Search Results (216)

The respiratory system is directly exposed to various environmental factors, and specifically allergens and environmental pollutants, which are ligands/agonists of the aryl hydrocarbon receptor (AhR) and promote chronic lung diseases in humans. AhR, a ligand-activated transcription factor, is involved in the metabolism of xenobiotics, assigning their carcinogenic and toxic effects, and is also involved in normal homeostasis, organogenesis, and immune system function. Exogenous and endogenous AhR ligands are both high-molecular-weight compounds with a planar structure and low-molecular-weight compounds of diverse chemical structures. After entering the cell, the ligands bind to AhR and induce the activation of signaling cascades. The lung immune system responds to pathogens and environmental toxins first with a pro-inflammatory innate immune response, and then with an anti-inflammatory adaptive immune response. An imbalance between these immune systems may have an effect on the course of the disease. Activation of AhR by exogenous or endogenous ligands can affect this balance and lead to dysregulation of the immune response, leading to inflammatory complications in the lungs. Individual features of AhR expression or components of the AhR-dependent signaling pathway may also play a role in the superposition of the functions of these two links of immunity. This review summarizes advances in the comprehension of AhR’s role in immunomodulation and inflammatory responses in the lungs following data in experimental rodent models, in vitro studies utilizing lung structural cells and isolated immune cell lines, and humans. The molecular mechanisms of AhR’s regulation of immunity and inflammation and the potential of AhR as a therapeutic target for inflammatory lung disease are also considered. Full article

Objectives: Inflammatory bowel disease (IBD) is associated with extraintestinal comorbidities, and lung diseases are widespread manifestations. Respiratory bacterial insult is a common illness that results in acute lung injury (ALI) in critical patients. IBD concurrence with respiratory infection may further exacerbate lung injury. Tryptophan (Try), an essential amino acid, is processed by gut microbiota and produces aryl hydrocarbon receptor (AhR) ligands. These ligands can activate the AhR pathway that exerts anti-inflammatory properties and provides protection against mucosal barrier injury. This study investigated the effects of dietary Try on lipopolysaccharide (LPS)-stimulated ALI in mice with colitis induced by dextran sodium sulfate (DSS). Methods: Mice with colitis were allocated to four groups: (1) ND-Sal: normal diet + DSS + intratracheal saline injection; (2) ND-LPS: normal diet + DSS + intratracheal LPS injection; (3) TD-Sal: Try diet + DSS + intratracheal saline injection; (4) TD-LPS: Try diet + DSS + intratracheal LPS injection. Mice were sacrificed 24 h after the intratracheal injection. Results: Results showed that colitis resulted in a high disease activity index. Following induction of ALI in colitis mice, neutrophil populations and inflammatory cytokine levels in bronchoalveolar lavage fluid increased. Gene expression levels associated with toll-like receptor (TLR)4/nuclear factor (NF)-κB signaling were upregulated, and tight junction proteins decreased in the lungs. Dietary Try supplementation decreased circulating LPS levels, suppressed pulmonary TLR4/NF-κB signaling, upregulated AhR/interleukin-22 expression, attenuated oxidative stress and improved the capillary–epithelial barrier integrity in DSS-treated mice. Conclusions: These findings imply that Try may have potential therapeutic significance in bacterial-induced ALI in a colitis condition. Full article

