Aryl Hydrocarbon Receptor Research Articles

Probiotic-derived extracellular vesicles alleviate AFB1-induced intestinal injury by modulating the gut microbiota and AHR activation

BackgroundAflatoxin B1 (AFB1) is a mycotoxin that widely found in the environment and mouldy foods. AFB1 initially targets the intestine, and AFB1-induced intestinal injury cannot be ignored. Lactobacillus amylovorus (LA), a predominant species of Lactobacillus, plays a role in carbohydrate metabolism. Extracellular vesicles (EVs), small lipid membrane vesicles, are widely involved in diverse cellular processes. However, the mechanism by which Lactobacillus amylovorus-QC1H-derived EVs (LA.EVs) protect against AFB1-induced intestinal injury remains unclear.ResultsIn our study, a new strain named Lactobacillus amylovorus-QC1H (LA-QC1H) was isolated from pig faeces. Then, EVs derived from LA-QC1H were extracted via ultracentrifugation. Our results showed that LA.EVs significantly alleviated AFB1-induced intestinal injury by inhibiting the production of proinflammatory cytokines, decreasing intestinal permeability and increasing the expression of tight junction proteins. Moreover, 16 S rRNA analysis revealed that LA.EVs modulated AFB1-induced gut dysbiosis in mice. However, LA.EVs did not exert beneficial effects in antibiotic-treated mice. LA.EVs treatment increased intestinal levels of indole-3-acetic acid (IAA) and activated intestinal aryl hydrocarbon receptor (AHR)/interleukin-22 (IL-22) signalling in AFB1-exposed mice. Inhibition of intestinal AHR signalling markedly weakened the protective effect of LA.EVs in AFB1-exposed mice.ConclusionsLA.EVs alleviated AFB1-induced intestinal injury by modulating the gut microbiota, activating the intestinal AHR/IL-22 signalling, reducing the inflammatory response and promoting intestinal barrier repair in mice.

Cytokines and Madness: A Unifying Hypothesis of Schizophrenia Involving Interleukin-22.

Schizophrenia is a severe neuropsychiatric illness of uncertain etiopathogenesis in which antipsychotic drugs can attenuate the symptoms, but patients rarely return to the premorbid level of functioning. In fact, with each relapse, people living with schizophrenia progress toward disability and cognitive impairment. Moreover, our patients desire to live normal lives, to manage their daily affairs independently, date, get married, and raise and support a family. Those of us who work daily with schizophrenia patients know that these objectives are rarely met despite the novel and allegedly improved dopamine blockers. We hypothesize that poor outcomes in schizophrenia reflect the gray matter volume reduction, which continues despite antipsychotic treatment. We hypothesize further that increased gut barrier permeability, due to dysfunctional aryl hydrocarbon receptor (AhR), downregulates the gut barrier protectors, brain-derived neurotrophic factor (BDNF), and interleukin-22 (IL-22), facilitating microbial translocation into the systemic circulation, eventually reaching the brain. Recombinant human IL-22 could ameliorate the outcome of schizophrenia by limiting bacterial translocation and by initiating tissue repair. This short review examines the signal transducer and transcription-three (STAT3)/AhR axis and downregulation of IL-22 and BDNF with subsequent increase in gut barrier permeability. Based on the hypothesis presented here, we discuss alternative schizophrenia interventions, including AhR antagonists, mitochondrial transplant, membrane lipid replacement, and recombinant human IL-22.

Dioxin-Induced PAI-1 Expression: A Novel Pathway to Pancreatic β-Cell Failure in Type 2 Diabetes.

