T.; Ohnishi, T.; Harvey, R.G. Generation of reactive oxygen species during the enzymatic oxidation of polycyclic aromatic hydrocarbon trans-dihydrodiols catalyzed by dihydrodiol dehydrogenase. Chem Res Toxicol 1996, 9, 84-92, doi:DOI 10.1021/tx950055s.
172. Shou, M.; Harvey, R.G.; Penning, T.M. Reactivity of Benzo[a]Pyrene-7,8-Dione with DNA - Evidence for the Formation of Deoxyguanosine Adducts. Carcinogenesis 1993, 14, 475-482, doi:DOI 10.1093/carcin/14.3.475.
173. Shultz, C.A.; Quinn, A.M.; Park, J.H.; Harvey, R.G.; Bolton, J.L.; Maser, E.; Penning, T.M. Specificity of Human Aldo-Keto Reductases, NAD(P)H:Quinone Oxidoreductase, and Carbonyl Reductases to Redox-Cycle Polycyclic Aromatic Hydrocarbon Diones and 4-Hydroxyequilenin-o-quinone. Chem Res Toxicol 2011, 24, 2153-2166, doi:10.1021/tx200294c.
174. Tsuji, G.; Takahara, M.; Uchi, H.; Matsuda, T.; Chiba, T.; Takeuchi, S.; Yasukawa, F.; Moroi, Y.; Furue, M. Identification of ketoconazole as an AhR-Nrf2 activator in cultured human keratinocytes: the basis of its anti-inflammatory effect. J Invest Dermatol 2012, 132, 59-68, doi:10.1038/jid.2011.194.
175. Takei, K.; Hashimoto-Hachiya, A.; Takahara, M.; Tsuji, G.; Nakahara, T.; Furue, M. Cynaropicrin attenuates UVB-induced oxidative stress via the AhR-Nrf2-Nqo1 pathway. Toxicol Lett 2015, 234, 74-80, doi:10.1016/j.toxlet.2015.02.007.
176. Takei, K.; Mitoma, C.; Hashimoto-Hachiya, A.; Uchi, H.; Takahara, M.; Tsuji, G.; Kido-Nakahara, M.; Nakahara, T.; Furue, M. Antioxidant soybean tar Glyteer rescues T-helper-mediated downregulation of filaggrin expression via aryl hydrocarbon receptor. J Dermatol 2015, 42, 171-180, doi:10.1111/1346-8138.12717.
177. Nakahara, T.; Mitoma, C.; Hashimoto-Hachiya, A.; Takahara, M.; Tsuji, G.; Uchi, H.; Yan, X.; Hachisuka, J.; Chiba, T.; Esaki, H.; et al. Antioxidant Opuntia ficus-indica Extract Activates AHR-NRF2 Signaling and Upregulates Filaggrin and Loricrin Expression in Human Keratinocytes. J Med Food 2015, 18, 1143-1149, doi:10.1089/jmf.2014.3396.
178. Haarmann-Stemmann, T.; Abel, J.; Fritsche, E.; Krutmann, J. The AhR-Nrf2 pathway in keratinocytes: on the road to chemoprevention? J Invest Dermatol 2012, 132, 7-9, doi:10.1038/jid.2011.359.
179. Jaiswal, A.K. Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radic Biol Med 2004, 36, 1199-1207, doi:10.1016/j.freeradbiomed.2004.02.074.
180. Niestroy, J.; Barbara, A.; Herbst, K.; Rode, S.; van Liempt, M.; Roos, P.H. Single and concerted effects of benzo[a]pyrene and flavonoids on the AhR and Nrf2-pathway in the human colon carcinoma cell line Caco-2. Toxicol In Vitro 2011, 25, 671-683, doi:10.1016/j.tiv.2011.01.008.
181. Han, S.G.; Han, S.S.; Toborek, M.; Hennig, B. EGCG protects endothelial cells against PCB 126-induced inflammation through inhibition of AhR and induction of Nrf2-regulated genes. Toxicol Appl Pharmacol 2012, 261, 181-188, doi:10.1016/j.taap.2012.03.024.
182. Tonelli, C.; Chio, I.I.C.; Tuveson, D.A. Transcriptional Regulation by Nrf2. Antioxid Redox Signal 2018, 29, 1727-1745, doi:10.1089/ars.2017.7342.
183. Tian, W.; Rojo de la Vega, M.; Schmidlin, C.J.; Ooi, A.; Zhang, D.D. Kelch-like ECH-associated protein 1 (KEAP1) differentially regulates nuclear factor erythroid-2-related factors 1 and 2 (NRF1 and NRF2). J Biol Chem 2018, 293, 2029-2040, doi:10.1074/jbc.RA117.000428.
184. Huang, Y.; Li, W.; Su, Z.Y.; Kong, A.N. The complexity of the Nrf2 pathway: beyond the antioxidant response. J Nutr Biochem 2015, 26, 1401-1413, doi:10.1016/j.jnutbio.2015.08.001.
185. Blank, V. Small Maf proteins in mammalian gene control: mere dimerization partners or dynamic transcriptional regulators? J Mol Biol 2008, 376, 913-925, doi:10.1016/j.jmb.2007.11.074.
186. Zhang, D.D. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev 2006, 38, 769-789, doi:10.1080/03602530600971974.
187. Yamamoto, M.; Kensler, T.W.; Motohashi, H. The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis. Physiol Rev 2018, 98, 1169-1203, doi:10.1152/physrev.00023.2017.
188. Hayes, J.D.; Dinkova-Kostova, A.T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci 2014, 39, 199-218, doi:10.1016/j.tibs.2014.02.002.
189. Rushmore, T.H.; Morton, M.R.; Pickett, C.B. The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem 1991, 266, 11632-11639.
190. Telakowski-Hopkins, C.A.; King, R.G.; Pickett, C.B. Glutathione S-transferase Ya subunit gene: identification of regulatory elements required for basal level and inducible expression. Proc Natl Acad Sci U S A 1988, 85, 1000-1004, doi:10.1073/pnas.85.4.1000.
191. Itoh, K.; Chiba, T.; Takahashi, S.; Ishii, T.; Igarashi, K.; Katoh, Y.; Oyake, T.; Hayashi, N.; Satoh, K.; Hatayama, I.; et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 1997, 236, 313-322, doi:10.1006/bbrc.1997.6943.
192. Thimmulappa, R.K.; Mai, K.H.; Srisuma, S.; Kensler, T.W.; Yamamoto, M.; Biswal, S. Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res 2002, 62, 5196-5203.
193. Kumar, H.; Kim, I.S.; More, S.V.; Kim, B.W.; Choi, D.K. Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases. Nat Prod Rep 2014, 31, 109-139, doi:10.1039/c3np70065h.
194. Corenblum, M.J.; Ray, S.; Remley, Q.W.; Long, M.; Harder, B.; Zhang, D.D.; Barnes, C.A.; Madhavan, L. Reduced Nrf2 expression mediates the decline in neural stem cell function during a critical middle-age period. Aging Cell 2016, 15, 725-736, doi:10.1111/acel.12482.
195. Cuadrado, A.; Rojo, A.I.; Wells, G.; Hayes, J.D.; Cousin, S.P.; Rumsey, W.L.; Attucks, O.C.; Franklin, S.; Levonen, A.L.; Kensler, T.W.; et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov 2019, 18, 295-317, doi:10.1038/s41573-018-0008-x.
196. Dodson, M.; de la Vega, M.R.; Cholanians, A.B.; Schmidlin, C.J.; Chapman, E.; Zhang, D.D. Modulating NRF2 in Disease: Timing Is Everything. Annu Rev Pharmacol Toxicol 2019, 59, 555-575, doi:10.1146/annurev-pharmtox-010818-021856.
197. La Rosa, P.; Russo, M.; D'Amico, J.; Petrillo, S.; Aquilano, K.; Lettieri-Barbato, D.; Turchi, R.; Bertini, E.S.; Piemonte, F. Nrf2 Induction Re-establishes a Proper Neuronal Differentiation Program in Friedreich's Ataxia Neural Stem Cells. Front Cell Neurosci 2019, 13, 356, doi:10.3389/fncel.2019.00356.