Tryptophan (Trp) metabolism sits at the intersection of nutrition, the microbiome, mucosal immunity, and tumor adaptation. The broad observation that microbial indoles can support barrier function, whereas tumors exploit kynurenine-pathway metabolism to suppress immunity, is already established in publications. The specific contribution of this review is to organize that literature into a context- and network-based translational framework. Rather than treating indoleamine 2,3-dioxygenase 1 (IDO1) as a single bottleneck, we frame tumor Trp metabolism as a compensatory system linking IDO1, tryptophan 2,3-dioxygenase (TDO2), interleukin-4-induced gene 1 (IL4I1), amino-acid transport, amino-acid stress sensing, and downstream aryl hydrocarbon receptor (AHR) signaling. In healthy tissue, especially the gut, dietary Trp and microbiota-derived indoles can promote epithelial integrity, interleukin-22 (IL-22)-associated programs, and mucosal restraint. In tumors, the same substrate pool is redirected toward Kynurenine, kynurenic acid, indole-3-pyruvate, and related catabolites that impair cytotoxic lymphocytes, expand regulatory T-cell (Treg) and suppressive myeloid compartments, and reinforce invasion and treatment resistance. We also argue that the potential metabolite biomarker interpretation should be context-dependent. Finally, we propose a clinical-context–specific framework for intervention. Dietary and microbiome-based strategies may be most effective in prevention, premalignant states, or supportive care, whereas established cancers are more likely to require biomarker-guided targeting of tumor-associated catabolic pathways and convergent signaling mechanisms. The “paradox” is therefore not that Trp changes chemistry across settings, but that the same nutrient is routed through different cellular contexts, enzymes, ligands, and cell states. Full article

During infection in vitro with the strain 438/06 of bovine coronavirus (BCoV), a β-coronavirus similar to severe acute respiratory syndrome (SARS) CoV-2, treatment with 6-pentyl-α-pyrone (6PP), a fungal metabolite obtained from Trichoderma atroviride, was recently shown to influence viral load by reducing viral entry. Herein, the ability of 6PP to counteract the BCoV infection was further investigated both in vitro and in silico. Following the BCoV (strain 282/23) infection in bovine (MDBK) cells, the 6PP in co-treatment increased cell viability, reduced morphological signs of cell death, and significantly inhibited viral yield, by lessening the expression of the viral spike (S) protein, as well as the gene transcription of the viral nucleocapsid (NP) protein. In addition, a noticeable down-regulation in the expression of aryl hydrocarbon receptor (AhR) signaling, a strategic modulator of CoVs infection, was found. Molecular docking studies were performed to evaluate the potential interaction between 6PP and AhR involved in the BCoV infection. The docking 3D structural model showed that 6PP fits into a binding pocket positioned between the PASB and TAD domains of bovine AhR (bAhR), where the ligand is stabilized through hydrophobic interactions. In addition, the obtained computational data strongly suggest that the bAhR binding mechanism of 6PP is principally mediated by a well-conserved hydrophobic cavity playing a key role in the modulation of the receptor functions. Overall, our findings showed an antiviral action of 6PP versus BCoV infection in vitro and in silico. Full article

Background/Objectives: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic environmental contaminant whose adverse biological effects are primarily mediated through activation of the aryl hydrocarbon receptor (AhR). Upon ligand binding, AhR undergoes conformational changes that initiate nuclear translocation and transcriptional activation of xenobiotic-responsive genes, contributing to toxicity, carcinogenesis, and dysregulated immune and metabolic responses. Understanding the molecular basis of AhR activation by TCDD is therefore critical for the rational development of targeted therapeutic strategies. Methods: In this study, molecular docking simulations were employed to characterize the interaction of TCDD and selected AhR antagonists (CH223191, BAY 2416964, GNF-351) with the ligand-binding domain of AhR, with particular emphasis on the canonical PAS-B domain. Results: Docking analyses identified the PAS-B cavity (pocket C1) as the most biologically relevant binding site for high-affinity ligands, consistent with experimental evidence. Comparative docking of known AhR antagonists revealed stable binding poses characterized by hydrophobic packing, π–π interactions, and hydrogen-bonding networks that competitively block agonist access and prevent receptor activation. These findings support a competitive antagonism mechanism as a viable approach to counteract TCDD-induced AhR signaling. Conclusions: Collectively, this in silico study provides mechanistic insight into TCDD toxicity at the molecular level and highlights AhR antagonism as a promising strategy for the development of targeted therapies against dioxin-related pathologies. Full article