Exposure to environment-polluting chemicals (EPCs), which are ligands of the aryl hydrocarbon receptor (AhR), is associated with the development of type 2 diabetes (T2D). This study explores the mechanisms by which AhR ligands contribute to β-cell failure in T2D. Incubation of RINm5F rat pancreatic β-cells with low-dose 2,3,7,8-tetrachlorodibenzodioxin (TCDD), the most potent AhR ligand, inhibited glucose-stimulated insulin secretion (GSIS). A single injection of TCDD in wild type mice reduced the size of Langerhans islets, but not in AhR liver knock-out mice (AhR-LKO). RNA-seq database analysis identified Serpine1, encoding for plasminogen activator inhibitor type-1 (PAI-1) as a TCDD-mediated secretory protein that is synthesized in an AhR-dependent manner in the liver. Elevated PAI-1 levels were shown to induce Caspase-3/7-dependent apoptosis in RINm5F cells, suggesting a novel pathway through which EPCs exacerbate T2D. These findings support the hypothesis that chronic exposure to AhR ligands may directly inhibit GSIS in pancreatic β-cells and indirectly induce β-cell apoptosis through increased PAI-1. This study provides new insights into the EPC-PAI-1 axis as a missing link between pancreatic β-cell failure and the progression of T2D and offers a potential target for therapeutic intervention.

Aryl-hydrocarbon receptor in smooth muscle cells protect against dioxin induced adverse remodeling of atherosclerosis.

Environmental exposure to dioxin has been linked to increased myocardial infarction. Smooth muscle cells (SMC) in the coronary vasculature play a critical role in atherosclerotic plaque remodeling due to their phenotypic plasticity, however, the detailed mechanism linking dioxin exposure to adverse SMC modulation is not well understood. Single-cell RNA and ATAC sequencing and histological analyses were performed on the aorta from mouse models of atherosclerosis exposed to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) or control. Primary human coronary artery SMC (HCASMC) treated in culture with TCDD were used to perform RNA-Seq, ATAC-Seq, and functional phenotypic assays. ChIP-Seq was performed with antibodies against Aryl-hydrocarbon receptor (AHR) and TCF21, two of known SMC modulating transcription factors. Modulated SMC were the most transcriptionally responsive cell type to dioxin in the atherosclerotic aorta. Dioxin accelerated disease phenotype by promoting a modulated SMC phenotype early, resulting in increased lesion size, migration of SMC, and macrophage recruitment to the lesion. We found C3 expressing modulated SMCs to be likely contributing to the increased macrophage recruitment and inflammation. Analysis of the RNA-Seq data from HCASMC treated with TCDD showed differential enrichment of biological pathways related to cell migration, localization, and inflammation. Furthermore, ATAC-Seq data showed a significant activation for pathways regulating vascular development, cell migration, inflammation, and apoptosis. With TCDD treatment, there was also enrichment of AHR ChIP-Seq peaks, while the TCF21 enrichment decreased significantly. The SMC-specific Ahr knockout resulted in increased oxidative stress in SMC, increased lesion size and macrophage content, and loss of SMC lineage cells in the lesion cap when exposed to TCDD, consistent with a more vulnerable plaque phenotype. Dioxin adversely remodels atherosclerotic plaque by accelerating the SMC- phenotypic modulation, and increasing inflammation and oxidative stress resulting in increased macrophage recruitment and lesion size. Dioxin may adversely affect the SMC phenotype and disease state by affecting the TCF21 occupancy in the open chromatin regions. Furthermore, we observed that SMC-specific deletion of Ahr in mice resulted in worsening of dioxin mediated SMC modulation and atherosclerosis, suggesting that Ahr in SMC confers protection against dioxin by promoting a stable plaque phenotype and reducing dioxin induced oxidative stress. Exposure to dioxin, an environmental pollutant present in tobacco smoke and air pollution, accelerates smooth muscle cell modulation, and atherosclerosis.Dioxin exposure leads to inflammatory smooth muscle cell phenotype characterized by complement pathway activation and increased macrophage recruitment to plaqueAryl-hydrocarbon receptor in SMC protects against oxidative stress, and promotes a stable plaque phenotype.

The role of aryl hydrocarbon receptor in the occurrence and development of periodontitis.