198. Robledinos-Anton, N.; Rojo, A.I.; Ferreiro, E.; Nunez, A.; Krause, K.H.; Jaquet, V.; Cuadrado, A. Transcription factor NRF2 controls the fate of neural stem cells in the subgranular zone of the hippocampus. Redox Biol 2017, 13, 393-401, doi:10.1016/j.redox.2017.06.010.
199. He, F.; Ru, X.; Wen, T. NRF2, a Transcription Factor for Stress Response and Beyond. Int J Mol Sci 2020, 21, doi:10.3390/ijms21134777.
200. Kohle, C.; Bock, K.W. Coordinate regulation of Phase I and II xenobiotic metabolisms by the Ah receptor and Nrf2. Biochem Pharmacol 2007, 73, 1853-1862, doi:10.1016/j.bcp.2007.01.009.
201. Ma, Q.; Kinneer, K.; Bi, Y.; Chan, J.Y.; Kan, Y.W. Induction of murine NAD(P)H:quinone oxidoreductase by 2,3,7,8-tetrachlorodibenzo-p-dioxin requires the CNC (cap 'n' collar) basic leucine zipper transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2): cross-interaction between AhR (aryl hydrocarbon receptor) and Nrf2 signal transduction. Biochem J 2004, 377, 205-213, doi:10.1042/BJ20031123.
202. Mimura, J.; Fujii-Kuriyama, Y. Functional role of AhR in the expression of toxic effects by TCDD. Biochim Biophys Acta 2003, 1619, 263-268, doi:10.1016/s0304-4165(02)00485-3.
203. Amakura, Y.; Tsutsumi, T.; Nakamura, M.; Kitagawa, H.; Fujino, J.; Sasaki, K.; Yoshida, T.; Toyoda, M. Preliminary screening of the inhibitory effect of food extracts on activation of the aryl hydrocarbon receptor induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biol Pharm Bull 2002, 25, 272-274, doi:10.1248/bpb.25.272.
204. Amakura, Y.; Tsutsumi, T.; Sasaki, K.; Yoshida, T.; Maitani, T. Screening of the inhibitory effect of vegetable constituents on the aryl hydrocarbon receptor-mediated activity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biol Pharm Bull 2003, 26, 1754-1760, doi:10.1248/bpb.26.1754.
205. Amakura, Y.; Tsutsumi, T.; Sasaki, K.; Nakamura, M.; Yoshida, T.; Maitani, T. Influence of food polyphenols on aryl hydrocarbon receptor-signaling pathway estimated by in vitro bioassay. Phytochemistry 2008, 69, 3117-3130, doi:10.1016/j.phytochem.2007.07.022.
206. Furue, M.; Fuyuno, Y.; Mitoma, C.; Uchi, H.; Tsuji, G. Therapeutic Agents with AHR Inhibiting and NRF2 Activating Activity for Managing Chloracne. Antioxidants (Basel) 2018, 7, doi:10.3390/antiox7070090.
207. Marchand, A.; Barouki, R.; Garlatti, M. Regulation of NAD(P)H:quinone oxidoreductase 1 gene expression by CYP1A1 activity. Mol Pharmacol 2004, 65, 1029-1037, doi:10.1124/mol.65.4.1029.
208. Ramos-Gomez, M.; Kwak, M.K.; Dolan, P.M.; Itoh, K.; Yamamoto, M.; Talalay, P.; Kensler, T.W. Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci U S A 2001, 98, 3410-3415, doi:10.1073/pnas.051618798.
209. Gao, X.; Dinkova-Kostova, A.T.; Talalay, P. Powerful and prolonged protection of human retinal pigment epithelial cells, keratinocytes, and mouse leukemia cells against oxidative damage: the indirect antioxidant effects of sulforaphane. Proc Natl Acad Sci U S A 2001, 98, 15221-15226, doi:10.1073/pnas.261572998.
210. Nguyen, T.; Sherratt, P.J.; Pickett, C.B. Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 2003, 43, 233-260, doi:10.1146/annurev.pharmtox.43.100901.140229.
211. Favreau, L.V.; Pickett, C.B. Transcriptional regulation of the rat NAD(P)H:quinone reductase gene. Identification of regulatory elements controlling basal level expression and inducible expression by planar aromatic compounds and phenolic antioxidants. J Biol Chem 1991, 266, 4556-4561.
212. Hussain, T.; Tan, B.; Yin, Y.; Blachier, F.; Tossou, M.C.; Rahu, N. Oxidative Stress and Inflammation: What Polyphenols Can Do for Us? Oxid Med Cell Longev 2016, 2016, 7432797, doi:10.1155/2016/7432797.
213. Yoshikawa T, N.Y. What Is Oxidative Stress? J. Japan Medical Association 2002, 45, 271–276.
214. Uttara, B.; Singh, A.V.; Zamboni, P.; Mahajan, R.T. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 2009, 7, 65-74, doi:10.2174/157015909787602823.
215. Pizzino, G.; Irrera, N.; Cucinotta, M.; Pallio, G.; Mannino, F.; Arcoraci, V.; Squadrito, F.; Altavilla, D.; Bitto, A. Oxidative Stress: Harms and Benefits for Human Health. Oxid Med Cell Longev 2017, 2017, 8416763, doi:10.1155/2017/8416763.
216. Pham-Huy, L.A.; He, H.; Pham-Huy, C. Free radicals, antioxidants in disease and health. Int J Biomed Sci 2008, 4, 89-96.
217. Neavin, D.R.; Liu, D.; Ray, B.; Weinshilboum, R.M. The Role of the Aryl Hydrocarbon Receptor (AHR) in Immune and Inflammatory Diseases. Int J Mol Sci 2018, 19, doi:10.3390/ijms19123851.
218. Singh, A.; Kukreti, R.; Saso, L.; Kukreti, S. Oxidative Stress: A Key Modulator in Neurodegenerative Diseases. Molecules 2019, 24, doi:10.3390/molecules24081583.
219. Gemma, C.; Vila, J.; Bachstetter, A.; Bickford, P.C. Oxidative Stress and the Aging Brain: From Theory to Prevention. In Brain Aging: Models, Methods, and Mechanisms, Riddle, D.R., Ed.; Frontiers in Neuroscience; Boca Raton (FL), 2007.
220. Demers-Lamarche, J.; Guillebaud, G.; Tlili, M.; Todkar, K.; Belanger, N.; Grondin, M.; Nguyen, A.P.; Michel, J.; Germain, M. Loss of Mitochondrial Function Impairs Lysosomes. J Biol Chem 2016, 291, 10263-10276, doi:10.1074/jbc.M115.695825.
221. Lefaki, M.; Papaevgeniou, N.; Chondrogianni, N. Redox regulation of proteasome function. Redox Biol 2017, 13, 452-458, doi:10.1016/j.redox.2017.07.005.
222. Dalton, T.P.; Puga, A.; Shertzer, H.G. Induction of cellular oxidative stress by aryl hydrocarbon receptor activation. Chem Biol Interact 2002, 141, 77-95, doi:10.1016/s0009-2797(02)00067-4.
223. Liu, H.; Shi, L.; Giesy, J.P.; Yu, H. Polychlorinated diphenyl sulfides can induce ROS and genotoxicity via the AhR-CYP1A1 pathway. Chemosphere 2019, 223, 165-170, doi:10.1016/j.chemosphere.2019.01.169.
224. Huang, P.; Rannug, A.; Ahlbom, E.; Hakansson, H.; Ceccatelli, S. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the expression of cytochrome P450 1A1, the aryl hydrocarbon receptor, and the aryl hydrocarbon receptor nuclear translocator in rat brain and pituitary. Toxicol Appl Pharmacol 2000, 169, 159-167, doi:10.1006/taap.2000.9064.
225. Bansal, S.; Leu, A.N.; Gonzalez, F.J.; Guengerich, F.P.; Chowdhury, A.R.; Anandatheerthavarada, H.K.; Avadhani, N.G. Mitochondrial targeting of cytochrome P450 (CYP) 1B1 and its role in polycyclic aromatic hydrocarbon-induced mitochondrial dysfunction. J Biol Chem 2014, 289, 9936-9951, doi:10.1074/jbc.M113.525659.