The escalating consumption of red meat is a potent environmental risk factor for inflammatory bowel disease (IBD), which is characterized by compromised expression of the xenobiotic transporter P-glycoprotein (MDR1/ABCB1). While gut microbiota metabolize dietary tryptophan into diverse indole derivatives that function as aryl hydrocarbon receptor (AhR) ligands, their differential regulation of MDR1 remains an unresolved AhR paradox. Here, we investigated the mechanisms by which two distinct metabolites, indole-3-acetic acid (IAA) and skatole, regulate MDR1 expression in human colonic epithelial Caco-2 cells. We observed that IAA selectively enhances MDR1 protein stability via an AhR-dependent pathway without inducing de novo transcription, suggesting a mechanism we term enhanced proteostasis mediated by the AhR-Hsp90 complex. Conversely, skatole, a toxic dysbiotic metabolite linked to red meat intake, triggered a time-dependent depletion of MDR1 and potently abrogated the protective efficacy of IAA. Our findings are consistent with a model in which skatole acts as a putative structural disruptor, potentially destabilizing the chaperone complex essential for MDR1 integrity. This destruction is facilitated by a key bacterial enzyme, indoleacetate decarboxylase (IAD), which is a pH-dependent metabolic switch in the gut. The modern Western diet, characterized by high protein and low fiber content, elevates colonic pH, thereby activating IAD to convert protective IAA into toxic skatole. These findings provide a molecular framework for the red meat–microbiome–barrier failure axis and highlight the restoration of the IAA/skatole balance through dietary intervention as a promising therapeutic strategy. Full article

Microbiota-derived indoles and short-chain fatty acids (SCFAs) modulate intestinal immunity via the aryl hydrocarbon receptor (AhR) and vitamin D receptor (VDR). This review proposes an operational AhR–VDR axis—three testable models (sequential, parallel, reciprocal)—to explain how indoles (AhR) and SCFAs/vitamin D (VDR) may cooperate to drive IL-22–mediated repair, antimicrobial peptide production, autophagy, and tight-junction restoration. We critically evaluate prebiotics, probiotics, and postbiotics: prebiotics shift fermentation toward SCFAs but show context-dependent effects; probiotics can supply indole-type AhR ligands yet are strain-specific; postbiotics offer standardized ligand delivery but face formulation challenges. We distinguish Salmonella-specific findings (e.g., SCFA suppression of SPI-1) from general colitis data and prioritize molecular validation, temporal mapping, multi-omics responder stratification, and standardized postbiotic development for clinical translation. Full article

The family Arenaviridae encompasses zoonotic, rodent-borne pathogens (e.g., Lassa, Machupo, and Junín viruses) that cause severe viral hemorrhagic fevers with high case fatality rates. The current therapeutic landscape is severely limited, underscoring the urgent need for novel antiviral strategies. A promising approach involves combining directly acting antivirals with host-targeted antivirals. A compelling host-targeted antiviral target is the aryl hydrocarbon receptor (AHR). This ubiquitous ligand-activated transcription factor is a recognized pro-viral host factor across multiple viral families. Building on prior work with Junín and Tacaribe viruses, we investigated whether the AHR inhibitor CH223191 could enhance the virus-directed antiviral activity of favipiravir against these viruses. First, we evaluated the toxicity and antiviral potential of CH223191 against a lethal Junín virus infection in male and female hTfR1 mice. After demonstrating substantial protection, we conducted preliminary assays to study the antiviral effects of combining CH223191 and favipiravir on Tacaribe virus (TCRV) infections in the Vero cell culture model. We observed synergistic interaction with all four models (ZIP, Loewe, Bliss, and HSA). We next determined the sub-optimal dose of favipiravir and conducted an antiviral combination study in the AG129 mouse model infected with TCRV. The combination effectively protected mice from a lethal TCRV infection and showed cooperative effects, reducing weight loss and viral loads. Overall, these results show that the AHR is a promising pharmacological target for the development of novel antivirals. Furthermore, we discovered a cooperative interaction between the activities of favipiravir and CH223191. Full article