Periodontitis is a condition characterized by dysbiosis of microbiota and compromised host immunological responses, resulting in the degradation of periodontal tissues. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, plays a crucial role in the pathogenesis of periodontitis. AHR serves as a pivotal mediator for the adverse impacts of exogenous pollutants on oral health. Research indicates elevated expression of AHR in individuals with periodontitis compared to those without the condition. However, subsequent to the identification of endogenous AHR ligands, researches have elucidated numerous significant advantageous roles associated with AHR activation in bone, immune, and epithelial cells. This review concentrates on the modulation of the AHR pathway and the intricate functions that AHR plays in periodontitis. It discusses the characteristics of AHR ligands, detailing the established physiological functions in maintaining alveolar bone equilibrium, regulating immunity, facilitating interactions between the oral microbiome and host, and providing protection to epithelial tissues, while also exploring its potential roles in systemic disorders related to periodontitis.

Unveiling the Immune effects of AHR in tumors: a decade of insights from bibliometric analysis (2010–2023)

BackgroundThe Aryl Hydrocarbon Receptor (AHR) is a transcription factor that regulates several biological processes. Its potential in anti-tumor immunotherapy is becoming clearer, yet no bibliometric studies on this topic exist. This study aims to understand the current research landscape and identify future directions through a bibliometric analysis of AHR’s anti-tumor immunological effects.Methods We conducted a comprehensive bibliometric analysis of AHR antitumor immunotherapy papers in the Web of Science Core Collection. Various aspects of the publications were analyzed, and research hotspots and future trends were identified using scientific bibliometric tools and statistical methods.ResultsWe collected 592 English papers published between 2010 and 2023, with an almost annual increase. Most publications were from the USA, followed by China, Germany, and Italy. The journal “Frontiers in Immunology” had the most papers, and the most cited paper was Christiane A. Opitz’s “An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor.” The research is centered around AHR gene expression, with a growing focus on intestinal disease and the development of Programmed cell death ligand 1 (PD-L1) drugs.ConclusionThis bibliometric study highlights the significance of AHR in immunomodulatory research, outlining the research trends and key contributors. It suggests AHR’s immune effects may mediate the process of colitis cancer transformation, providing valuable insights for future anti-tumor immunotherapy strategies based on AHR.

Unique and Common Agonists Activate the Insect Juvenile Hormone Receptor and the Human AHR

Transcription factors of the bHLH-PAS family play vital roles in animal development, physiology, and disease. Two members of the family require binding of low-molecular weight ligands for their activity: the vertebrate aryl hydrocarbon receptor (AHR) and the insect juvenile hormone receptor (JHR). In the fly Drosophila melanogaster, the paralogous proteins GCE and MET constitute the ligand-binding component of JHR complexes. Whilst GCE/MET and AHR are phylogenetically heterologous, their mode of action is similar. JHR is targeted by several synthetic agonists that serve as insecticides disrupting the insect endocrine system. AHR is an important regulator of human endocrine homeostasis, and it responds to environmental pollutants and endocrine disruptors. Whether AHR signaling is affected by compounds that can activate JHR has not been reported. To address this question, we screened a chemical library of 50,000 compounds to identify 93 novel JHR agonists in a reporter system based on Drosophila cells. Of these compounds, 26% modulated AHR signaling in an analogous reporter assay in a human cell line, indicating a significant overlap in the agonist repertoires of the two receptors. To explore the structural features of agonist-dependent activation of JHR and AHR, we compared the ligand-binding cavities and their interactions with selective and common ligands of AHR and GCE. Molecular dynamics modeling revealed ligand-specific as well as conserved side chains within the respective cavities. Significance of predicted interactions was supported through site-directed mutagenesis. The results have indicated that synthetic insect juvenile hormone agonists might interfere with AHR signaling in human cells.