226. Nebert, D.W.; Karp, C.L. Endogenous functions of the aryl hydrocarbon receptor (AHR): intersection of cytochrome P450 1 (CYP1)-metabolized eicosanoids and AHR biology. J Biol Chem 2008, 283, 36061-36065, doi:10.1074/jbc.R800053200.
227. Perepechaeva, M.L.; Grishanova, A.Y. The Role of Aryl Hydrocarbon Receptor (AhR) in Brain Tumors. Int J Mol Sci 2020, 21, doi:10.3390/ijms21082863.
228. Kolluri, S.K.; Jin, U.H.; Safe, S. Erratum to: Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target. Arch Toxicol 2017, 91, 3209, doi:10.1007/s00204-017-2026-6.
229. Park, H.; Jin, U.H.; Karki, K.; Jayaraman, A.; Allred, C.; Michelhaugh, S.K.; Mittal, S.; Chapkin, R.S.; Safe, S. Dopamine is an aryl hydrocarbon receptor agonist. Biochem J 2020, 477, 3899-3910, doi:10.1042/BCJ20200440.
230. Zhou, Y.; Zhao, W.J.; Quan, W.; Qiao, C.M.; Cui, C.; Hong, H.; Shi, Y.; Niu, G.Y.; Zhao, L.P.; Shen, Y.Q. Dynamic changes of activated AHR in microglia and astrocytes in the substantia nigra-striatum system in an MPTP-induced Parkinson's disease mouse model. Brain Res Bull 2021, 176, 174-183, doi:10.1016/j.brainresbull.2021.08.013.
231. Ramos-Garcia, N.A.; Orozco-Ibarra, M.; Estudillo, E.; Elizondo, G.; Gomez Apo, E.; Chavez Macias, L.G.; Sosa-Ortiz, A.L.; Torres-Ramos, M.A. Aryl Hydrocarbon Receptor in Post-Mortem Hippocampus and in Serum from Young, Elder, and Alzheimer's Patients. Int J Mol Sci 2020, 21, doi:10.3390/ijms21061983.
232. Rothhammer, V.; Borucki, D.M.; Tjon, E.C.; Takenaka, M.C.; Chao, C.C.; Ardura-Fabregat, A.; de Lima, K.A.; Gutierrez-Vazquez, C.; Hewson, P.; Staszewski, O.; et al. Microglial control of astrocytes in response to microbial metabolites. Nature 2018, 557, 724-728, doi:10.1038/s41586-018-0119-x.
233. Ojo, E.S.; Tischkau, S.A. The Role of AhR in the Hallmarks of Brain Aging: Friend and Foe. Cells 2021, 10, doi:10.3390/cells10102729.
234. Choudhary, M.; Malek, G. The Aryl Hydrocarbon Receptor: A Mediator and Potential Therapeutic Target for Ocular and Non-Ocular Neurodegenerative Diseases. Int J Mol Sci 2020, 21, doi:10.3390/ijms21186777.
235. Gatz, M.; Reynolds, C.A.; Fratiglioni, L.; Johansson, B.; Mortimer, J.A.; Berg, S.; Fiske, A.; Pedersen, N.L. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 2006, 63, 168-174, doi:10.1001/archpsyc.63.2.168.
236. Rath, S.N.; Jena, L.; Patri, M. Understanding ligands driven mechanism of wild and mutant aryl hydrocarbon receptor in presence of phytochemicals combating Parkinson's disease: an in silico and in vivo study. J Biomol Struct Dyn 2020, 38, 807-826, doi:10.1080/07391102.2019.1590240.
237. Datla, K.P.; Christidou, M.; Widmer, W.W.; Rooprai, H.K.; Dexter, D.T. Tissue distribution and neuroprotective effects of citrus flavonoid tangeretin in a rat model of Parkinson's disease. Neuroreport 2001, 12, 3871-3875, doi:10.1097/00001756-200112040-00053.
238. Gonzalez-Barbosa, E.; Garcia-Aguilar, R.; Vega, L.; Cabanas-Cortes, M.A.; Gonzalez, F.J.; Segovia, J.; Morales-Lazaro, S.L.; Cisneros, B.; Elizondo, G. Parkin is transcriptionally regulated by the aryl hydrocarbon receptor: Impact on alpha-synuclein protein levels. Biochem Pharmacol 2019, 168, 429-437, doi:10.1016/j.bcp.2019.08.002.
239. Ogura, J.; Miyauchi, S.; Shimono, K.; Yang, S.; Gonchigar, S.; Ganapathy, V.; Bhutia, Y.D. Carbidopa is an activator of aryl hydrocarbon receptor with potential for cancer therapy. Biochem J 2017, 474, 3391-3402, doi:10.1042/BCJ20170583.
240. Qian, C.; Yang, C.; Lu, M.; Bao, J.; Shen, H.; Deng, B.; Li, S.; Li, W.; Zhang, M.; Cao, C. Activating AhR alleviates cognitive deficits of Alzheimer's disease model mice by upregulating endogenous Abeta catabolic enzyme Neprilysin. Theranostics 2021, 11, 8797-8812, doi:10.7150/thno.61601.
241. Duan, Z.; Zhang, S.; Liang, H.; Xing, Z.; Guo, L.; Shi, L.; Du, L.; Kuang, C.; Takikawa, O.; Yang, Q. Amyloid beta neurotoxicity is IDO1-Kyn-AhR dependent and blocked by IDO1 inhibitor. Signal Transduct Target Ther 2020, 5, 96, doi:10.1038/s41392-020-0188-9.
242. Wingerchuk, D.M. Smoking: effects on multiple sclerosis susceptibility and disease progression. Ther Adv Neurol Disord 2012, 5, 13-22, doi:10.1177/1756285611425694.
243. Zeilinger, S.; Kuhnel, B.; Klopp, N.; Baurecht, H.; Kleinschmidt, A.; Gieger, C.; Weidinger, S.; Lattka, E.; Adamski, J.; Peters, A.; et al. Tobacco smoking leads to extensive genome-wide changes in DNA methylation. PLoS One 2013, 8, e63812, doi:10.1371/journal.pone.0063812.
244. Ash, P.E.A.; Stanford, E.A.; Al Abdulatif, A.; Ramirez-Cardenas, A.; Ballance, H.I.; Boudeau, S.; Jeh, A.; Murithi, J.M.; Tripodis, Y.; Murphy, G.J.; et al. Dioxins and related environmental contaminants increase TDP-43 levels. Mol Neurodegener 2017, 12, 35, doi:10.1186/s13024-017-0177-9.
245. Rothhammer, V.; Borucki, D.M.; Kenison, J.E.; Hewson, P.; Wang, Z.; Bakshi, R.; Sherr, D.H.; Quintana, F.J. Detection of aryl hydrocarbon receptor agonists in human samples. Sci Rep 2018, 8, 4970, doi:10.1038/s41598-018-23323-4.
246. Wheeler, M.A.; Quintana, F.J. Regulation of Astrocyte Functions in Multiple Sclerosis. Cold Spring Harb Perspect Med 2019, 9, doi:10.1101/cshperspect.a029009.
247. Rothhammer, V.; Mascanfroni, I.D.; Bunse, L.; Takenaka, M.C.; Kenison, J.E.; Mayo, L.; Chao, C.C.; Patel, B.; Yan, R.; Blain, M.; et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med 2016, 22, 586-597, doi:10.1038/nm.4106.
248. Jangi, S.; Gandhi, R.; Cox, L.M.; Li, N.; von Glehn, F.; Yan, R.; Patel, B.; Mazzola, M.A.; Liu, S.; Glanz, B.L.; et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun 2016, 7, 12015, doi:10.1038/ncomms12015.
249. Quintana, F.J. Regulation of central nervous system autoimmunity by the aryl hydrocarbon receptor. Semin Immunopathol 2013, 35, 627-635, doi:10.1007/s00281-013-0397-1.
250. Hanieh, H. Toward understanding the role of aryl hydrocarbon receptor in the immune system: current progress and future trends. Biomed Res Int 2014, 2014, 520763, doi:10.1155/2014/520763.