Kynurenic acid (KYNA), a small molecule derived from the tryptophan–kynurenine pathway, can readily diffuse across biological membranes and act as an endogenous ligand for receptors such as the aryl hydrocarbon receptor (Ahr). While KYNA dysregulation is implicated in neurodegenerative disorders, the role of the KYNA–Ahr-IL-6 axis in MSC proliferation and differentiation remains poorly defined. We investigated the impact of KYNA on murine bone marrow-derived MSCs (BM-MSCs) at various concentrations (10–200 μM) and time points (8–48 h). The BM-MSC phenotype was assessed via flow cytometry; proliferation, via cell counting; and the gene expression of Ahr, Cyp1a1, Cyp1b1, and Il-6, via quantitative real-time PCR. Multipotency was evaluated through adipogenic, osteogenic, and chondrogenic differentiation assays with histochemical confirmation. KYNA significantly upregulated Ahr mRNA expression. Among the tested concentrations, 100 μM KYNA induced the highest Ahr expression (~19.1 ± 1.5-fold greater than that of the untreated controls, p < 0.005). Notably, 10 and 50 μM KYNA caused moderate induction, whereas compared with 100 μM KYNA, 200 μM did not further increase expression. In addition, KYN treatment increased Cyp1a1, Cyp1b1, and Il-6 expression, with increases of ~64.6 ± 4.5-fold, ~43.6 ± 2.3-fold, and ~41.6 ± 1.2-fold, respectively. Compared with no treatment, 100 µM KYNA enhanced BM-MSC proliferation by 1.210 ± 0.02, 1.189 ± 0.03, and 1.242 ± 0.02-fold across passages P3, P4, and P5, respectively (p < 0.05), without altering Sca-1, CD90, or CD45 expression or impairing trilineage differentiation potential. KYNA may activate the AHR–IL-6 signaling axis to promote BM-MSC expansion. This controlled proliferative effect, without loss of phenotypic or functional integrity, highlights the pharmacological potential of KYNA as a small-molecule modulator for stem cell-based therapies. Full article

Metabolic-dysfunction-associated fatty liver disease (MAFLD) is a chronic liver disease characterized by abnormal lipid metabolism. The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor involved in regulating multiple physiological processes. Recent studies have demonstrated that AHR exerts a multifaceted regulatory role in liver diseases by integrating metabolic and immune signaling pathways; however, the specific role of AHR in MAFLD is not clear. In our work, a rat model of MAFLD was established by feeding wild-type (WT) and AHR knockout (AHR^−/−) rats with a high-fat, high-fructose, and high-cholesterol diet (HFHFrHCD) for 10 weeks, and then the liver injury markers, lipid-related biochemical indices and liver histopathology were examined to elucidate the effect of AHR on MAFLD progression. We discovered that AHR deficiency can elevate plasma transaminase levels, increase hepatic triglyceride (TG) and total cholesterol (TC), and exacerbate insulin resistance (IR) under an overnutrition environment. Subsequently, liver transcriptome and RT-qPCR were performed to investigate the underlying mechanism, which revealed that the hepatic bile acid synthesis was inhibited because of lower Cytochrome P450 Family 7 Subfamily A Member 1 (CYP7A1) expression in the liver when AHR was knockout. Additionally, intestinal flora dysbiosis occurred in AHR^−/− rats fed with HFHFrHCD, which might also contribute to the hepatic cholesterol accumulation. Taken together, our results suggested that AHR might play an important role in regulating cholesterol metabolism by inhibiting bile acid synthesis and breaking the steady state of the gut microbiota during the MAFLD progression. Full article