Gut microbiota-derived tryptophan metabolites regulated by Wuji Wan to attenuate colitis through AhR signaling activation

Disruption of the intestinal mucosal barrier caused by gut dysbiosis and metabolic imbalance is the underlying pathology of inflammatory bowel disease (IBD). Traditional Chinese medicine Wuji Wan (WJW) is commonly used to treat digestive system disorders and showed therapeutic potential for IBD. In this interdisciplinary study, we aim to investigate the pharmacological effects of WJW against experimental colitis by combining functional metabolomics and gut-microbiota sequencing techniques. Treatment with WJW altered the profile of the intestinal microbiota and notably increased the abundance of Lactobacillus, thereby facilitating the conversion of tryptophan into indole-3-acetic acid (IAA) and indoleacrylic acid (IA). These indole derivatives activated the aryl hydrocarbon receptor (AhR) pathway, which reduced colonic inflammation and restored the expression of intestinal barrier proteins. Interestingly, the beneficial effects of WJW on gut barrier function improvement and tryptophan metabolism were disappeared in the absence of gut microbiota. Finally, pre-treatment with the AhR antagonist CH-223191 confirmed the essential role of IAA-mediated AhR activation in the therapeutic effects of WJW. Overall, WJW enhanced intestinal barrier function and reduced colonic inflammation in a murine colitis model by modulating Lactobacillus–IAA–AhR signaling pathway. This study provides novel insights into colitis pathogenesis and presents an effective therapeutic and preventive approach against IBD.

Kynurenine’s Effect on the Different Stages of Osteoblastic Differentiation

This study focuses on the dynamics of age-related changes in osteoblasts’ matrix production, with a specific focus on the involvement of the aryl hydrocarbon receptor (AhR). The AhR is activated by kynurenine, a metabolite of the amino acid tryptophan that tends to increase with age. Kynurenine has been known to impair osteoblasts’ bone formation ability, however, the point at which this occurs is unknown. The study utilizes a 21-day differentiation process of mesenchymal stem cells. “Window experiments” that vary the intervals of kynurenine treatment to explore its impact at different stages of osteoblast development were utilized. The experimental setup involves four distinct conditions: a control group with a vehicle, a group treated with kynurenine, a group with an AhR antagonist (BAY), and a group treated with both kynurenine and BAY. The AhR antagonist, specifically BAY2416964, serves to investigate whether any observed effects of kynurenine are mediated through AhR signaling. Results, analyzed through alizarin red staining, demonstrate a notable negative impact of kynurenine on matrix production, particularly in the middle stages of osteoblast differentiation. The study further employs crystal violet staining to confirm the presence of cells in the experimental wells, providing assurance of the reliability of the alizarin staining procedure. Importantly, this staining procedure also suggests that the effects of kynurenine on mineralized matrix production are largely independent of any potential impacts on cell viability.

Kynurenine’s Effect on the Different Stages of Osteoblastic Differentiation

This study focuses on the dynamics of age-related changes in osteoblasts’ matrix production, with a specific focus on the involvement of the aryl hydrocarbon receptor (AhR). The AhR is activated by kynurenine, a metabolite of the amino acid tryptophan that tends to increase with age. Kynurenine has been known to impair osteoblasts’ bone formation ability, however, the point at which this occurs is unknown. The study utilizes a 21-day differentiation process of mesenchymal stem cells. “Window experiments” that vary the intervals of kynurenine treatment to explore its impact at different stages of osteoblast development were utilized. The experimental setup involves four distinct conditions: a control group with a vehicle, a group treated with kynurenine, a group with an AhR antagonist (BAY), and a group treated with both kynurenine and BAY. The AhR antagonist, specifically BAY2416964, serves to investigate whether any observed effects of kynurenine are mediated through AhR signaling. Results, analyzed through alizarin red staining, demonstrate a notable negative impact of kynurenine on matrix production, particularly in the middle stages of osteoblast differentiation. The study further employs crystal violet staining to confirm the presence of cells in the experimental wells, provid-ing assurance of the reliability of the alizarin staining procedure. Importantly, this staining procedure also suggests that the effects of kynurenine on mineralized matrix production are largely independent of any potential impacts on cell viability.