251. Duarte, J.H.; Di Meglio, P.; Hirota, K.; Ahlfors, H.; Stockinger, B. Differential influences of the aryl hydrocarbon receptor on Th17 mediated responses in vitro and in vivo. PLoS One 2013, 8, e79819, doi:10.1371/journal.pone.0079819.
252. Kaye, J.; Piryatinsky, V.; Birnberg, T.; Hingaly, T.; Raymond, E.; Kashi, R.; Amit-Romach, E.; Caballero, I.S.; Towfic, F.; Ator, M.A.; et al. Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A 2016, 113, E6145-E6152, doi:10.1073/pnas.1607843113.
253. Mackenzie, I.R.; Rademakers, R. The role of transactive response DNA-binding protein-43 in amyotrophic lateral sclerosis and frontotemporal dementia. Curr Opin Neurol 2008, 21, 693-700, doi:10.1097/WCO.0b013e3283168d1d.
254. Soshilov, A.A.; Denison, M.S. Ligand promiscuity of aryl hydrocarbon receptor agonists and antagonists revealed by site-directed mutagenesis. Mol Cell Biol 2014, 34, 1707-1719, doi:10.1128/MCB.01183-13.
255. Santosa, S.; Jones, P.J. Oxidative stress in ocular disease: does lutein play a protective role? CMAJ 2005, 173, 861-862, doi:10.1503/cmaj.1031425.
256. Meyer, C.H.; Sekundo, W. Nutritional supplementation to prevent cataract formation. Dev Ophthalmol 2005, 38, 103-119, doi:10.1159/000082771.
257. Beatty, S.; Koh, H.; Phil, M.; Henson, D.; Boulton, M. The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 2000, 45, 115-134, doi:10.1016/s0039-6257(00)00140-5.
258. Hammond, C.L.; Roztocil, E.; Gupta, V.; Feldon, S.E.; Woeller, C.F. More than Meets the Eye: The Aryl Hydrocarbon Receptor is an Environmental Sensor, Physiological Regulator and a Therapeutic Target in Ocular Disease. Front Toxicol 2022, 4, 791082, doi:10.3389/ftox.2022.791082.
259. Vasiliou, V.; Gonzalez, F.J. Role of CYP1B1 in glaucoma. Annu Rev Pharmacol Toxicol 2008, 48, 333-358, doi:10.1146/annurev.pharmtox.48.061807.154729.
260. Oki, N.O.; Edwards, S.W. An integrative data mining approach to identifying adverse outcome pathway signatures. Toxicology 2016, 350-352, 49-61, doi:10.1016/j.tox.2016.04.004.
261. Reis, L.M.; Tyler, R.C.; Weh, E.; Hendee, K.E.; Kariminejad, A.; Abdul-Rahman, O.; Ben-Omran, T.; Manning, M.A.; Yesilyurt, A.; McCarty, C.A.; et al. Analysis of CYP1B1 in pediatric and adult glaucoma and other ocular phenotypes. Mol Vis 2016, 22, 1229-1238.
262. Volotinen, M.; Maenpaa, J.; Kankuri, E.; Oksala, O.; Pelkonen, O.; Nakajima, M.; Yokoi, T.; Hakkola, J. Expression of cytochrome P450 (CYP) enzymes in human nonpigmented ciliary epithelial cells: induction of CYP1B1 expression by TCDD. Invest Ophthalmol Vis Sci 2009, 50, 3099-3105, doi:10.1167/iovs.08-2790.
263. Kim, S.Y.; Yang, H.J.; Chang, Y.S.; Kim, J.W.; Brooks, M.; Chew, E.Y.; Wong, W.T.; Fariss, R.N.; Rachel, R.A.; Cogliati, T.; et al. Deletion of aryl hydrocarbon receptor AHR in mice leads to subretinal accumulation of microglia and RPE atrophy. Invest Ophthalmol Vis Sci 2014, 55, 6031-6040, doi:10.1167/iovs.14-15091.
264. Choudhary, M.; Kazmin, D.; Hu, P.; Thomas, R.S.; McDonnell, D.P.; Malek, G. Aryl hydrocarbon receptor knock-out exacerbates choroidal neovascularization via multiple pathogenic pathways. J Pathol 2015, 235, 101-112, doi:10.1002/path.4433.
265. Takeuchi, A.; Takeuchi, M.; Oikawa, K.; Sonoda, K.H.; Usui, Y.; Okunuki, Y.; Takeda, A.; Oshima, Y.; Yoshida, K.; Usui, M.; et al. Effects of dioxin on vascular endothelial growth factor (VEGF) production in the retina associated with choroidal neovascularization. Invest Ophthalmol Vis Sci 2009, 50, 3410-3416, doi:10.1167/iovs.08-2299.
266. Perepechaeva, M.L.; Kolosova, N.G.; Stefanova, N.A.; Fursova, A.; Grishanova, A.Y. The influence of changes in expression of redox-sensitive genes on the development of retinopathy in rats. Exp Mol Pathol 2016, 101, 124-132, doi:10.1016/j.yexmp.2016.07.008.
267. Perepechaeva, M.L.; Grishanova, A.Y.; Rudnitskaya, E.A.; Kolosova, N.G. The Mitochondria-Targeted Antioxidant SkQ1 Downregulates Aryl Hydrocarbon Receptor-Dependent Genes in the Retina of OXYS Rats with AMD-Like Retinopathy. J Ophthalmol 2014, 2014, 530943, doi:10.1155/2014/530943.
268. Perepechaeva, M.L.; Stefanova, N.A.; Grishanova, A.Y. Expression of genes for AhR and Nrf2 signal pathways in the retina of OXYS rats during the development of retinopathy and melatonin-induced changes in this process. Bull Exp Biol Med 2014, 157, 424-429, doi:10.1007/s10517-014-2582-1.
269. Gutierrez, M.A.; Davis, S.S.; Rosko, A.; Nguyen, S.M.; Mitchell, K.P.; Mateen, S.; Neves, J.; Garcia, T.Y.; Mooney, S.; Perdew, G.H.; et al. A novel AhR ligand, 2AI, protects the retina from environmental stress. Sci Rep 2016, 6, 29025, doi:10.1038/srep29025.
270. Khan, A.S.; Wolf, A.; Langmann, T. The AhR ligand 2, 2'-aminophenyl indole (2AI) regulates microglia homeostasis and reduces pro-inflammatory signaling. Biochem Biophys Res Commun 2021, 579, 15-21, doi:10.1016/j.bbrc.2021.09.054.
271. Nadeem, A.; Masood, A.; Siddiqui, N. Oxidant--antioxidant imbalance in asthma: scientific evidence, epidemiological data and possible therapeutic options. Ther Adv Respir Dis 2008, 2, 215-235, doi:10.1177/1753465808094971.
272. Guo, R.F.; Ward, P.A. Role of oxidants in lung injury during sepsis. Antioxid Redox Signal 2007, 9, 1991-2002, doi:10.1089/ars.2007.1785.
273. Hoshino, Y.; Mishima, M. Redox-based therapeutics for lung diseases. Antioxid Redox Signal 2008, 10, 701-704, doi:10.1089/ars.2007.1961.
274. MacNee, W. Oxidative stress and lung inflammation in airways disease. Eur J Pharmacol 2001, 429, 195-207, doi:10.1016/s0014-2999(01)01320-6.
275. White, K.E.; Ding, Q.; Moore, B.B.; Peters-Golden, M.; Ware, L.B.; Matthay, M.A.; Olman, M.A. Prostaglandin E2 mediates IL-1beta-related fibroblast mitogenic effects in acute lung injury through differential utilization of prostanoid receptors. J Immunol 2008, 180, 637-646, doi:10.4049/jimmunol.180.1.637.
276. Lora, J.M.; Zhang, D.M.; Liao, S.M.; Burwell, T.; King, A.M.; Barker, P.A.; Singh, L.; Keaveney, M.; Morgenstern, J.; Gutierrez-Ramos, J.C.; et al. Tumor necrosis factor-alpha triggers mucus production in airway epithelium through an IkappaB kinase beta-dependent mechanism. J Biol Chem 2005, 280, 36510-36517, doi:10.1074/jbc.M507977200.