Environmental allergens trigger epithelial reactive oxygen species (ROS) production and cellular senescence, contributing to airway inflammation. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor responsive to environmental stimuli, may modulate this process. Single-cell transcriptomics from allergen-challenged bronchoalveolar brushings of allergic asthma and non-asthmatic allergic control subjects were analyzed for ROS, senescence, and AhR activity. Club cell-specific p16 knockout (p16^ΔScgb1a1) and AhR-deficient (AhR^ΔScgb1a1) mice were used to assess epithelial senescence and AhR function. Single-cell analysis revealed epithelial senescence as a hallmark of allergen-induced asthma. p16^ΔScgb1a1 mice exhibited reduced ROS levels and airway inflammation. Single-cell analysis also demonstrated increased AhR activity and ROS generation in airway epithelial cells of allergen-treated asthmatics, and ROS correlated positively with AhR activity and senescence. It was documented that the regulation of AhR on senescence was attenuated by VAF347, whereas AhR deficiency exacerbated ROS generation and inflammation in AhR^ΔScgb1a1 mice. RNA-seq identified senescence as a key AhR-regulated pathway, implicating c-Myc, TGF-β2, and SERPINE1 as major targets. AhR binding to the c-Myc promoter was confirmed by ChIP-PCR, and pharmacologic inhibition of c-Myc with EN4 reduced allergen-induced ROS, senescence, and inflammation. These findings demonstrate that epithelial AhR suppresses allergen-induced ROS generation and cellular senescence via direct regulation of c-Myc. Full article

Osteoporosis is a systemic skeletal disease that severely impairs the health of the elderly population. The interaction between the receptor activator of the NF-κB ligand (RANKL) and its receptor RANK is critical for osteoclast differentiation and function. Therefore, targeting the RANKL/RANK interaction represents a promising strategy for osteoporosis. In this study, we employed a newly established yeast two-hybrid system based on RANKL/RANK interaction and identified IMB-R38, a novel benzamide compound that dose-dependently blocked RANKL/RANK interaction by inhibiting the growth of AH109 cells harboring pAD-RANKL/pBD-RANK plasmids in quadruple-dropout medium. IMB-R38 significantly suppressed osteoclast differentiation, disrupted F-actin ring formation, and downregulated the expression of osteoclast-specific genes, including NFATc1 and MMP9 in RANKL-induced RAW264.7 macrophages. IMB-R38 also promoted osteoblast differentiation by upregulating the expression of osteogenic genes. Importantly, in a dexamethasone (DXM)-induced osteoporotic zebrafish model, IMB-R38 significantly increased bone mineralization, with anti-osteoporosis efficacy superior to that of alendronate sodium (Alen). RT-qPCR assays showed that IMB-R38 significantly upregulated the mRNA expression of osteogenesis genes (Bmp2, Runx2a, Runx2b, Sp7, Alp, and Oc) while markedly downregulating that of the osteoclastogenesis genes (Mmp9, Mmp13, and Mmp2) compared with the DXM group. Mechanistically, an SPR assay confirmed that IMB-R38 directly binds with RANK but not RANKL to disrupt RANKL/RANK interaction. Furthermore, Asp168 of RANK was identified as a key amino acid that mediates both RANKL interaction and IMB-R38 binding. The inhibition of RANKL/RANK by IMB-R38 suppressed JNK phosphorylation and, consequently, osteoclast differentiation and function. Collectively, our findings identify IMB-R38 as a novel RANKL/RANK inhibitor with therapeutic potential for osteoporosis through its regulation of bone metabolism. Full article