Characterization of AhR-mediated potency in sediments from Kongsfjorden, Svalbard: Application of effect-directed analysis and nontarget screening

In this study, we aimed to identify the major aryl hydrocarbon receptor (AhR) agonists in surface sediments (S1–S10, n = 10) from Kongsfjorden, Arctic Svalbard, using effect-directed analysis. High AhR-mediated potencies were observed in the mid-polar fractions and RP-HPLC subfractions (F2.6–F2.8; log KOW 5–8) in the sediments of sites S2 and S3, which are located near abandoned coal mine areas, as assessed by the H4IIE-luc bioassay. The concentrations of traditional polycyclic aromatic hydrocarbon (t-PAHs), emerging PAHs, alkyl-PAHs, and styrene oligomers ranged from 6.1 to 2100 ng g−1 dry weight (dw), 0.5–1000 ng g−1 dw, 47 to 79,000 ng g−1 dw, and 4.2–130 ng g−1 dw, respectively, with elevated levels in S2 and S3. Principal component analysis coupled with multiple linear regression suggested that t-PAHs in sediments primarily originated from coal, petroleum combustion, and coal combustion. Twenty-four target AhR agonists accounted for 3.2%–100% (mean = 47%) of the total AhR-mediated potencies in S2 and S3. Nontarget screening via GC-QTOFMS in the highly potent fractions identified 48 AhR agonist candidates through four-step selection criteria. Among these, 27 compounds were identified as coal-derived substances. VirtualToxLab in silico modeling predicted that most of the 48 tentative AhR agonist candidates could bind to AhR. Overall, our findings indicate significant contamination of the Kongsfjorden sediments by coal-derived substances, highlighting the need for further studies to assess the ecological risks associated with these contaminants.

Cigarette smoke-induced attenuation of the prostaglandin transporter SLCO2A1 expression through aryl hydrocarbon receptor

Cigarette smoke-induced attenuation of the prostaglandin transporter SLCO2A1 expression through aryl hydrocarbon receptor

Novel Regulatory Mechanisms for Expression of Drug Metabolism-related Factors

Interindividual differences in the expression and activity of drug-metabolizing enzymes, including cytochrome P450, UDP-glucuronosyltransferase, and esterases, cause variability of therapeutic effectiveness and side effects during drug treatment. Conventional research has focused on transcriptional regulation by transcription factors and nuclear receptors such as aryl hydrocarbon receptor, pregnane X receptor (PXR), constitutive androstane receptor, and hepatocyte nuclear factor 4α, as the major mechanisms causing the differences in the expression of drug-metabolizing enzymes. Recently, we have revealed that adenosine-to-inosine RNA editing and methylation of adenosine at the N6 position on RNA, two major types of posttranscriptional modification, play a pivotal role in the regulation of drug metabolism. In addition, switch/sucrose non-fermentable complex, a chromatin remodeler, is required for PXR-mediated transcriptional regulation of drug-metabolizing enzymes. This review article introduces the significance of these epitranscriptomic and epigenetic regulations as factors in determining drug metabolism potency. Further research on this link is expected to lead to a deeper understanding of interindividual differences in the therapeutic effectiveness and side effects of medicines.