277. Perrais, M.; Pigny, P.; Copin, M.C.; Aubert, J.P.; Van Seuningen, I. Induction of MUC2 and MUC5AC mucins by factors of the epidermal growth factor (EGF) family is mediated by EGF receptor/Ras/Raf/extracellular signal-regulated kinase cascade and Sp1. J Biol Chem 2002, 277, 32258-32267, doi:10.1074/jbc.M204862200.
278. Wang, J.H.; Trigg, C.J.; Devalia, J.L.; Jordan, S.; Davies, R.J. Effect of inhaled beclomethasone dipropionate on expression of proinflammatory cytokines and activated eosinophils in the bronchial epithelium of patients with mild asthma. J Allergy Clin Immunol 1994, 94, 1025-1034, doi:10.1016/0091-6749(94)90121-x.
279. Shivanna, B.; Chu, C.; Moorthy, B. The Aryl Hydrocarbon Receptor (AHR): A Novel Therapeutic Target for Pulmonary Diseases? Int J Mol Sci 2022, 23, doi:10.3390/ijms23031516.
280. Chiba, T.; Uchi, H.; Tsuji, G.; Gondo, H.; Moroi, Y.; Furue, M. Arylhydrocarbon receptor (AhR) activation in airway epithelial cells induces MUC5AC via reactive oxygen species (ROS) production. Pulm Pharmacol Ther 2011, 24, 133-140, doi:10.1016/j.pupt.2010.08.002.
281. Alexandrov, K.; Rojas, M.; Satarug, S. The critical DNA damage by benzo(a)pyrene in lung tissues of smokers and approaches to preventing its formation. Toxicol Lett 2010, 198, 63-68, doi:10.1016/j.toxlet.2010.04.009.
282. Beamer, C.A.; Shepherd, D.M. Role of the aryl hydrocarbon receptor (AhR) in lung inflammation. Semin Immunopathol 2013, 35, 693-704, doi:10.1007/s00281-013-0391-7.
283. Chiba, T.; Chihara, J.; Furue, M. Role of the Arylhydrocarbon Receptor (AhR) in the Pathology of Asthma and COPD. J Allergy (Cairo) 2012, 2012, 372384, doi:10.1155/2012/372384.
284. Zago, M.; Sheridan, J.A.; Traboulsi, H.; Hecht, E.; Zhang, Y.; Guerrina, N.; Matthews, J.; Nair, P.; Eidelman, D.H.; Hamid, Q.; et al. Low levels of the AhR in chronic obstructive pulmonary disease (COPD)-derived lung cells increases COX-2 protein by altering mRNA stability. PLoS One 2017, 12, e0180881, doi:10.1371/journal.pone.0180881.
285. Ying, S.; Meng, Q.; Zeibecoglou, K.; Robinson, D.S.; Macfarlane, A.; Humbert, M.; Kay, A.B. Eosinophil chemotactic chemokines (eotaxin, eotaxin-2, RANTES, monocyte chemoattractant protein-3 (MCP-3), and MCP-4), and C-C chemokine receptor 3 expression in bronchial biopsies from atopic and nonatopic (Intrinsic) asthmatics. J Immunol 1999, 163, 6321-6329.
286. Yao, H.; Rahman, I. Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease. Toxicol Appl Pharmacol 2011, 254, 72-85, doi:10.1016/j.taap.2009.10.022.
287. van Eeden, S.F.; Sin, D.D. Oxidative stress in chronic obstructive pulmonary disease: a lung and systemic process. Can Respir J 2013, 20, 27-29, doi:10.1155/2013/509130.
288. Guerrina, N.; Traboulsi, H.; Eidelman, D.H.; Baglole, C.J. The Aryl Hydrocarbon Receptor and the Maintenance of Lung Health. Int J Mol Sci 2018, 19, doi:10.3390/ijms19123882.
289. Thorley, A.J.; Tetley, T.D. Pulmonary epithelium, cigarette smoke, and chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2007, 2, 409-428.
290. Barnes, P.J. Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 2016, 138, 16-27, doi:10.1016/j.jaci.2016.05.011.
291. Iu, M.; Zago, M.; Rico de Souza, A.; Bouttier, M.; Pareek, S.; White, J.H.; Hamid, Q.; Eidelman, D.H.; Baglole, C.J. RelB attenuates cigarette smoke extract-induced apoptosis in association with transcriptional regulation of the aryl hydrocarbon receptor. Free Radic Biol Med 2017, 108, 19-31, doi:10.1016/j.freeradbiomed.2017.02.045.
292. Sarill, M.; Zago, M.; Sheridan, J.A.; Nair, P.; Matthews, J.; Gomez, A.; Roussel, L.; Rousseau, S.; Hamid, Q.; Eidelman, D.H.; et al. The aryl hydrocarbon receptor suppresses cigarette-smoke-induced oxidative stress in association with dioxin response element (DRE)-independent regulation of sulfiredoxin 1. Free Radic Biol Med 2015, 89, 342-357, doi:10.1016/j.freeradbiomed.2015.08.007.
293. Wong, P.S.; Vogel, C.F.; Kokosinski, K.; Matsumura, F. Arylhydrocarbon receptor activation in NCI-H441 cells and C57BL/6 mice: possible mechanisms for lung dysfunction. Am J Respir Cell Mol Biol 2010, 42, 210-217, doi:10.1165/rcmb.2008-0228OC.
294. Marshall, N.B.; Kerkvliet, N.I. Dioxin and immune regulation: emerging role of aryl hydrocarbon receptor in the generation of regulatory T cells. Ann N Y Acad Sci 2010, 1183, 25-37, doi:10.1111/j.1749-6632.2009.05125.x.
295. Lai, H.; Rogers, D.F. New pharmacotherapy for airway mucus hypersecretion in asthma and COPD: targeting intracellular signaling pathways. J Aerosol Med Pulm Drug Deliv 2010, 23, 219-231, doi:10.1089/jamp.2009.0802.
296. Chiba, T.; Uchi, H.; Yasukawa, F.; Furue, M. Role of the arylhydrocarbon receptor in lung disease. Int Arch Allergy Immunol 2011, 155 Suppl 1, 129-134, doi:10.1159/000327499.
297. Thatcher, T.H.; Maggirwar, S.B.; Baglole, C.J.; Lakatos, H.F.; Gasiewicz, T.A.; Phipps, R.P.; Sime, P.J. Aryl hydrocarbon receptor-deficient mice develop heightened inflammatory responses to cigarette smoke and endotoxin associated with rapid loss of the nuclear factor-kappaB component RelB. Am J Pathol 2007, 170, 855-864, doi:10.2353/ajpath.2007.060391.
298. Moorthy, B.; Parker, K.M.; Smith, C.V.; Bend, J.R.; Welty, S.E. Potentiation of oxygen-induced lung injury in rats by the mechanism-based cytochrome P-450 inhibitor, 1-aminobenzotriazole. J Pharmacol Exp Ther 2000, 292, 553-560.
299. Luebke, R.W.; Copeland, C.B.; Daniels, M.; Lambert, A.L.; Gilmour, M.I. Suppression of allergic immune responses to house dust mite (HDM) in rats exposed to 2,3,7,8-TCDD. Toxicol Sci 2001, 62, 71-79, doi:10.1093/toxsci/62.1.71.
300. Moon, D.O.; Kim, M.O.; Lee, H.J.; Choi, Y.H.; Park, Y.M.; Heo, M.S.; Kim, G.Y. Curcumin attenuates ovalbumin-induced airway inflammation by regulating nitric oxide. Biochem Biophys Res Commun 2008, 375, 275-279, doi:10.1016/j.bbrc.2008.08.025.
301. Shivanna, B.; Jiang, W.; Wang, L.; Couroucli, X.I.; Moorthy, B. Omeprazole attenuates hyperoxic lung injury in mice via aryl hydrocarbon receptor activation and is associated with increased expression of cytochrome P4501A enzymes. J Pharmacol Exp Ther 2011, 339, 106-114, doi:10.1124/jpet.111.182980.