The emergence of multidrug-resistant Staphylococcus aureus underscores the urgent need for novel therapeutic agents targeting essential bacterial pathways. The lipoteichoic acid synthase (LtaS) is crucial for the synthesis of lipoteichoic acid in the cell wall of Gram-positive bacteria and represents a promising and vulnerable target for antimicrobial drug development. This study employed a comprehensive computational pipeline to identify potent inhibitors of the LtaS enzyme. A library of natural compounds was retrieved from the COCONUT database and screened against the crystal structure of the extracellular domain of LtaS (eLtaS) (PDB ID: 2W5R, obtained from the Protein Data Bank) through a multi-stage molecular docking strategy. This process started with High-Throughput Virtual Screening (HTVS), followed by Standard Precision (SP) docking, and culminated in Extra Precision (XP) docking to refine the selection of hits. The top-ranking compounds from XP docking were subsequently subjected to MM-GBSA binding free energy calculations for further filtration. The stability and dynamic behavior of the resulting candidate complexes were then evaluated using 100 ns molecular dynamics (MD) simulations, which confirmed the structural integrity and binding stability of the ligands. Density Functional Theory calculations revealed that screened ligands exhibit improved electronic stabilization and charge-transfer characteristics compared to a reference compound, suggesting enhanced reactivity and stability relevant for hit identification. Finally, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) profiling was conducted to assess the drug-likeness and pharmacokinetic safety of the lead compounds. These findings support them as promising orally active leads for further optimization. Our integrated approach shortlisted eight initial hits (A–H) that showed interesting scaffold diversity and finally identified two compounds, herein referred to as Compound A and Compound B, which demonstrated stable binding, favorable free energy, and an acceptable Absorption, Distribution, Metabolism, and Excretion, and Toxicity (ADMET) profile. These candidates emerge as promising starting points for developing novel anti-staphylococcal agents targeting the LtaS enzyme that cand be further proved by experimental validation. Full article

Pharmacological compounds can disrupt glucose homeostasis, leading to impaired glucose tolerance, hyperglycemia, or newly diagnosed diabetes, as well as worsening glycemic control in patients with pre-existing diabetes. Traditional risk factors alone cannot explain the rapidly growing global incidence of diabetes. Therefore, prevention of insulin resistance could represent an effective strategy. Achieving this goal requires a deeper understanding of the mechanisms underlying the development of insulin resistance, with particular attention to the aryl hydrocarbon receptor (AhR). AhR, a transcription factor functioning as a xenobiotic sensor, plays a key role in various molecular pathways regulating normal homeostasis, organogenesis, and immune function. Activated by a range of exogenous and endogenous ligands, AhR is involved in the regulation of glucose and lipid metabolism as well as insulin sensitivity. However, current findings remain contradictory regarding whether AhR activation exerts beneficial or detrimental effects. This narrative review summarizes recent studies exploring the role of the AhR pathway in insulin secretion and glucose homeostasis across different tissues, and discusses molecular mechanisms involved in this process. Considering that several drugs act as AhR ligands, the review also compares how these ligands affect metabolic pathways of glucose and lipid metabolism and insulin sensitivity, producing either positive or negative effects. Full article

Anti-TNF-α therapy is widely used for inflammatory bowel disease (IBD), but response rates vary, and long-term efficacy declines in many patients. Given the limitations of existing treatments, novel therapeutic strategies are needed. This study investigates whether Lactobacillus murinus (L. murinus) attenuates tumor necrosis factor alpha (TNF-α)-induced pro-inflammatory responses in a human intestinal epithelial cell model of colitis by modulating the aryl hydrocarbon receptor (AHR). An in vitro model was established using Caco-2 cell monolayers treated with TNF-α to simulate intestinal inflammation. Cells were pre-treated with L. murinus or known AHR ligands, and the effects on AHR activation, barrier integrity, and inflammatory response were assessed via transepithelial electrical resistance (TEER) and IL-8 quantifications. As CYP1A1 is a well-established transcriptional target of AHR, its mRNA expression was used as a surrogate marker of AHR modulation in this model. TNF-α stimulation significantly disrupted epithelial barrier integrity and increased IL-8 secretion in a dose-dependent manner. L. murinus pre-treatment enhanced CYP1A1 expression and was associated with reduced TNF-α-induced barrier disruption and IL-8 secretion. Notably, the beneficial effects of L. murinus on epithelial integrity were not replicated by synthetic AHR ligands, suggesting ligand-selective differences in AHR related responses. These findings suggest that AHR-associated signaling induced by L. murinus may contribute to mitigation of TNF-α-induced epithelial barrier dysfunction and inflammation. This study identifies a potential probiotic-associated mechanism that warrants further investigation, including studies designed to establish a causal role of AHR dependency in the observed effects. In addition, future studies are needed to identify the specific L. murinus metabolites responsible for inducing CYP1A1 expression and activating the AHR pathway. Full article