Interleukin-10 deficiency suppresses colorectal cancer metastasis by enriching gut Parabacteroides distasonis

IntroductionThe intricate interplay of interleukin-10 (IL-10) and gut microbiota influences tumor development and progression, yet the impacts on colorectal cancer (CRC) metastasis remain incompletely understood. MethodsThe impact of Il10 deficiency on CRC metastasis was first evaluated in CRC metastasis tumor samples and mouse model. Antibiotic sterilization and fecal microbiota transplantation (FMT) experiment were used to assess the role of gut microbiota in IL-10 mediated CRC metastasis, and full-length 16S rDNA sequencing analysis further identified the potential target bacteria influencing CRC metastasis. The inhibitory effect of Parabacteroides distasonis (P. distasonis) on CRC metastasis was evaluated by oral administration in mice. Key metabolites involved in P. distasonis inhibition of CRC metastasis was identified by widely-targeted metabolome analysis and validated both in vivo and in vitro. The underlying mechanisms of P-hydroxyphenyl acetic acid (4-HPAA) inhibiting CRC metastasis was investigated via RNA-sequencing and validated in cellular experiments. ResultsWe revealed that serum IL-10 levels were markedly elevated in metastatic CRC patients compared to non-metastatic cases. In parallel, Il10-deficiency (Il10−/−) in mice resulted in decreased CRC metastasis in a gut microbiota-dependent manner. Mechanistically, Il10−/− mice reshaped gut microbiota composition, notably enriching P. distasonis. The enriched P. distasonis produced 4-HPAA, which activated the aryl hydrocarbon receptor (AHR) and subsequently inhibited the expression of VEGFA, a typical oncogene, thereby sequentially suppressing CRC metastasis. Importantly, engineered bacteria capable of producing 4-HPAA effectively hindered CRC metastasis. Furthermore, AHR depletion significantly disrupted the 4-HPAA-induced reduction in CRC cell migration and the inhibition of metastasis in both in vitro and in vivo lung metastasis mouse models. ConclusionsThese findings demonstrate the significance of IL-10 deficiency in suppressing CRC metastasis through the 4-HPPA-AHR-VEGFA axis mediated by gut P. distasonis, suggesting that P. distasonis or 4-HPAA supplementation could offer a promising therapeutic strategy for CRC metastasis prevention.

Construction and validation of a mouse model for studying severe human adenovirus infections

Human adenoviruses (HAdVs) are highly contagious pathogens with various genotypes implicated in acute respiratory disease (ARD) and linked to mortality, especially in immunosuppressed patients, young children, and military recruits. Currently, no vaccines or specific drugs are approved for clinical use. The hosts of adenoviruses are strictly species-specific, which strongly limits the development of vaccines and drugs against HAdVs. In this study, immunocompetent BALB/c mice were challenged with different doses of human adenovirus type 5 (HAdV-5) via tail intravenous injection (i.v.). All mice challenged with a high dose of HAdV-5 (3.2×1010 TCID50/kg) died within 3 to 5 days, while those receiving a low dose of HAdV-5 (8×109 or 4×109 TCID50/kg) survived. Interestingly, among the mice receiving a medium dose of HAdV-5 (1.6×1010 TCID50/kg), 60% (n = 3/5) of male mice died, while all female mice survived. This suggests that male mice may be more susceptible to HAdV-5 infection than female mice, consistent with clinical findings in children. HAdV-5 DNA was mainly distributed in the liver, followed by the spleen and lungs. Pathological changes were observed in the lungs, liver, and spleen, with severity increasing in correlation with the virus challenge dosage. Transcriptome and qPCR analyses of the liver indicated that the down-regulated expression of the H2-Aa, H2-Ea-ps, CD74, and H2-Eb1 genes in male mice, as well as the AHR gene in female mice, may contribute to the observed higher mortality rates in male mice. Therefore, this effective, feasible, and cost-efficient mouse model could serve as a candidate for evaluating HAdV vaccines and anti-adenovirus therapeutics.

Tapinarof cream for the treatment of atopic dermatitis: Efficacy and safety results from two Japanese phase 3 trials.