302. Wang, E.; Liu, X.; Tu, W.; Do, D.C.; Yu, H.; Yang, L.; Zhou, Y.; Xu, D.; Huang, S.K.; Yang, P.; et al. Benzo(a)pyrene facilitates dermatophagoides group 1 (Der f 1)-induced epithelial cytokine release through aryl hydrocarbon receptor in asthma. Allergy 2019, 74, 1675-1690, doi:10.1111/all.13784.
303. Dean, A.; Gregorc, T.; Docherty, C.K.; Harvey, K.Y.; Nilsen, M.; Morrell, N.W.; MacLean, M.R. Role of the Aryl Hydrocarbon Receptor in Sugen 5416-induced Experimental Pulmonary Hypertension. Am J Respir Cell Mol Biol 2018, 58, 320-330, doi:10.1165/rcmb.2017-0260OC.
304. Walston, J.; Xue, Q.; Semba, R.D.; Ferrucci, L.; Cappola, A.R.; Ricks, M.; Guralnik, J.; Fried, L.P. Serum antioxidants, inflammation, and total mortality in older women. Am J Epidemiol 2006, 163, 18-26, doi:10.1093/aje/kwj007.
305. Mahajan A, T.V. Antioxidants and rheumatoid arthritis. J. Indian Rheumatol. Ass. 2004, 12, 139–142.
306. Talbot, J.; Peres, R.S.; Pinto, L.G.; Oliveira, R.D.R.; Lima, K.A.; Donate, P.B.; Silva, J.R.; Ryffel, B.; Cunha, T.M.; Alves-Filho, J.C.; et al. Smoking-induced aggravation of experimental arthritis is dependent of aryl hydrocarbon receptor activation in Th17 cells. Arthritis Res Ther 2018, 20, 119, doi:10.1186/s13075-018-1609-9.
307. Tamaki, A.; Hayashi, H.; Nakajima, H.; Takii, T.; Katagiri, D.; Miyazawa, K.; Hirose, K.; Onozaki, K. Polycyclic aromatic hydrocarbon increases mRNA level for interleukin 1 beta in human fibroblast-like synoviocyte line via aryl hydrocarbon receptor. Biol Pharm Bull 2004, 27, 407-410, doi:10.1248/bpb.27.407.
308. Xi, X.; Ye, Q.; Fan, D.; Cao, X.; Wang, Q.; Wang, X.; Zhang, M.; Xu, Y.; Xiao, C. Polycyclic Aromatic Hydrocarbons Affect Rheumatoid Arthritis Pathogenesis via Aryl Hydrocarbon Receptor. Front Immunol 2022, 13, 797815, doi:10.3389/fimmu.2022.797815.
309. Hui, W.; Dai, Y. Therapeutic potential of aryl hydrocarbon receptor ligands derived from natural products in rheumatoid arthritis. Basic Clin Pharmacol Toxicol 2020, 126, 469-474, doi:10.1111/bcpt.13372.
310. O'Driscoll, C.A.; Gallo, M.E.; Hoffmann, E.J.; Fechner, J.H.; Schauer, J.J.; Bradfield, C.A.; Mezrich, J.D. Polycyclic aromatic hydrocarbons (PAHs) present in ambient urban dust drive proinflammatory T cell and dendritic cell responses via the aryl hydrocarbon receptor (AHR) in vitro. PLoS One 2018, 13, e0209690, doi:10.1371/journal.pone.0209690.
311. Villa, M.; Gialitakis, M.; Tolaini, M.; Ahlfors, H.; Henderson, C.J.; Wolf, C.R.; Brink, R.; Stockinger, B. Aryl hydrocarbon receptor is required for optimal B-cell proliferation. EMBO J 2017, 36, 116-128, doi:10.15252/embj.201695027.
312. Fukui, S.; Iwamoto, N.; Takatani, A.; Igawa, T.; Shimizu, T.; Umeda, M.; Nishino, A.; Horai, Y.; Hirai, Y.; Koga, T.; et al. M1 and M2 Monocytes in Rheumatoid Arthritis: A Contribution of Imbalance of M1/M2 Monocytes to Osteoclastogenesis. Front Immunol 2017, 8, 1958, doi:10.3389/fimmu.2017.01958.
313. Van Raemdonck, K.; Umar, S.; Palasiewicz, K.; Volkov, S.; Volin, M.V.; Arami, S.; Chang, H.J.; Zanotti, B.; Sweiss, N.; Shahrara, S. CCL21/CCR7 signaling in macrophages promotes joint inflammation and Th17-mediated osteoclast formation in rheumatoid arthritis. Cell Mol Life Sci 2020, 77, 1387-1399, doi:10.1007/s00018-019-03235-w.
314. Iqbal, J.; Sun, L.; Cao, J.; Yuen, T.; Lu, P.; Bab, I.; Leu, N.A.; Srinivasan, S.; Wagage, S.; Hunter, C.A.; et al. Smoke carcinogens cause bone loss through the aryl hydrocarbon receptor and induction of Cyp1 enzymes. Proc Natl Acad Sci U S A 2013, 110, 11115-11120, doi:10.1073/pnas.1220919110.
315. Nakahama, T.; Kimura, A.; Nguyen, N.T.; Chinen, I.; Hanieh, H.; Nohara, K.; Fujii-Kuriyama, Y.; Kishimoto, T. Aryl hydrocarbon receptor deficiency in T cells suppresses the development of collagen-induced arthritis. Proc Natl Acad Sci U S A 2011, 108, 14222-14227, doi:10.1073/pnas.1111786108.
316. Quintana, F.J.; Basso, A.S.; Iglesias, A.H.; Korn, T.; Farez, M.F.; Bettelli, E.; Caccamo, M.; Oukka, M.; Weiner, H.L. Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 2008, 453, 65-71, doi:10.1038/nature06880.
317. Miki, Y.; Hata, S.; Ono, K.; Suzuki, T.; Ito, K.; Kumamoto, H.; Sasano, H. Roles of Aryl Hydrocarbon Receptor in Aromatase-Dependent Cell Proliferation in Human Osteoblasts. Int J Mol Sci 2017, 18, doi:10.3390/ijms18102159.
318. Jonsson, M.E.; Mattsson, A.; Shaik, S.; Brunstrom, B. Toxicity and cytochrome P450 1A mRNA induction by 6-formylindolo[3,2-b]carbazole (FICZ) in chicken and Japanese quail embryos. Comp Biochem Physiol C Toxicol Pharmacol 2016, 179, 125-136, doi:10.1016/j.cbpc.2015.09.014.
319. Pierre, S.; Chevallier, A.; Teixeira-Clerc, F.; Ambolet-Camoit, A.; Bui, L.C.; Bats, A.S.; Fournet, J.C.; Fernandez-Salguero, P.; Aggerbeck, M.; Lotersztajn, S.; et al. Aryl hydrocarbon receptor-dependent induction of liver fibrosis by dioxin. Toxicol Sci 2014, 137, 114-124, doi:10.1093/toxsci/kft236.
320. Kalkhof, S.; Dautel, F.; Loguercio, S.; Baumann, S.; Trump, S.; Jungnickel, H.; Otto, W.; Rudzok, S.; Potratz, S.; Luch, A.; et al. Pathway and time-resolved benzo[a]pyrene toxicity on Hepa1c1c7 cells at toxic and subtoxic exposure. J Proteome Res 2015, 14, 164-182, doi:10.1021/pr500957t.
321. Esser, C.; Bargen, I.; Weighardt, H.; Haarmann-Stemmann, T.; Krutmann, J. Functions of the aryl hydrocarbon receptor in the skin. Semin Immunopathol 2013, 35, 677-691, doi:10.1007/s00281-013-0394-4.
322. Peng, F.; Xue, C.H.; Hwang, S.K.; Li, W.H.; Chen, Z.; Zhang, J.Z. Exposure to fine particulate matter associated with senile lentigo in Chinese women: a cross-sectional study. J Eur Acad Dermatol Venereol 2017, 31, 355-360, doi:10.1111/jdv.13834.