Tapinarof is a nonsteroidal, topical, aryl hydrocarbon receptor agonist. We evaluated the efficacy and safety of tapinarof cream 1% in Japanese patients aged ≥12 years with atopic dermatitis (AD) in two phase 3 trials, ZBB4-1 and ZBB4-2. ZBB4-1 (N = 216) consisted of an 8-week, double-blind, vehicle-controlled treatment period (period 1) and a 16-week extension treatment period (period 2). Patients were randomized 2:1 to tapinarof or vehicle in period 1; subsequently, all patients who enrolled in period 2 received tapinarof. ZBB4-2 (N = 291) was a 52-week, open-label, uncontrolled trial in which all patients received tapinarof. In period 1 of ZBB4-1, the proportion of patients who achieved an Investigator's Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) with ≥2-grade improvement from baseline at week 8 (IGA treatment success, the primary end point) was 20.24% in the tapinarof group and 2.24% in the vehicle group (p = 0.0007). The proportion of patients with ≥75% improvement from baseline in Eczema Area and Severity Index (EASI) score at week 8 (EASI-75 response, the key secondary end point) was 40.3% in the tapinarof group and 4.3% in the vehicle group (p < 0.0001). In ZBB4-2, IGA treatment success rate was 28.1% at week 16, 32.3% at week 24, and 41.3% at week 52, and EASI-75 response rate was 53.3% at week 16, 63.7% at week 24, and 76.6% at week 52, indicating that efficacy responses improved over time and were maintained over 52 weeks. Across the two trials, most adverse events (AEs) were mild or moderate; common AEs included folliculitis, acne, and headache. In summary, tapinarof cream 1% was effective and generally safe for up to 52 weeks of treatment in Japanese patients with AD.

The mode of toxic action of ionic liquids: Narrowing down possibilities using high-throughput, in vitro cell-based bioassays

Growing concerns about the environmental impact of ionic liquids (ILs) have spurred research into their (eco)toxic effects, but studies on their mode of toxic action (MOA) still remain limited. However, understanding the MOA and identifying structural features responsible for enhanced toxicity is crucial for characterising the hazard and designing safer alternatives. Therefore, 45 ILs, with systematically varied chemical structures, were tested for cytotoxicity and two specific endpoints in reporter gene assays targeting the Nrf2-ARE mediated oxidative stress response (AREc32) and aryl hydrocarbon receptor activation (AhR-CALUX). While none of the ILs activated the reporter genes, cytotoxicity was high and markedly different between cell lines. Seven and 25 ILs proved more cytotoxic than predicted by baseline toxicity model in the AREc32 and the AhR-CALUX assays, respectively. The length of the side chain and headgroup structures of ILs altered the MOA of ILs. Cellular metabolism of the ILs, investigated by LC-MS/MS, showed side-chain oxidation of the long-chain quaternary ammonium compounds in AhR-CALUX cells and, to a lower extent, in AREc32 cells, however, this transformation could not explain the high cytotoxicity. Effect data for 72 ILs for ten endpoints retrieved from the Tox21 database identified the inhibition of aromatase activity and of mitochondrial membrane potential as potential MOAs. However, in vitro fluorimetric assays for these endpoints demonstrated that effects were activated in a non-specific manner, probably through cytotoxicity. Although many of the ILs tested induced cytotoxicity at concentrations lower than baseline toxicity, the specific MOAs responsible could not be identified. Alternatively, we suggest that the descriptors currently used may fail to define the affinity of ILs for cells. Testing of the affinity of ILs for a diverse range of biomolecules is needed to accurately describe their interactions with cells.

Telmisartan potentiates the ITE-induced aryl hydrocarbon receptor activity in human liver cell line.

Telmisartan is an angiotensin receptor blocker (ARB) approved by the Food and Drug Administration of the US for the treatment of hypertension. It possesses unique pharmacologic properties, including the longest half-life among all ARBs; this leads to a 24-h sustained reduction of blood pressure. Besides well-known antihypertensive and cardioprotective effects, there is also strong clinical evidence that telmisartan confers renoprotection. Aryl hydrocarbon receptor (AhR) belongs to the steroid receptor family. 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is an endogenous ligand of AhR. Cytochrome P450 (CYP) 1A1 is an AhR-target gene. In this article, we demonstrated that telmisartan (2.5-60μM) enhanced CYP1A1 promoter activity and expressions of mRNA and protein. Telmisartan-induced CYP1A1 expression was blocked by the AhR antagonist CH-223191 in liver cell lines and was negligible in the AhR signaling-deficient mutant cells. In addition, telmisartan induced transcriptional activity mediated by aryl hydrocarbon response element in both human and mouse cells, and was able to induce AhR translocation into the nucleus. Accordingly, telmisartan is an AhR agonist. It also acted synergistically with ITE to further enhance the expression of CYP1A1 mRNA and protein. This synergistic effect was more pronounced in cells with AhR overexpression compared to those without. AhR activity has strong association with the progression of chronic renal disease. Our study demonstrated that telmisartan is an AhR agonist and has synergistic effect with ITE, an indole derivative, to potentiate the effect on AhR. This finding may provide additional clues about the mechanism of the protective effect of telmisartan on the kidney.

Poria cocos: traditional uses, triterpenoid components and their renoprotective pharmacology.

Poria cocos and its surface layer of Poria cocos (Schw.) Wolf (Polyporaceae), are used in traditional Chinese medicine for its diuretic and renoprotective effects. Phytochemical studies have shown that lanostane and 3,4-seco-lanostane tetracyclic triterpenoids are the main components of P. cocos and its surface layer. Accumulating evidence shows that triterpenoid components in P. cocos and its surface layer contribute to their renoprotective effect. The surface layer of P. cocos showed a stronger diuretic effect than P. cocos. The ethanol extract of the surface layer and its components improved acute kidney injury, acute kidney injury-to-chronic kidney disease transition and chronic kidney disease such as diabetic kidney disease, nephrotic syndrome and tubulointerstitial nephropathy, and protected against renal fibrosis. It has been elucidated that P. cocos and its surface layer exert a diuretic effect and improve kidney diseases through a variety of molecular mechanisms such as aberrant pathways TGF-β1/Smad, Wnt/β-catenin, IκB/NF-κB and Keap1/Nrf2 signaling as well as the activation of renin-angiotensin system, matrix metalloproteinases, aryl hydrocarbon receptor and endogenous metabolites. These studies further confirm the renoprotective effect of P. cocos and its surface layer and provide a beneficial basis to its clinical use in traditional medicine.

Effect of tunnel wash water treatment processes on trace elements, organic micropollutants, and biological effects

Tunnel wash water (TWW) contains high levels of trace elements and organic micropollutants, especially in the dissolved fraction. Discharge poses significant environmental risks. This field study aimed at improving conventional sedimentation treatment by addition of novel secondary treatments: bag filtration, ceramic microfiltration, or granular activated carbon (GAC) filtration. Removal of nine trace elements, 16 polycyclic aromatic hydrocarbons (PAHs), 38 per- and polyfluoroalkyl substances (PFASs), seven benzothiazoles (BTHs), seven benzotriazoles (BTRs), five bisphenols (BPs), and five benzophenones was investigated. Primary sedimentation significantly reduced particles and associated contaminants, achieving over 73 % average removal for trace elements, 65 % for PAHs, and 71 % for PFASs. Subsequent GAC removed over 70 % of dissolved Cr, Cu, Pb, and Zn and over 92 % of dissolved PFASs, BTHs, BTRs, and BPs, including several persistent, mobile and toxic compounds. Following GAC filtration, Cr, Ni, Pb, anthracene, fluoranthene, perfluorooctanesulfonic acid, and bisphenol-A were below environmental quality standards (EQS). GAC consistently reduced responses in in vitro bioassays with endpoints activation of the aryl hydrocarbon receptor, oxidative stress response, and neurotoxicity below effect-based trigger values for surface water. GAC filtration is thus recommended for future TWW treatment. Assessing water quality remains a challenging task due to lack of EQSs for many chemicals.