323. Guo, Y.L.; Yu, M.L.; Hsu, C.C.; Rogan, W.J. Chloracne, goiter, arthritis, and anemia after polychlorinated biphenyl poisoning: 14-year follow-Up of the Taiwan Yucheng cohort. Environ Health Perspect 1999, 107, 715-719, doi:10.1289/ehp.99107715.
324. Caputo, R.; Monti, M.; Ermacora, E.; Carminati, G.; Gelmetti, C.; Gianotti, R.; Gianni, E.; Puccinelli, V. Cutaneous manifestations of tetrachlorodibenzo-p-dioxin in children and adolescents. Follow-up 10 years after the Seveso, Italy, accident. J Am Acad Dermatol 1988, 19, 812-819, doi:10.1016/s0190-9622(88)70238-8.
325. Furue M., U.T., Urabe K., Ishikawa T., Kuwabara M. . Overview of Yusho. Journal of Dermatological Science Supplement 2005, 1, doi:10.1016/j.descs.2005.03.002.
326. Mitoma, C.; Mine, Y.; Utani, A.; Imafuku, S.; Muto, M.; Akimoto, T.; Kanekura, T.; Furue, M.; Uchi, H. Current skin symptoms of Yusho patients exposed to high levels of 2,3,4,7,8-pentachlorinated dibenzofuran and polychlorinated biphenyls in 1968. Chemosphere 2015, 137, 45-51, doi:10.1016/j.chemosphere.2015.03.070.
327. Hu, T.; Pan, Z.; Yu, Q.; Mo, X.; Song, N.; Yan, M.; Zouboulis, C.C.; Xia, L.; Ju, Q. Benzo(a)pyrene induces interleukin (IL)-6 production and reduces lipid synthesis in human SZ95 sebocytes via the aryl hydrocarbon receptor signaling pathway. Environ Toxicol Pharmacol 2016, 43, 54-60, doi:10.1016/j.etap.2016.02.011.
328. Sun, Y.V.; Boverhof, D.R.; Burgoon, L.D.; Fielden, M.R.; Zacharewski, T.R. Comparative analysis of dioxin response elements in human, mouse and rat genomic sequences. Nucleic Acids Res 2004, 32, 4512-4523, doi:10.1093/nar/gkh782.
329. Hidaka, T.; Ogawa, E.; Kobayashi, E.H.; Suzuki, T.; Funayama, R.; Nagashima, T.; Fujimura, T.; Aiba, S.; Nakayama, K.; Okuyama, R.; et al. The aryl hydrocarbon receptor AhR links atopic dermatitis and air pollution via induction of the neurotrophic factor artemin. Nat Immunol 2017, 18, 64-73, doi:10.1038/ni.3614.
330. Schallreuter, K.U.; Salem, M.A.; Gibbons, N.C.; Maitland, D.J.; Marsch, E.; Elwary, S.M.; Healey, A.R. Blunted epidermal L-tryptophan metabolism in vitiligo affects immune response and ROS scavenging by Fenton chemistry, part 2: Epidermal H2O2/ONOO(-)-mediated stress in vitiligo hampers indoleamine 2,3-dioxygenase and aryl hydrocarbon receptor-mediated immune response signaling. FASEB J 2012, 26, 2471-2485, doi:10.1096/fj.11-201897.
331. van den Bogaard, E.H.; Bergboer, J.G.; Vonk-Bergers, M.; van Vlijmen-Willems, I.M.; Hato, S.V.; van der Valk, P.G.; Schroder, J.M.; Joosten, I.; Zeeuwen, P.L.; Schalkwijk, J. Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis. J Clin Invest 2013, 123, 917-927, doi:10.1172/JCI65642.
332. Di Meglio, P.; Duarte, J.H.; Ahlfors, H.; Owens, N.D.; Li, Y.; Villanova, F.; Tosi, I.; Hirota, K.; Nestle, F.O.; Mrowietz, U.; et al. Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions. Immunity 2014, 40, 989-1001, doi:10.1016/j.immuni.2014.04.019.
333. Di Meglio, P.; Perera, G.K.; Nestle, F.O. The multitasking organ: recent insights into skin immune function. Immunity 2011, 35, 857-869, doi:10.1016/j.immuni.2011.12.003.
334. Kostyuk, V.A.; Potapovich, A.I.; Lulli, D.; Stancato, A.; De Luca, C.; Pastore, S.; Korkina, L. Modulation of human keratinocyte responses to solar UV by plant polyphenols as a basis for chemoprevention of non-melanoma skin cancers. Curr Med Chem 2013, 20, 869-879.
335. Sheipouri, D.; Braidy, N.; Guillemin, G.J. Kynurenine Pathway in Skin Cells: Implications for UV-Induced Skin Damage. Int J Tryptophan Res 2012, 5, 15-25, doi:10.4137/IJTR.S9835.
336. Droge, W. Free radicals in the physiological control of cell function. Physiol Rev 2002, 82, 47-95, doi:10.1152/physrev.00018.2001.
337. Podkowinska, A.; Formanowicz, D. Chronic Kidney Disease as Oxidative Stress- and Inflammatory-Mediated Cardiovascular Disease. Antioxidants (Basel) 2020, 9, doi:10.3390/antiox9080752.
338. Mo, Y.; Lu, Z.; Wang, L.; Ji, C.; Zou, C.; Liu, X. The Aryl Hydrocarbon Receptor in Chronic Kidney Disease: Friend or Foe? Front Cell Dev Biol 2020, 8, 589752, doi:10.3389/fcell.2020.589752.
339. Liu, J.R.; Miao, H.; Deng, D.Q.; Vaziri, N.D.; Li, P.; Zhao, Y.Y. Gut microbiota-derived tryptophan metabolism mediates renal fibrosis by aryl hydrocarbon receptor signaling activation. Cell Mol Life Sci 2021, 78, 909-922, doi:10.1007/s00018-020-03645-1.
340. Alkhalaf, L.M.; Ryan, K.S. Biosynthetic manipulation of tryptophan in bacteria: pathways and mechanisms. Chem Biol 2015, 22, 317-328, doi:10.1016/j.chembiol.2015.02.005.
341. Scott, S.A.; Fu, J.; Chang, P.V. Microbial tryptophan metabolites regulate gut barrier function via the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A 2020, 117, 19376-19387, doi:10.1073/pnas.2000047117.
342. Huc, T.; Nowinski, A.; Drapala, A.; Konopelski, P.; Ufnal, M. Indole and indoxyl sulfate, gut bacteria metabolites of tryptophan, change arterial blood pressure via peripheral and central mechanisms in rats. Pharmacol Res 2018, 130, 172-179, doi:10.1016/j.phrs.2017.12.025.
343. Lu, H.; Lei, X.; Klaassen, C. Gender differences in renal nuclear receptors and aryl hydrocarbon receptor in 5/6 nephrectomized rats. Kidney Int 2006, 70, 1920-1928, doi:10.1038/sj.ki.5001880.
344. Dou, L.; Poitevin, S.; Sallee, M.; Addi, T.; Gondouin, B.; McKay, N.; Denison, M.S.; Jourde-Chiche, N.; Duval-Sabatier, A.; Cerini, C.; et al. Aryl hydrocarbon receptor is activated in patients and mice with chronic kidney disease. Kidney Int 2018, 93, 986-999, doi:10.1016/j.kint.2017.11.010.
345. Kim, J.T.; Kim, S.H.; Min, H.K.; Jeon, S.J.; Sung, S.A.; Park, W.H.; Lee, H.K.; Choi, H.S.; Pak, Y.K.; Lee, S.Y. Effect of Dialysis on Aryl Hydrocarbon Receptor Transactivating Activity in Patients with Chronic Kidney Disease. Yonsei Med J 2020, 61, 56-63, doi:10.3349/ymj.2020.61.1.56.
346. Walker, J.A.; Richards, S.; Belghasem, M.E.; Arinze, N.; Yoo, S.B.; Tashjian, J.Y.; Whelan, S.A.; Lee, N.; Kolachalama, V.B.; Francis, J.; et al. Temporal and tissue-specific activation of aryl hydrocarbon receptor in discrete mouse models of kidney disease. Kidney Int 2020, 97, 538-550, doi:10.1016/j.kint.2019.09.029.
347. Ichii, O.; Otsuka-Kanazawa, S.; Nakamura, T.; Ueno, M.; Kon, Y.; Chen, W.; Rosenberg, A.Z.; Kopp, J.B. Podocyte injury caused by indoxyl sulfate, a uremic toxin and aryl-hydrocarbon receptor ligand. PLoS One 2014, 9, e108448, doi:10.1371/journal.pone.0108448.
348. Ng, H.Y.; Yisireyili, M.; Saito, S.; Lee, C.T.; Adelibieke, Y.; Nishijima, F.; Niwa, T. Indoxyl sulfate downregulates expression of Mas receptor via OAT3/AhR/Stat3 pathway in proximal tubular cells. PLoS One 2014, 9, e91517, doi:10.1371/journal.pone.0091517.
349. Mutsaers, H.A.; Stribos, E.G.; Glorieux, G.; Vanholder, R.; Olinga, P. Chronic Kidney Disease and Fibrosis: The Role of Uremic Retention Solutes. Front Med (Lausanne) 2015, 2, 60, doi:10.3389/fmed.2015.00060.
350. Kim, J.T.; Kim, S.S.; Jun, D.W.; Hwang, Y.H.; Park, W.H.; Pak, Y.K.; Lee, H.K. Serum arylhydrocarbon receptor transactivating activity is elevated in type 2 diabetic patients with diabetic nephropathy. J Diabetes Investig 2013, 4, 483-491, doi:10.1111/jdi.12081.
351. Lee, W.J.; Liu, S.H.; Chiang, C.K.; Lin, S.Y.; Liang, K.W.; Chen, C.H.; Tien, H.R.; Chen, P.H.; Wu, J.P.; Tsai, Y.C.; et al. Aryl Hydrocarbon Receptor Deficiency Attenuates Oxidative Stress-Related Mesangial Cell Activation and Macrophage Infiltration and Extracellular Matrix Accumulation in Diabetic Nephropathy. Antioxid Redox Signal 2016, 24, 217-231, doi:10.1089/ars.2015.6310.
352. Bahorun T, S.M., Luximon-Ramma V, Aruoma OI. Free Radicals and Antioxidants in Cardiovascular Health and Disease. Internet J. Med. Update. 2006, 1, 1–17.
353. Willcox, J.K.; Ash, S.L.; Catignani, G.L. Antioxidants and prevention of chronic disease. Crit Rev Food Sci Nutr 2004, 44, 275-295, doi:10.1080/10408690490468489.
354. Chatterjee, M.; Saluja, R.; Kanneganti, S.; Chinta, S.; Dikshit, M. Biochemical and molecular evaluation of neutrophil NOS in spontaneously hypertensive rats. Cell Mol Biol (Noisy-le-grand) 2007, 53, 84-93.
355. Ceriello, A. Possible role of oxidative stress in the pathogenesis of hypertension. Diabetes Care 2008, 31 Suppl 2, S181-184, doi:10.2337/dc08-s245.
356. Carreira, V.S.; Fan, Y.; Wang, Q.; Zhang, X.; Kurita, H.; Ko, C.I.; Naticchioni, M.; Jiang, M.; Koch, S.; Medvedovic, M.; et al. Ah Receptor Signaling Controls the Expression of Cardiac Development and Homeostasis Genes. Toxicol Sci 2015, 147, 425-435, doi:10.1093/toxsci/kfv138.
357. Zhang, N. The role of endogenous aryl hydrocarbon receptor signaling in cardiovascular physiology. J Cardiovasc Dis Res 2011, 2, 91-95, doi:10.4103/0975-3583.83033.
358. Vanholder, R.; Fouque, D.; Glorieux, G.; Heine, G.H.; Kanbay, M.; Mallamaci, F.; Massy, Z.A.; Ortiz, A.; Rossignol, P.; Wiecek, A.; et al. Clinical management of the uraemic syndrome in chronic kidney disease. Lancet Diabetes Endocrinol 2016, 4, 360-373, doi:10.1016/S2213-8587(16)00033-4.
359. Sallee, M.; Dou, L.; Cerini, C.; Poitevin, S.; Brunet, P.; Burtey, S. The aryl hydrocarbon receptor-activating effect of uremic toxins from tryptophan metabolism: a new concept to understand cardiovascular complications of chronic kidney disease. Toxins (Basel) 2014, 6, 934-949, doi:10.3390/toxins6030934.
360. Humblet, O.; Birnbaum, L.; Rimm, E.; Mittleman, M.A.; Hauser, R. Dioxins and cardiovascular disease mortality. Environ Health Perspect 2008, 116, 1443-1448, doi:10.1289/ehp.11579.
361. Lowenstein, J. Agent Orange and heart disease: is there a connection? FASEB J 2014, 28, 1531-1533, doi:10.1096/fj.14-0402ufm.
362. Oesterling, E.; Toborek, M.; Hennig, B. Benzo[a]pyrene induces intercellular adhesion molecule-1 through a caveolae and aryl hydrocarbon receptor mediated pathway. Toxicol Appl Pharmacol 2008, 232, 309-316, doi:10.1016/j.taap.2008.07.001.
363. Reynolds, L.M.; Wan, M.; Ding, J.; Taylor, J.R.; Lohman, K.; Su, D.; Bennett, B.D.; Porter, D.K.; Gimple, R.; Pittman, G.S.; et al. DNA Methylation of the Aryl Hydrocarbon Receptor Repressor Associations With Cigarette Smoking and Subclinical Atherosclerosis. Circ Cardiovasc Genet 2015, 8, 707-716, doi:10.1161/CIRCGENETICS.115.001097.
364. Tsirpanlis, G. Cellular senescence, cardiovascular risk, and CKD: a review of established and hypothetical interconnections. Am J Kidney Dis 2008, 51, 131-144, doi:10.1053/j.ajkd.2007.07.035.
365. Vogel, C.F.; Sciullo, E.; Li, W.; Wong, P.; Lazennec, G.; Matsumura, F. RelB, a new partner of aryl hydrocarbon receptor-mediated transcription. Mol Endocrinol 2007, 21, 2941-2955, doi:10.1210/me.2007-0211.
366. Wang, J.N.; Che, Y.; Yuan, Z.Y.; Lu, Z.L.; Li, Y.; Zhang, Z.R.; Li, N.; Li, R.D.; Wan, J.; Sun, H.D.; et al. Acetyl-macrocalin B suppresses tumor growth in esophageal squamous cell carcinoma and exhibits synergistic anti-cancer effects with the Chk1/2 inhibitor AZD7762. Toxicol Appl Pharmacol 2019, 365, 71-83, doi:10.1016/j.taap.2019.01.005.
367. Vogel, C.F.; Sciullo, E.; Wong, P.; Kuzmicky, P.; Kado, N.; Matsumura, F. Induction of proinflammatory cytokines and C-reactive protein in human macrophage cell line U937 exposed to air pollution particulates. Environ Health Perspect 2005, 113, 1536-1541, doi:10.1289/ehp.8094.
368. Hennig, B.; Meerarani, P.; Slim, R.; Toborek, M.; Daugherty, A.; Silverstone, A.E.; Robertson, L.W. Proinflammatory properties of coplanar PCBs: in vitro and in vivo evidence. Toxicol Appl Pharmacol 2002, 181, 174-183, doi:10.1006/taap.2002.9408.
369. Yisireyili, M.; Saito, S.; Abudureyimu, S.; Adelibieke, Y.; Ng, H.Y.; Nishijima, F.; Takeshita, K.; Murohara, T.; Niwa, T. Indoxyl sulfate-induced activation of (pro)renin receptor promotes cell proliferation and tissue factor expression in vascular smooth muscle cells. PLoS One 2014, 9, e109268, doi:10.1371/journal.pone.0109268.
370. Zhu, K.; Meng, Q.; Zhang, Z.; Yi, T.; He, Y.; Zheng, J.; Lei, W. Aryl hydrocarbon receptor pathway: Role, regulation and intervention in atherosclerosis therapy (Review). Mol Med Rep 2019, 20, 4763-4773, doi:10.3892/mmr.2019.10748.